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Mesenchymal stromal cells therapy in radiation oncology regenerative medicine

Osama Muhammad Maria

Experimental Medicine Department, Faculty of Medicine, McGill University, Montreal, Quebec, Canada

Radiation Oncology Department, Jewish General Hospital, McGill University, Montreal, Quebec, Canada

Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, Quebec, Canada

Nicoletta Eliopoulos

Surgery Department, Faculty of Medicine, McGill University, Montreal, Quebec, Canada

Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, Quebec, Canada

Thierry Muanza

Experimental Medicine Department, Faculty of Medicine, McGill University, Montreal, Quebec, Canada

Radiation Oncology Department, Jewish General Hospital, McGill University, Montreal, Quebec, Canada

Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, Quebec, Canada

Oncology Department, McGill University, Montreal, Quebec, Canada

E-mail : tmuanza@yaoo.com

DOI: 10.15761/JSCRM.1000108

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Abstract

Mesenchymal stromal cells (MSCs) are multipotent somatic cells resident in many tissues and organs. They have specific characteristics that distinguish them from other cell types. They are self-renewing cells with multi-lineage differentiation potential. In addition, they possess anti-inflammatory and immunomodulatory properties. Studies have shown that they could be used as vehicles to deliver certain therapeutic gene products as well. These cells possess secretory capabilities of certain cytokines and growth factors that mediate various paracrine effects. They increase the secretion of the anti-inflammatory interleukin-10 (IL-10) together with lowering the availabilities of tumor necrosis factor-alpha (TNF-α), interferon-gamma (INF-γ), and interleukin -1-beta (IL-1β) by signaling to the immune system elements, e.g. dendritic cells, T-cells, B-cells, and natural Killer cells (NK cells). Recently, studies have investigated such anti-inflammatory properties of MSCs in the repair of radiation-induced normal tissue injury, also called radiation oncology regenerative medicine (RORM), supported by the recently known MSCs radiation resistance potential. In this review, we summarize MSCs radio-resistant mechanisms, anti-inflammatory properties, and their application in RORM with special attention to adipose tissue-derived MSCs (aMSCs).

Key words

: adipose tissue, anti-inflammatory, cell cycle, DNA repair, mesenchymal stromal cells, msc, normal tissue injury, radiation oncology regenerative medicine, radiation resistance

Abbreviations

 aMSCs: Adipose tissue-derived mesenchymal stromal cells, ATM: Ataxia telangiectasia mutated protein, b-FGF: Basic fibroblast growth factor, Chk: Check point cell cycle kinase, DSB: Double stranded DNA breaks, HGF: Hepatocyte growth factor, HR: Homologous recombination,HSCs: Hematopoietic stem cells, IL-10: Interleukine-10, IL-1β: Interleukine-1-beta, IDO: Indoleamine 2,3-dioxygenase, INF-γ: Interferon-gamma, MSCs: Mesenchymal stromal cells, NHEJ: Non-homologous end-joining, NK: Natural killer cells, NO: Nitric oxide, PGE2: Prostaglandin-E2, RORM: Radiation oncology regenerative medicine, TGF-β: Tumor growth factor-beta, TNF-α: Tumor necrosis factor-alpha

Introduction

Mesenchymal stromal/Stem cells (MSCs) are multipotent somatic progenitor cells that have been isolated from different tissues, such as bone marrow, adipose tissue, muscles and skin [1-3]. They can be expanded ex-vivo to hundreds of million cells, maintaining their phenotype and characteristics, and used as therapies in different diseases [1-3]. Another property of these cells is their homing to the site of tissue injury, an ability that widens the choices for their route of administration [2,4,5]. In addition to their multi-lineage differentiation potential [6], these cells possess anti-inflammatory and immunomodulatory properties and paracrine effects that qualified them for regenerative medicine applications (Figure 1) [7-11]. Furthermore, MSCs could be genetically engineered and used as vehicles for delivering therapeutic gene products [12-14]. Studies in radiotherapy have shown that MSCs can be recruited to the radiation injury site where they secrete many cytokines and growth factors, e.g. prostaglandin-E2 (PGE2), nitric oxide (NO), hepatocyte growth factor (HGF), interleukin-10 (IL-10), tumor growth factor-beta (TGF-β), and indoleamine 2,3-dioxygenase (IDO) [15]. These soluble mediators inhibit the major components of the immune system and inflammation, e.g. dendritic cells, T-cells, B-cells, and natural killer cells (NK cells) [15]. The final result will be an increase in the secretion of the anti-inflammatory interleukin-10 (IL-10) together with lowering the availability of pro-inflammatory mediators and cytokines, e.g. tumor necrosis factor-alpha (TNF-α), interferon-gamma (INF-γ), and interleukin -1-beta (IL-1β) [15] (Figure 1).

Figure 1. MSCs anti-inflammatory properties

MSCs recruited to the radiation injury site secrete many cytokines and growth factors, e.g. prostaglandin-E2 (PGE2), nitric oxide (NO), hepatocyte growth factor (HGF), interleukin-10 (IL-10), tumor growth factor-beta (TGF-β), and indoleamine 2,3-dioxygenase (IDO). These soluble mediators inhibit the major components of the immune system and inflammation, e.g. dendritic cells, T-cells, B-cells, and natural killer cells (NK cells). The final result will be an increase in the secretion of the anti-inflammatory interleukin-10 (IL-10) together with lowering the availability of the pro-inflammatory mediators and cytokines, e.g. tumor necrosis factor-alpha (TNF-α), interferon-gamma (INF-γ), and interleukin -1-beta (IL-1β) [15].

Mesenchymal stromal cells (MSCs) clinical trials in various disorders

 MSCs have been applied for various repairs, such as of arthritis [16], cardiac muscle [17,18], lung tissue [14], diabetes [19], skin [20-23], skeletal tissue [24], and digestive tract tissue [12,25,26]. Table 1 shows 92 recent clinical trials for MSCs therapies in various disorders.

Table 1. Mesenchymal Stromal cells (MSCs) clinical trials in various disorders as listed on www.ClinicalTrials.gov by the National Institute of Health (NIH) by Nov. 2015

NCT #

Title

Conditions

Interventions

Last Verified

NCT01589549

Mesenchymal Stromal Cells for Acute Graft Versus Host Disease

Acute GVH Disease

Biological: Mesenchymal stromal cell therapy

Jun-15

NCT02057965

Mesenchymal Stromal Cell Therapy in Renal Recipients

Renal Transplant Rejection|Fibrosis

Drug: Mesenchymal Stromal Cells

Mar-15

NCT02032446

Umbilical Cord Derived Mesenchymal Stromal Cells For The Treatment of Severe Steroid-resistant Graft Versus Host Disease

Hematologic Malignancies

Biological: UMBILICAL CORD DERIVED MESENCHYMAL STROMAL CELLS (UC-MSC)

Apr-15

NCT02012153

Mesenchymal Stromal Cells in Kidney Transplant Recipients

Kidney Transplant Rejection

Biological: Mesenchymal Stromal Cells

Oct-15

NCT01090817

An Australian Study of Mesenchymal Stromal Cells for Crohn's Disease

Crohn Disease

Drug: Mesenchymal stromal cells (MSC) for infusion

Jun-15

NCT00644410

Autologous Mesenchymal Stromal Cell Therapy in Heart Failure

Congestive Heart Failure

Biological: Mesenchymal stromal cell| Biological: Saline

Mar-15

NCT01061099

Repeated Infusions of Mesenchymal Stromal Cells in Children With Osteogenesis Imperfecta

Osteogenesis Imperfecta Type II| Osteogenesis Imperfecta Type III

Biological: Mesenchymal Stromal Cells

Apr-15

NCT02150551

Safety and Tolerability Of Allogeneic Mesenchymal Stromal Cells in Pediatric Inflammatory Bowel Disease

Inflammatory Bowel Diseases

Biological: Allogeneic bone marrow-derived mesenchymal stromal cells

Sep-15

NCT01522716

Mesenchymal Stromal Cells as Treatment of Chronic Graft-versus-host Disease

Graft-Versus-Host Disease

Biological: Mesenchymal stromal cells

Nov-15

NCT02323789

A Phase I/II Study Evaluating Allogeneic Mesenchymal Stromal Cells in Adults With Recessive Dystrophic Epidermolysis Bullosa

Recessive Dystrophic Epidermolysis Bullosa

Drug: Mesenchymal stromal cells

Dec-14

NCT02291770

Treatment of Chronic Graft-Versus-Host Disease With Mesenchymal Stromal Cells

Chronic Graft-Versus-Host Disease

Biological: Mesenchymal Stromal Cells

Nov-14

NCT01764100

Mesenchymal Stromal Cells (MSCs) for the Treatment of Graft Versus Host Disease (GVHD)

Graft vs Host Disease

Genetic: Mesenchymal stromal cells

Jan-13

NCT02230514

Mesenchymal Stromal Cells for the Treatment of Non-union Fractures of Long Bones

Atrophic Nonunion of Fracture

Drug: XCEL-MT-OSTEO-ALPHA|Other: autologous iliac crest| Procedure: Surgery

Jul-15

NCT02215811

Treatment of Severe Acute Respiratory Distress Syndrome With Allogeneic Bone Marrow-derived Mesenchymal Stromal Cells

Acute Respiratory Distress Syndrome, Adult

Biological: Mesenchymal stromal cells

Aug-14

NCT01449032

Mesenchymal STROMAL CELL Therapy in Patients With Chronic Myocardial Ischemia (My Stromal Cell Trial)

Chronic Ischemic Heart Disease

Biological: MSC| Biological: Saline

Jun-14

NCT02580695

A Study to Assess Safety and Efficacy of Umbilical Cord-derived Mesenchymal Stromal Cells in Knee Osteoarthritis

Osteoarthritis

Biological: umbilical-cord mesenchymal stromal cells| Drug: Hyaluronic Acid

Oct-15

NCT01038596

Mesenchymal Stromal Cells and Osteoarthritis

Osteoarthritis

 

Dec-09

NCT02495766

Autologous Mesenchymal Stromal Cells for Multiple Sclerosis

Relapsing-Remitting Multiple Sclerosis| Secondary Progressive Multiple Sclerosis

Drug: XCEL-MC-ALPHA|Drug: Placebo

Nov-15

NCT02565459

MSC and Kidney Transplant Tolerance (Phase A)

Chronic Renal Failure

Biological: Mesenchymal Stromal Cells

Sep-15

NCT01849237

Russian Clinical Trial of Mesenchymal Cells in Patients With Septic Shock and Severe Neutropenia

Septic Shock| Nonchemotherapy Drug-induced Neutropenia| Neutropenia After Chemotherapy in Oncohematological Patients| Neutropenia in Patients With Aplastic Anemia

Genetic: Mesenchymal stromal cells|Drug: Standard therapy of septic shock

May-13

NCT02387151

Allogeneic Mesenchymal Stromal Cell Therapy in Renal Transplant Recipients

Rejection|Graft Loss

Procedure: mesenchymal stem cell infusion

Mar-15

NCT01175655

A Study to Evaluate the Potential of Mesenchymal Stromal Cells to Treat Obliterative Bronchiolitis After Lung Transplantation

Bronchiolitis Obliterans|Lung Transplantation

Other: MSC

Apr-15

NCT00957931

Allo-HCT MUD for Non-malignant Red Blood Cell (RBC) Disorders: Sickle Cell, Thal, and DBA: Reduced Intensity Conditioning, Co-tx MSCs

Sickle Cell Disease| Thalassemia| Diamond-Blackfan Anemia

Procedure: Bone marrow transplantation| Biological: Mesenchymal Stromal Cells

Dec-12

NCT01742260

Cranial Reconstruction Using Mesenchymal Stromal Cells and Resorbable Biomaterials

Surgically-Created Resection Cavity

Procedure: Repair of cranial defects by tissue engineering

Jun-15

NCT02260375

MSC Therapy in Liver Transplantation

Liver Transplant Rejection

Biological: Mesenchymal Stromal Cells

Sep-15

NCT01872624

Safety Study of Bone-marrow Derived Mesenchymal Stromal Cells Associated With Endobronchial Valves in Emphysema

Pulmonary Emphysema

Procedure: Bronchoscopy

Mar-15

NCT01586312

Treatment of Knee Osteoarthritis With Allogenic Mesenchymal Stem Cells

Osteoarthritis, Knee|Arthritis of Knee|Knee Osteoarthritis

Other: Allogenic mesenchymal stromal cells injection|Drug: Hyaluronic Acid

Sep-15

NCT01860417

Treatment of Degenerative Disc Disease With Allogenic Mesenchymal Stem Cells (MSV)

Degenerative Disc Disease| Intervertebral Disc Disease|Low Back Pain

Biological: Allogenic Mesenchymal Stromal Cells| Drug: Mepivacaine

Sep-15

NCT02384018

Mesenchymal Stem Cell and Islet           Co-transplantation

Chronic Pancreatitis| Diabetes

Biological: autologous mesenchymal stromal cell

Dec-14

NCT01306513

Safety and Feasibility Study of Administration of Mesenchymal Stem Cells for Treatment of Emphysema

Emphysema

Biological: autologous bone marrow derived mesenchymal stromal cells

Nov-12

NCT02359929

BMT Auto MSCs GvHD Ph1

Graft Versus Host Disease|Acute Graft Versus Host Disease|Chronic Graft Versus Host Disease

Biological: Autologous mesenchymal stromal cells (MSCs)

Aug-15

NCT02585622

Novel Stromal Cell Therapy for Diabetic Kidney Disease

Diabetic Kidney Disease

Biological: Mesenchymal Stromal Cells| Other: Placebo

Oct-15

NCT02033525

Mesenchymal Stromal Cells for Degenerative Meniscus Injury

Chronic Meniscal Injury

Drug: XCEL-M-ALPHA and standard rehabilitation| Other: Rehabilitation

Jul-15

NCT02589119

Stem Cell Fistula Plug in Cryptoglandular Perianal Fistulas (MSC-AFP)

Perianal Fistula| Cryptoglandular Perianal Fistula

Drug: MSC-AFP

Oct-15

NCT02421484

Cellular Immunotherapy for Septic Shock: A Phase I Trial

Septic Shock

Biological: Allogeneic bone marrow derived mesenchymal stromal cells

Apr-15

NCT02055625

Mesenchymal Stem Cells as a Treatment for Oral Complications of Graft-versus-host Disease

Graft -Versus-host-disease

Biological: Mesenchymal stromal cells

Mar-15

NCT02408432

Intravenous Administration of Allogeneic Bone Marrow Derived Multipotent Mesenchymal Stromal Cells (MSCs) in Patients With Recent Onset Anthracycline-Associated Cardiomyopathy

Cardiomyopathy

Biological: Human Mesenchymal Stem Cells (hMSCs)|Other: Standard of Care

Jun-15

NCT02181478

Intra-Osseous Co-Transplant of UCB and hMSC

Acute Lymphoblastic Leukemia| Acute Myelogenous Leukemia| Myelodysplastic Syndromes| Myelofibrosis| Relapsed Non-Hodgkin Lymphoma| Refractory Non-Hodgkin Lymphoma| Hodgkin Lymphoma| Refractory Hodgkin Lymphoma| Relapsed Chronic Lymphocytic Leukemia| Refractory Chronic Lymphocytic Leukemia| Lymphoid Malignancies| Chronic Myelogenous Leukemia

Drug: cyclophosphamide| Drug: fludarabine phosphate| Radiation: total-body irradiation|Drug: cyclosporine|Drug: mycophenolate mofetil|Procedure: umbilical cord blood transplantation| Procedure: mesenchymal stem cell transplantation

Jul-15

NCT02351011

Human Autologous MSCs for the Treatment of Mid to Late Stage Knee OA

Osteoarthritis of Knee

Biological: 1 x 10^6 MSCs|Biological: 10 x 10^6 MSCs|Biological: 50 x 10^6 MSCs

Feb-15

NCT02270307

MSC and Cyclophosphamide for Acute Graft-Versus-Host Disease (aGVHD) Prophylaxis

Leukemia| Multiple Myeloma

Drug: Cyclophosphamide| Biological: Mesenchymal stromal cells

Oct-14

NCT01922908

Mesenchymal Stromal Cells for Ischemic Stroke

Ischemic Stroke

Biological: MSC Infusion|Biological: Placebo Comparator

May-15

NCT02145923

Effectiveness and Safety of MMSCs for Enhancing Hematopoietic Recovery and Prophylaxis of Neutropenic Enterocolitis

Neutropenic Enterocolitis| Myeloablative Chemotherapy Induced Bone Marrow Aplasia

Procedure: Peripheral blood stem cell mobilisation and collection|Drug: High-dose chemotherapy| Drug: Bone marrow derived allogeneic MMSCs infusion|Procedure: Autologous peripheral blood stem cells infusion

Jun-15

NCT01275612

Mesenchymal Stem Cells In Cisplatin-Induced Acute Renal Failure In Patients With Solid Organ Cancers

Solid Tumors| Acute Kidney Injury

Biological: Mesenchymal stromal cell infusion

Oct-15

NCT01909154

Safety Study of Local Administration of Autologous Bone Marrow Stromal Cells in Chronic Paraplegia

Spinal Cord Injury

Biological: Mesenchymal stromal cell therapy

Nov-13

NCT00395200

Mesenchymal Stem Cells in Multiple Sclerosis (MSCIMS)

Multiple Sclerosis

Procedure: MSC Treatment

Oct-11

NCT00260338

Stem Cell Therapy for Vasculogenesis in Patients With Severe Myocardial Ischemia

Myocardial Ischemia| Coronary Heart Disease

Biological: stem cell

May-13

NCT01659762

A Phase I Study Evaluating Autologous Bone Marrow Derived Mesenchymal Stromal for Crohn's Disease.

Crohn's Disease

Biological: autologous mesenchymal stromal cell

Jul-15

NCT02382874

Allogenic AD-MSC Transplantation in Idiopathic Nephrotic Syndrome (Focal Segmental Glomerulosclerosis)

Focal Segmental Glomerulosclerosis

Biological: Intravenous injection

Mar-15

NCT02448849

Autologous BM-MSC Transplantation in Combination With Platelet Lysate (PL) for Nonunion Treatment

Bone Fracture

Biological: Percutaneous injection| Other: Percutaneous injection

Sep-15

NCT01915927

Stem Cell Fistula Plug in Perianal Crohn's Disease

Perianal Crohn's Disease

Drug: MSC-AFP

Jun-15

NCT01686139

Safety Study of Stem Cells Treatment in Diabetic Foot Ulcers

Type I Diabetes Mellitus With Ulcer| Type II Diabetes Mellitus With Ulcer

Biological: ABMD-MSC

Jan-14

NCT02017912

Phase 2, Randomized, Double Blind, Placebo Controlled Multicenter Study of Autologous MSC-NTF Cells in Patients With ALS

Amyotrophic Lateral Sclerosis (ALS)

Biological: Autologous MSC-NTF cells

Jul-15

NCT01463475

University of Wisconsin hMSC Cell Bank: Bone Marrow Donor Protocol

Graft Versus Host Disease (GVHD)|Acute Myocardial Infarction (AMI)

Procedure: Bone marrow aspirate

Dec-14

NCT02195323

Autologous Bone Marrow Derived Mesenchymal Stromal Cells (BM-MSCs) in Patients With Chronic Kidney Disease (CKD)

Chronic Kidney Disease

Biological: Intravenous injection

Oct-13

NCT02409940

To Elucidate the Effect of Mesenchymal Stem Cells on the T Cell Repertoire of the Kidney Transplant Patients

Renal Transplant Rejection

Biological: Mesenchymal Stem Cells

Apr-15

NCT00908856

Autologous Cell Therapy After Stroke

Stroke

Biological: autologous bone marrow mononuclear cell transfusion| Biological: marrow stromal cells| Drug: placebo

Dec-14

NCT02247973

Mesenchymal Stem Cells Co-transplantation in Alternative Donor Transplantation of Severe Aplastic Anemia.

Severe Aplastic Anemia

Biological: mesenchymal stem cells| Biological: mesenchymal stem cells

Sep-14

NCT01446614

Mesenchymal Stem Cells Transplantation to Patients With Parkinson's Disease

Parkinson's Disease

Biological: bone marrow derived mesenchymal stem cells

Oct-11

NCT01446640

Mesenchymal Stem Cells Transplantation to Patients With Spinal Cord Injury

Spinal Cord Injury

Biological: bone marrow derived mesenchymal stem cells

Oct-11

NCT01305694

Mesenchymal Stem Cells Transplantation to Patients With Relapsed/Refractory Aplastic Anemia.

Aplastic Anemia

Biological: bone marrow derived mesenchymal stem cells

Feb-11

NCT01051882

Autologous Cultured Mesenchymal Bone Marrow Stromal Cells Secreting Neurotrophic Factors (MSC-NTF), in ALS Patients.

Amyotrophic Lateral Sclerosis

Biological: MSC-NTF cells transplantation (i.m.)| Biological: MSC-NTF cells transplantation (i.t.)

Aug-12

NCT01624701

Clinical Ex Vivo Expansion of Human Umbilical Cord Blood Stem and Progenitor Cells

Acute Leukemia| Chronic Leukemia| Myelodysplastic Syndrome| Lymphoma| Myeloma

Other: Ex-vivo expanded cord blood cells

Jun-12

NCT02336230

A Prospective Study of Remestemcel-L, Ex-vivo Cultured Adult Human Mesenchymal Stromal Cells, for the Treatment of Pediatric Patients Who Have Failed to Respond to Steroid Treatment for Acute GVHD

Grades B-D aGVHD

Drug: Remestemcel-L

Jan-15

NCT02525432

Autologous Stem Cell Study for Adult TBI (Phase 2b)

Brain Injuries, Traumatic| Brain Injuries, Acute| TBI (Traumatic Brain Injury)

Biological: Placebo Infusion| Biological: Autologous BMMNC Infusion| Device: Ultrasound

Oct-15

NCT02209311

Effectiveness and Safety of Method of Maxilla Alveolar Process Reconstruction Using Synthetic Tricalcium Phosphate and Autologous MMSCs

Partially Edentulous Maxilla| Alveolar Bone Atrophy| Alveolar Bone Loss

Procedure: Oral mucosa biopsy| Procedure: Sinus lift with implantation of tissue engineered construction| Device: Dental implant

Sep-15

NCT02379442

Early Treatment of Acute Graft Versus Host Disease With Bone Marrow-Derived Mesenchymal Stem Cells and Corticosteroids

Graft-Versus-Host Disease

Biological: MSC

Feb-15

NCT01144962

Dose-escalating Therapeutic Study of Allogeneic Bone Marrow Derived Mesenchymal Stem Cells for the Treatment of Fistulas in Patients With Refractory Perianal Crohn's Disease

Crohn's Disease| Fistula

Procedure: Localization, curettage of the fistulous tract and closure of the internal opening without MSC injection.| Procedure: Localization, curettage of the fistulous tract and closure of the internal opening with local MSC injection.

Dec-14

NCT02448121

Autologous Bone Marrow Stem Cell Transplantation for Hip Osteonecrosis in Sickle Cell Disease

Avascular Necrosis of Femur Head| Sickle Cell Disease

Procedure: Stem Cell Graft Group| Biological: Autologous bone marrow stem cell

Aug-15

NCT01892514

Randomized Clinical Trial for the Treatment of Osteonecrosis of the Femoral Head

Osteonecrosis

Procedure: core decompression

Apr-14

NCT02249676

Autologous Mesenchymal Stem Cells for the Treatment of Neuromyelitis Optica Spectrum Disorders

Devic's Syndrome| Devic's Neuromyelitis Optica| Devic Syndrome| Devic's Disease| Devic Disease

Biological: Autologous mesenchymal stem cells

Sep-14

NCT02482194

Autologous Mesenchymal Stem Cells Transplantation for Spinal Cord Injury- A Phase I Clinical Study

Spinal Cord Injury

Biological: mesenchymal stem cells

Jun-15

NCT00731744

Generation of Dendritic Cell Precursors From Cord Blood Stem Cells

Normal Full-Term Deliveries

Procedure: Normal full-term deliveries

Aug-08

NCT02037204

IMPACT: Safety and Feasibility of a Single-stage Procedure for Focal Cartilage Lesions of the Knee.

Foreign-Body Reaction| Inflammation| Effusion (L) Knee| Knee Pain Swelling

Other: Cartilage repair surgery

Jul-14

NCT01993368

Analysis of Osteoimmune Interactions Linking Inflammation and Bone Destruction in Aggressive Periodontitis

Aggressive Periodontitis| Chronic Periodontitis

Other: flow cytometry

Sep-15

NCT01777646

Autologous Cultured Mesenchymal Bone Marrow Stromal Cells Secreting Neurotrophic Factors (MSC-NTF), in Patients With Amyotrophic Lateral Sclerosis (ALS)

Amyotrophic Lateral Sclerosis

Biological: MSC_NTF cells transplantation by multiple intramuscular injections at 24 separate sites, in addition to a single intrathechal injection into the CSF

Jan-14

NCT01468064

Autologous Bone Marrow Stromal Cell and Endothelial Progenitor Cell Transplantation in Ischemic Stroke

Stroke| Infarction, Middle Cerebral Artery

Genetic: Autologous BMSCs transplantation| Genetic: Autologous EPCs transplantation| Genetic: IV infusion of placebo

Nov-15

NCT01071577

Collection of Bone Marrow From Healthy Volunteers and Patients for the Production of Clinical Bone Marrow Stromal Cell (BMSC) Products

Bone Marrow| Bone Marrow Stromal Cells| Mesenchymal Stem Cells| Blood Donors

 

Aug-15

NCT00186914

Stromal Therapy of Osteodysplasia After Allogeneic Bone Marrow Transplantation

Osteodysplasia

Biological: Marrow stromal cell infusion

Feb-08

NCT00781872

Mesenchymal Stem Cells for the Treatment of MS

Multiple Sclerosis

Biological: injection of autologous stem cells

Oct-08

NCT02467387

A Study to Assess the Effect of Intravenous Dose of (aMBMC) to Subjects With Non-ischemic Heart Failure

Non-Ischemic Heart Failure

Drug: Allogeneic Mesenchymal Bone Marrow Cells (aMBMC)| Drug: Lactated Ringer's Solution

Jun-15

NCT02442817

Linagliptin and Mesenchymal Stem Cells: A Pilot Study

Schizophrenia

Drug: Linagliptin

Apr-15

NCT02064062

Autologous Stem Cells in Achilles Tendinopathy

Achilles Tendinitis, Right Leg| Achilles Tendinitis| Achilles Degeneration| Achilles Tendon Thickening| Tendinopathy| Achilles Tendinitis, Left Leg

Biological: Autologous Mesenchymal Stem Cells

Feb-14

NCT01840540

MSC for Occlusive Disease of the Kidney

Atherosclerotic Renal Artery Stenosis| Ischemic Nephropathy| Renovascular Hypertension

Drug: Arterial infusion of autologous mesenchymal stem cells

Oct-15

NCT01795950

Safety Study of PLX-PAD Cells to Treat Pulmonary Arterial Hypertension (PAH)

Pulmonary Arterial Hypertension

Drug: PLX-PAD

Sep-15

NCT01377870

Evaluation of Autologous Mesenchymal Stem Cell Transplantation (Effects and Side Effects) in Multiple Sclerosis

Multiple Sclerosis

Biological: intravenous injection of mesenchymal stem cells| Biological: injection of cell free media

Aug-10

NCT01557543

Stem Cell Injection to Treat Heart Damage During Open Heart Surgery

Heart Disease| Ischemic Heart Disease| Coronary Artery Disease| Coronary Artery Disease (CAD)

Other: Cell Therapy

Nov-15

NCT00919958

Safety of Intramuscular Injection of Allogeneic PLX-PAD Cells for the Treatment of Critical Limb Ischemia

Peripheral Artery Disease| Peripheral Vascular Disease| Critical Limb Ischemia

Biological: PLX-PAD IM injection

Jun-12

NCT00951210

Safety of Intramuscular Injections (IM) of Allogeneic PLX-PAD Cells for the Treatment of Critical Limb Ischemia (CLI)

Peripheral Artery Disease| Peripheral Vascular Disease| Critical Limb Ischemia

Biological: PLX-PAD

Nov-11

NCT02323477

Human Umbilical Cord Stroma MSC in Myocardial Infarction

Chronic Ischemic Cardiomyopathy| Coronary Artery Bypass Surgery

Biological: stem cell transplantation

May-15

NCT01849159

Clinical Study of the Efficacy and Safety of the Application of Allogeneic Mesenchymal (Stromal) Cells of Bone Marrow, Cultured Under the Hypoxia in the Treatment of Patients With Severe Pulmonary Emphysema

Pulmonary Emphysema

Biological: Mesenchymal stem cells| Other: Reference therapy: 400 mL of 0.9% NaCl solution

Oct-15

NCT00821470

Treatment of Osteonecrosis of the Femoral Head by Bone Marrow Transplantation

Necrosis

Procedure: core decompression| Procedure: Bone marrow implantation into the necrotic lesion

Jan-09

NCT01172548

Safety and Efficacy Evaluation of Two Year Imatinib Treatment in Adjuvant Gastrointestinal Stromal Tumor (GIST)

Gastrointestinal Stromal Tumors

Drug: Imatinib mesylate

Mar-15

MSCs radio-biological response

The exposure of MSCs to ionizing radiation (IR) induces direct and indirect double stranded DNA breaks (DSB) which are detected by Poly (ADP-ribose) polymerase (PARP) and heterodimeric Ku protein complex (Ku70/80) sensor proteins [27,28]. At the DSB location, PARP started the signal amplification upon formation of the Mre11, RAD50, and NBS-1 protein complex which leads to recruitment and auto-phosphorylation of Ataxia Telangectasia mutated protein (ATM). Phosphorylated ATM (p-ATM) is a main station that leads to multiple downstream signals. P-ATM enhances the phosphorylation of histone H2X (to γ-H2AX) and DNA-PK (to p-DNA-PK), phosphorylates P53 (a tumor suppressor regulatory protein), activates the cell cycle checkpoint effector protein kinases (Chk-1 and Chk-2), and prepares for cell cycle arrest (G2/M). In addition, the Chk1 activation is augmented by the replication stress-mediated ATR pathway (through replication protein A, RPA), while the Chk2 activation is enhanced directly through Ku70/80-mediated p-DNA-PK signaling [27,28]. Cell division cycle phosphatase (Cdc25) is crucial for removing the inhibitory phosphorylation on specific residues on the cyclin-dependent kinase (Cdk). Chk1 phosphorylates Cdc25 in the presence of DNA damage resulting in the inhibition of Cdc25 activity. Chk1 and Chk2 are main inhibitors of Cdc25A and Cdc25C resulting in Cdk/cyclin-mediated cell cycle arrest [29]. It has been suggested that DSB in MSCs are repaired by activation of both the homologous recombination (HR, during S and G2 phases) and the non-homologous end-joining (NHEJ, during all cell cycle phases) DNA repair pathways [27,28,30]. Our recent study showed the activation of HR and NHEJ repair pathways in irradiated aMSCs [31]. In addition, p-ATM enhances the stabilization of the tumor suppressor regulatory protein and transcription factor P53 which up-regulates the expression and enhances the stabilization of the transcription factor and inhibitory regulatory protein p21, which potently inhibits Cdks which are needed for the G1/S transition leading to inhibition of the entry into S phase [27].

The application of MSCs in radiation oncology regenerative medicine (RORM) was enhanced by their efficient radiation-induced DNA repair machinery and their relative radiation resistance [30-34]. Such radiation resistance was mediated by many mechanisms, e.g. the ATM phosphorylation, activation of cell cycle check points (G2/M arrest), and activation of single and double stranded DNA repair by both homologous and non-homologous recombination mechanisms and other pathways [30,31] (Figure 2). DSB resulting from the direct and indirect radiation injury stimulate the phosphorylation of ATM which is the proximal step for cell cycle check point’s activation (G2/M arrest). In addition, the nuclear apoptotic factor P84 (P84/53E10 = the nuclear protein encoded by the N5 gene) is up regulated, which participates in the apoptotic response of the aMSCs. It has been documented that irradiated aMSCs showed p-ATM dependent and p-ATM independent (P84-mediated) G2/M arrest [31]. Phosphorylated histone-2AX (γ-H2AX) stimulated both the HR and the NHEJ of the dsDNA breaks and other repair mechanisms [35]. Rad-51 is considered one of the mandatory proteins for HR to occur. DNA-PK is the major protein in the NHEJ repair pathway. Studies have shown that both proteins (Rad-51 and DNA-PK) were up regulated in irradiated MSCs (Figure 2) [28,30,31].

Figure 2. MSCs radiobiological response

Double stranded DNA (dsDNA) breaks (DSB) resulting from the direct and indirect radiation injury stimulate the phosphorylation of Ataxia Telangectasia Mutated protein (ATM) which is the proximal step for cell cycle check points activation (G2/M arrest). The nuclear apoptotic factor P84 is up regulated, which participates in the apoptotic response of the cells. DSB stimulate the phosphorylation of histone-2AX through the Mre11, RAD50, NBS1 complex and p-ATM with a feedback loop amplification. Phosphorylated histone-2AX (γ-H2AX) stimulated both the homologous recombination repair (HR, active in S and G2 phases only) and the non-homologous end-joining repair (NHEJ, active in all cell cycle phases) of the DSB. Rad-51 is considered one of the mandatory proteins for HR to occur. DNA-PK is the major protein in the NHEJ repair pathway. Both proteins were up regulated in irradiated MSCs. P-ATM and p-DNA-PK activate the cell cycle check point kinases (Chk1 and Chk2) resulting in cyclin/Cdk-mediated G2/M cell cycle arrest by inhibiting the Cell division cycle phosphatase (Cdc25). P-ATM also stabilizes the tumor suppressor regulatory protein and transcription factor P53 which up-regulates the expression and enhances the stabilization of the inhibitory regulatory protein p21, which potently inhibits Cdks needed for the G1/S transition leading to inhibition of the entry into S phase.

MSCs applications in radiation oncology regenerative medicine (RORM)

Adding up all their beneficial characteristics, MSCs have been investigated in RORM preclinical and clinical studies (Table 2). Nevertheless, the few clinical data representing the therapeutic benefits of the application of MSCs in radiation-induced normal tissue injury are promising. Among these, in radiation-induced bone injury, MSCs therapy caused early hematopoietic recovery with improved osteonecrosis. In radiation-induced intestinal injury, MSCs therapy produced significant repopulation of intestinal epithelium with reduced pain, diarrhea, and hemorrhage. In radiation-induced skin injury, MSCs therapy showed significant improvement and repopulation of skin tissue [29]. The following are the clinical studies that have been investigating the potential application of MSCs in RORM.

Table 2. Mesenchymal stromal/stem cells (MSCs) preclinical and clinical studies in RORM [53,55]

Organ/ system

RT

dose (Gy)

Normal Tissue Endpoint

Paradigm

Stem cell type
therapy
(preclinical studies)

Stem cell type
therapy (clinical trial)

Follow
up time

Bone marrow

12

Bone marrow aplasia

Hematopoietic stem cell/progenitor depletion and stem cell ‘‘niche’’ destruction

BM, hSC, bmMSC

BM (81)

30 years

Brain

>57

Brain radio-necrosis, cognitive dysfunction

Inflammation, vascular breakdown, disruption of BBB, CNS progenitor depletion, stem cell ‘‘niche’’ destruction, hypoxia, demyelination, necrosis

hESC, hNSC

No

_

Salivary glands

> 35

Xerostomia, salivary flow

Stem cell/progenitor depletion

BM, bmMSC, salivary gland stem cell

No

_

Bone

>60

Bone growth alteration, bone weakening, and osteo- radionecrosis

Hypocellularity, hypovascularization, hypoxia, and fibro-necrosis

BM, bmMSC

BM associated to biomaterial (Phase I)

Few months

Skin

>50

Skin radionecrosis, pain

Chronic inflammation, damage to the microvasculature, epidermis stem cell/ progenitor depletion, ischemia, fibroblast death, and fibro-necrosis

bmMSC, aMSCs, EPC

bmMSC (local injection, 2 x 106/kg, repetitive injections, curative startegy) (compatio-nnal treatment) and lipoaspira-te (PhaseI)

8 years and 13 months

Liver

>35

Radiation-induced liver disease, sinusoidal obstructive syndrome

Vascular (sinusoidal) breakdown, hepatocyte cell death, and inhibition of hepatocellular regeneration

Hepatocyte

Hepatocy-te (intraspel-nic transplan-tation,

6 x106 cells) (Phase I)

_

Heart

>30-40

Atheroscler-osis, cardiac attack

Inflammation, damage to the microvasculature, ischemia, myocardial cell death, and fibro-necrosis

_

No

_

Colon-rectum

>35

Pelvic radiation disease, colo-rectal ulceration, rectitis, cystitis, and fistulae

Chronic inflammation, damage to the microvasculature, epithelial stem cell/progenitor depletion, ischemia, myofibroblast death, and fibro-necrosis

bmMSC

bmMSC (i.v. injection, 2 x 106/kg, repetitive injections) (compass-ional treatment)

4 years

aMSCs = adipose-derived mesenchymal stromal cell, bmMSC = bone marrow MSCs; BBB = blood brain barrier; BM = bone marrow; CNS = central nervous system; EPC = endothelial progenitor cells; GFAP = glial fibrillary acidic protein; hESC = human embryonic stem cell; hSC = human stem cells; hNSC = human neural stem cell, RT = radiation.

Skin repair application after radiation exposure

MSCs have been used in the repair of radiation-induced skin injuries where they were administered systemically and led to decreased radiation-induced skin fibrosis through enhancing the secretion of IL-10 and increasing the infiltration of anti-inflammatory regulatory CD163(+) macrophages, in addition to decreasing the secretionof IL-1 beta and the number of infiltrated pro-inflammatory CD80(+) macrophages [36]. It was suggested that the autologous grafting of MSCs is more efficient than the allogenic grafting in cutaneous radiation syndrome [20]. MSCs secrete growth factors and anti-inflammatory mediators that can be combined with other external growth factors, e.g. basic fibroblast growth factor (b-FGF) in order to improve the healing in radiation-induced skin damage [37]. The improved migration of fibroblasts and collagen production will protect the fibroblasts from the oxidative stress of UVB radiation [37].

Intestinal repair application after radiation exposure

MSCs have been applied for the repair of radiation-induced intestinal injury [26,38]. When MSCs were given before irradiation, treated mice showed higher body weight, thicker intestinal submucosal and muscle layer, significant higher survival rates and stromal derived factor-1 (SDF-1) expression, and lower numbers of radiation-induced ulcers [25,38]. Another study reported that MSCs therapy showed better maintenance of epithelial homeostasis, neovascularization, high anti-inflammatory IL-10, increased expression of VEGF, b-FGF and EGF in irradiated intestine, and increased the homing of CD31-positive hematopoietic stem cells or hematopoietic progenitor cells to the irradiated intestine [39]. MSCs therapy showed decreased activation and proliferation of T-lymphocytes together with increased local corticosterone secretion at the intestinal mucosa that highlighted an immunosuppressive effect of MSCs mediated by glucocorticoid receptors [40]. It was found that MSCs reparative and paracrine effects in radiation-induced intestinal injury were enhanced by pretreating them with TNF-alpha, IL-1 beta, and nitric oxide [41].

Lung tissue repair application after radiation exposure

MSCs therapy was shown to reduce radiation-induced lung tissue injury. Administration of MSCs resulted in decreased radiation-induced inflammatory response in terms of reduced pro-inflammatory mediators (IL-1 beta, IL-6, TNF-alpha), increased anti-inflammatory mediators (IL-10), reduced expression of TGF-β, alpha-smooth muscle actin (Alpha-SMA) and type 1 collagen level, and control of the pro- and anti-apoptotic mediators (Bcl-2, Bax, and caspase-3) protecting the lung tissue from apoptosis [42]. Moreover, MSCs therapy reduced bronchial epithelium senescence and lowered the risk of metastatic spread in lung tissue [43]. In addition, MSCs therapy decreased the mortality rate in mice with radiation-induced lung injury [44]. These cells showed a proven beneficial therapeutic effect in radiation pneumonitis as well [45].

Hematopoietic system homeostasis radiation injury

MSCs therapy has been shown to reduce the radiation-induced bone marrow apoptosis, and enhancemegakaryopoiesis and platelet recovery [46]. Moreover, MSCs therapy resulted in improved recovery of the hematopoietic system through decreased apoptosis and radiation-induced oxidative stress [47,48].

Radiation-induced cardiac injuries

A case report of a patient suffering from late radiation cardiomyopathy and radiation exudative pericarditis after radiotherapy of Hodgkin lymphoma showed that systemically transplanted MSCs partially differentiated to cardiomyocytes [49].

Radiation-induced salivary gland injury

In irradiated mice, systemically transplanted MSCs resulted in improvement of the saliva flow rate, lower salivary gland damage and atrophic acini, and higher mucin and amylase production [50].

Radiation-induced oral mucositis

Bone marrow-derived mesenchymal stromal cells (bmMSCs) therapy have been applied in fractionated radiation-induced oral mucositis where the administration of a systemic single dose of 6 million MSCs resulted in a significant decrease in ED50 (the RT dose that produces ulcer in 50% of irradiated mice) [51]. The first MSCs therapy for RIOM was done in 2014 by Schmidt et al. and concluded that transplantation of bone marrow (BM) or bmMSCs could modulate RIOM in fractionated RT, depending on the time of plantation [52]. Nevertheless, in another study they also concluded that bmMSCs plantation had no therapeutic benefits on RIOM in single dose RT when compared to the therapeutic gain by the mobilization of endogenous BM stem cells [53]. Further studies are needed in this field since the initial studies showed significant clinically relevant therapeutic effects.

Liver tissue protection

MSCs therapy reduced the radiation-induced liver injury by anti-oxidative, vascular protection, hepatocyte differentiation, and trophic mechanisms. There was decreased expression of Nrf2 and superoxide dismutase (SOD) in MSCs-treated irradiated liver which showed decreased apoptotic cells as well.These findings suggested that, these effects were mediated by an anti-oxidative mechanism. The increased expression of VEGF and Angiopoietin-1 (Ang-1) in the perivascular region, associated with an increased expression of VEGFr1, r2 suggested the vascular protection mechanism in the livers of MSCs-treated animals. After engrafting, MSCs showed expression of cytokeratin CK18 and CK19 and alpha-fetoprotein (AFP) genes which suggested hepatocyte differentiation. The increased secretion of nerve growth factor (NGF), hepatocyte growth factor (HGF), and anti-inflammatory molecules IL-10, IL1-RA suggested MSCs’ trophic effects [40, 54]. MSCs conditioned media improved the viability of liver sinusoidal endothelial cells (SECs) in vitro. Infusion of MSCs conditioned media significantly reduced the radiation-induced SECs apoptosis and improved the histopathological picture of irradiated livers. In addition, there was increased secretion of anti-inflammatory cytokines and decreased secretion of pro-inflammatory cytokines [40,55].

Studies with gene-modified MSCs for RORM

Genetically modified MSCs have been applied in RORM studies. HGF-expressing MSCs have improved the radiation-induced intestinal injury where they increased the expression of anti-inflammatory mediators and improved the histopathological picture of irradiated intestine [12]. Hepatocyte growth factor gene-modified adipose-derived mesenchymal stem cells improved the radiation induced liver damage in a rat model [13]. A similar picture was noted with TGF-beta-expressing MSCs therapy in radiation-induced lung injury [14].

Summary

Although limited data are available for the clinical application of MSCs in radiation-induced normal tissue injury, promising therapeutic benefits have been shown in a small number of isolated clinical studies [29].

Isolated clinical case reports showed promising beneficial effects of MSCs therapy; e.g. regenerating hematopoiesis and osteoradionecrosis, improved breathing parameters and lung immune function, improved intestinal mucosal inflammation, hemorrhages, fistulization, pain and diarrhea, and regenerated skin ulceration, in ionizing radiation-induced injury of bone, lung, intestine, and skin, respectively [29,40,56,57]. Table 2 summarizes the recent preclinical and clinical studies conducted in RORM applying MSCs therapies.

Adipose tissue-derived MSCs (aMSCs)

Adipose tissue-derived mesenchymal stem/stromal cells (aMSCs) are multipotent progenitor cells located in the stromal vascular fraction (SVF) of adipose tissue [2]. They are characterized by expressing cell surface antigens Sca1, CD106, CD105, CD73, CD29, and CD44, and lacking the expression of hematopoietic stem cells (HSCs) surface antigens (e.g. CD11b and CD45) [2,3,58]. In addition to their multi-lineage differentiation potential, they have anti-inflammatory/immune-modulatory and paracrine effects [59-61]. In addition, MSCs can home to the site of tissue injury that is caused by irradiation and inflammation [2,5,62].These advantages, in addition to their source abundance, ease of isolation and high cell count after expansion, render aMSCs promising for cellular therapies [63]. Table 3 lists 22 clinical trials using aMSCs therapy for various disorders, with no trial yet found for their application in RORM, following a search on the clinical trials website of the NIH, i.e. https://clinicaltrials.gov/, in Nov. 2015.

Table 3. Adipose Mesenchymal stromal cells (aMSCs) clinical trials www.ClinicalTrials.gov by the national Institute of Health in RORM

NCT #

Title

Conditions

Interventions

Last Verified

NCT02603744

Autologous Adipose Derived Mesenchymal Stromal Cells (aMSCs) Transplantation in Women With Premature Ovarian Failure (POF)

Premature Ovarian Failure

Biological: Intraovarian injection of aMSCs

Nov-15

NCT01449032

MSCs Therapy in Patients With Chronic Myocardial Ischemia (MyStromalCell Trial)

Chronic Ischemic Heart Disease

Biological: MSCs|Biological: Saline

Jun-14

NCT01585857

ADIPOA - Clinical Study

Osteoarthritis

Biological: Autologous aMSCs administrated for intra-articular use|Biological: Autologous aMSCs administrated for intra-articular use

Dec-14

NCT02382874

Allogenic aMSCs Transplantation in Idiopathic Nephrotic Syndrome (Focal Segmental Glomerulosclerosis)

Focal Segmental Glomerulosclerosis

Biological: Intravenous injection

Mar-15

NCT02240823

Can Fat Derived Stem Cells (SVF) be Used in the Treatment of Erectile Dysfunction After Prostatectomy

Delayed Graft Function

Other: aMSCs

Oct-15

NCT02326935

Multi-Center Study Safety of aMSCs for the Treatment of Multiple Sclerosis

Multiple Sclerosis

Biological: Autologous aMSCs

Jan-15

NCT00913289

Liver Regeneration Therapy Using Autologous aMSCs

Liver Cirrhosis

Biological: aMSCs

Oct-12

NCT01062750

Liver Regeneration Therapy by Intrahepatic Arterial Administration of Autologous aMSCs

Liver Cirrhosis

Biological: aMSCs dosage

Sep-15

NCT02338271

Autologous aMSCs Therapy for Intervertebral Disc Degeneration

Low Back Pain

Other: autologous aMSCs

Jan-15

NCT01709279

Clinical Trial of Autologous aMSCs Therapy for Ischemic Heart Failure

Ischemic Heart Failure

Biological: aMSCs dosage

Oct-12

NCT01739504

Autologous aMSCs Delivered Intra-articularly in Patients With Osteoarthritis.

Osteoarthritis

Procedure: Autologous aMSCs harvesting through Liposuction for Intra-articular Injection

Oct-15

NCT02145897

To Evaluate the Safety and Efficacy of IM and IV Administration of Autologous aMSCs for Treatment of CLI

Critical Limb Ischemia

(CLI)

Biological: Autologous Stromal Vascular Fraction (SVF)|Biological: Autologous aMSCs| Other: Control

May-14

NCT01840540

MSC for Occlusive Disease of the Kidney

Atherosclerot-ic Renal Artery Stenosis| Ischemic Nephropathy|Renovascular Hypertension

Drug: Arterial infusion of autologous mesenchymal stem cells

Oct-15

NCT02135380

Evaluate Safety and Efficacy of Intravenous Autologous aMSC for Treatment of Idiopathic Pulmonary Fibrosis

Idiopathic Pulmonary Fibrosis

Biological: Autologous Stromal Vascular Fraction (SVF)|Biological: Autologous aMSCs |Other: Control

May-14

NCT01548092

Stromal Vascular Fraction (SVF) for Treatment of Recto-vaginal Fistula

Recto-vaginal Fistula

Drug: aMSCs without expanded

Mar-12

NCT01771913

Immunophenotyping of Fresh Stromal Vascular Fraction From aMSCs Enriched Fat Grafts

Breast Reconstruction|Contour Irregularities|Volume Insufficiency

Genetic: centrifuged fat graft| Genetic: aMSCs enriched fat graft

Jul-15

NCT01849159

Clinical Study of the Efficacy and Safety of the Application of Allogeneic Mesenchymal (Stromal) Cells of Bone Marrow, Cultured Under the Hypoxia in the Treatment of Patients With Severe Pulmonary Emphysema

Pulmonary Emphysema

Biological: Mesenchymal stem cells|Other: Reference therapy: 400 mL of 0.9% NaCl solution

Oct-15

NCT01532076

Effectiveness of aMSCs as Osteogenic Component in Composite Grafts

Osteoporotic Fractures

Procedure: Cellularized composite graft augmentation|Procedure: Acellular composite graft augmentation

Sep-14

NCT02387723

CSCC_ASC Therapy in Patients With Severe Heart Failure

Clinical Patient Safety of Allogeneic Stem Cell Therapy

Biological: Allogeneic aMSCs (CSCC_ASC)

Mar-15

NCT01730547

Mesenchymal Stem Cells for Multiple Sclerosis

Multiple Sclerosis

Biological: Autologous mesenchymal stem cells

Jan-15

NCT02492490

Effect of SVF-derived MSC in DCD Renal Transplantation

Uremia

Other: SVF-derived MSC transplantations|Drug: Basiliximab

Nov-14

NCT02492308

Induction With SVF Derived MSC in Living-related Kidney Transplantation

Living-relative Kidney Transplantation

Procedure: SVF-MSC induction|Drug: Basiliximab induction

Jul-15

MSCs mechanisms of action in RORM

There are proposed mechanisms of action of MSCs radio-protective properties in radiation-induced normal tissue injury repair. Homing and paracrine effects with anti-inflammatory/immunomodulatory mechanisms are supported by in-vitro data from radiation-induced intestinal injury studies and [59-62]. MSCs therapy in radiation-induced intestinal injury showed the homing of systemically administered MSCs in measurable numbers at the intestinal injury site [25,26,41]. There were increased levels of IL-10, VEGF, b-FGF, and EGF. Histopathological studies showed improved intestinal epithelial homeostasis that may be due to MSCs overexpressing stromal cell-derived factor receptor CXCR-4 [29]. These findings suggest that the paracrine and the anti-inflammatory effect of MSCs is the expected radio-protective mechanism of action of MSCs in RORM [29].

Challenges facing MSCs therapy

The fear of MSCs-mediated radioprotection of tumor tissues has been a raised concern after the availability of in-vitro data suggesting that breast cancer cells grow and proliferate more with MSCs-therapy owing to high insulin-like factor production [53]. Also, MSCs have some angiogenic properties evident by increased secretion of platelets derived growth factor (PDGF), VEGF and TGF-β at the tumor perivascular area and parenchyma in low dose irradiated mice owing to MSCs infiltration at the tumor site [53]. MSCs angiogenic properties might counteract the anti-angiogenic cancer therapies, a question that needs to be answered with solid in-vitro and in-vivo studies [28,29].

Another challenge appeared in MSCs therapies. MSCs have been found to have heterogeneous radiation resistant populations, both in human and mouse MSCs [53]. A finding that might interfere with the overall radio-protective and tissue regenerative properties of MSCs. Nevertheless, studies may find molecular biomarkers for isolating homogenous populations of MSCs with uniform high RT resistance profile [28,29].

A further challenge that has been found to be more frequent in mouse MSCs than in human MSCs, is MSCs in-vitro transformation (the tumorigenic potential of MSCs) [53]. Such challenge carries a significant worry for MSCs therapies, since MSCs are radio-resistant cells. Thus, their transformation may signify the generation of a severe form of radio-resistant tumor that is extremely hard to control. Tight and fine validation of MSCs before each single dose therapy is recommended for preventing the use of any potentially transformed cells [28,29,34].

Conclusion

MSCs have been widely used in preclinical studies of radiation oncology regenerative medicine. MSCs have been shown to be reliable candidates in radiation oncology regenerative medicine translational and clinical research. The strong potential of MSCs therapy in RIOM is supported by their relative radiation resistance and robust DNA repair mechanisms, multi-lineage differentiation potential, and anti-inflammatory/immunomodulatory properties. Nevertheless, few but considerable challenges in MSCs therapies are requiring more research in order to develop solid solutions. However, the overall data collected from preclinical and clinical studies with MSCs therapy promise with cell therapy choices competing the traditional therapies. Adipose-tissue derived mesenchymal stromal/stem cells are reliable candidates for radiation oncology regenerative medicine applications owing to the advantages they possess, e.g. source abundance, enhanced anti-inflammatory effects, robust IL-10 secretion, easy isolation, high expansion.

Authorship and contributions

Osama Maria: Conception and design, collection and/or assembly of data, review writing, final approval of the review.

Nicoletta Eliopoulos: Conception, design and final approval of the review.

Thierry Muanza: Conception and design, financial support and final approval of the review.

Acknowledgements

Osama Muhammad Maria is an awardee of the LDI/TD studentship, and Fonds de Récherche du Quebec - Santé (FRQS) doctoral fellowship. This study was supported partially by Ride to Conquer Cancer (RTCC, Jewish General Hospital Foundation) and FRQS grants. This work was partially supported by Canadian Institutes of Health Research (CIHR) Operating Grant MOP-15017 (N. Eliopoulos).

Disclosure of potential conflict of interest

None

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Editorial Information

Editor-in-Chief

Article Type

Review Article

Publication history

Received: June 05, 2016
Accepted: July 04, 2016
Published: July 07, 2016

Copyright

©2016 Maria OM. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Citation

Maria OM, Eliopoulos N, Muanza T (2016). Mesenchymal stromal cells therapy in radiation oncology regenerative medicine. J Stem Cell Res Med 1: DOI: 10.15761/JSCRM.1000108

Corresponding author

Dr. Thierry Muanza, MD, MSc, FRCPC

Radiation Oncology, Translational Research Lab, Department of Radiation Oncology, Jewish General Hospital and Lady Davis Institute Research Centre, McGill University, 3755, Côte-St.-Catherine Road, Suite G002, Montréal, Québec, Canada, H3T 1E2, Tel: +1 (514)-340-8288, Fax: + 1 (514)-340-7548

Table 1. Mesenchymal Stromal cells (MSCs) clinical trials in various disorders as listed on www.ClinicalTrials.gov by the National Institute of Health (NIH) by Nov. 2015

NCT #

Title

Conditions

Interventions

Last Verified

NCT01589549

Mesenchymal Stromal Cells for Acute Graft Versus Host Disease

Acute GVH Disease

Biological: Mesenchymal stromal cell therapy

Jun-15

NCT02057965

Mesenchymal Stromal Cell Therapy in Renal Recipients

Renal Transplant Rejection|Fibrosis

Drug: Mesenchymal Stromal Cells

Mar-15

NCT02032446

Umbilical Cord Derived Mesenchymal Stromal Cells For The Treatment of Severe Steroid-resistant Graft Versus Host Disease

Hematologic Malignancies

Biological: UMBILICAL CORD DERIVED MESENCHYMAL STROMAL CELLS (UC-MSC)

Apr-15

NCT02012153

Mesenchymal Stromal Cells in Kidney Transplant Recipients

Kidney Transplant Rejection

Biological: Mesenchymal Stromal Cells

Oct-15

NCT01090817

An Australian Study of Mesenchymal Stromal Cells for Crohn's Disease

Crohn Disease

Drug: Mesenchymal stromal cells (MSC) for infusion

Jun-15

NCT00644410

Autologous Mesenchymal Stromal Cell Therapy in Heart Failure

Congestive Heart Failure

Biological: Mesenchymal stromal cell| Biological: Saline

Mar-15

NCT01061099

Repeated Infusions of Mesenchymal Stromal Cells in Children With Osteogenesis Imperfecta

Osteogenesis Imperfecta Type II| Osteogenesis Imperfecta Type III

Biological: Mesenchymal Stromal Cells

Apr-15

NCT02150551

Safety and Tolerability Of Allogeneic Mesenchymal Stromal Cells in Pediatric Inflammatory Bowel Disease

Inflammatory Bowel Diseases

Biological: Allogeneic bone marrow-derived mesenchymal stromal cells

Sep-15

NCT01522716

Mesenchymal Stromal Cells as Treatment of Chronic Graft-versus-host Disease

Graft-Versus-Host Disease

Biological: Mesenchymal stromal cells

Nov-15

NCT02323789

A Phase I/II Study Evaluating Allogeneic Mesenchymal Stromal Cells in Adults With Recessive Dystrophic Epidermolysis Bullosa

Recessive Dystrophic Epidermolysis Bullosa

Drug: Mesenchymal stromal cells

Dec-14

NCT02291770

Treatment of Chronic Graft-Versus-Host Disease With Mesenchymal Stromal Cells

Chronic Graft-Versus-Host Disease

Biological: Mesenchymal Stromal Cells

Nov-14

NCT01764100

Mesenchymal Stromal Cells (MSCs) for the Treatment of Graft Versus Host Disease (GVHD)

Graft vs Host Disease

Genetic: Mesenchymal stromal cells

Jan-13

NCT02230514

Mesenchymal Stromal Cells for the Treatment of Non-union Fractures of Long Bones

Atrophic Nonunion of Fracture

Drug: XCEL-MT-OSTEO-ALPHA|Other: autologous iliac crest| Procedure: Surgery

Jul-15

NCT02215811

Treatment of Severe Acute Respiratory Distress Syndrome With Allogeneic Bone Marrow-derived Mesenchymal Stromal Cells

Acute Respiratory Distress Syndrome, Adult

Biological: Mesenchymal stromal cells

Aug-14

NCT01449032

Mesenchymal STROMAL CELL Therapy in Patients With Chronic Myocardial Ischemia (My Stromal Cell Trial)

Chronic Ischemic Heart Disease

Biological: MSC| Biological: Saline

Jun-14

NCT02580695

A Study to Assess Safety and Efficacy of Umbilical Cord-derived Mesenchymal Stromal Cells in Knee Osteoarthritis

Osteoarthritis

Biological: umbilical-cord mesenchymal stromal cells| Drug: Hyaluronic Acid

Oct-15

NCT01038596

Mesenchymal Stromal Cells and Osteoarthritis

Osteoarthritis

 

Dec-09

NCT02495766

Autologous Mesenchymal Stromal Cells for Multiple Sclerosis

Relapsing-Remitting Multiple Sclerosis| Secondary Progressive Multiple Sclerosis

Drug: XCEL-MC-ALPHA|Drug: Placebo

Nov-15

NCT02565459

MSC and Kidney Transplant Tolerance (Phase A)

Chronic Renal Failure

Biological: Mesenchymal Stromal Cells

Sep-15

NCT01849237

Russian Clinical Trial of Mesenchymal Cells in Patients With Septic Shock and Severe Neutropenia

Septic Shock| Nonchemotherapy Drug-induced Neutropenia| Neutropenia After Chemotherapy in Oncohematological Patients| Neutropenia in Patients With Aplastic Anemia

Genetic: Mesenchymal stromal cells|Drug: Standard therapy of septic shock

May-13

NCT02387151

Allogeneic Mesenchymal Stromal Cell Therapy in Renal Transplant Recipients

Rejection|Graft Loss

Procedure: mesenchymal stem cell infusion

Mar-15

NCT01175655

A Study to Evaluate the Potential of Mesenchymal Stromal Cells to Treat Obliterative Bronchiolitis After Lung Transplantation

Bronchiolitis Obliterans|Lung Transplantation

Other: MSC

Apr-15

NCT00957931

Allo-HCT MUD for Non-malignant Red Blood Cell (RBC) Disorders: Sickle Cell, Thal, and DBA: Reduced Intensity Conditioning, Co-tx MSCs

Sickle Cell Disease| Thalassemia| Diamond-Blackfan Anemia

Procedure: Bone marrow transplantation| Biological: Mesenchymal Stromal Cells

Dec-12

NCT01742260

Cranial Reconstruction Using Mesenchymal Stromal Cells and Resorbable Biomaterials

Surgically-Created Resection Cavity

Procedure: Repair of cranial defects by tissue engineering

Jun-15

NCT02260375

MSC Therapy in Liver Transplantation

Liver Transplant Rejection

Biological: Mesenchymal Stromal Cells

Sep-15

NCT01872624

Safety Study of Bone-marrow Derived Mesenchymal Stromal Cells Associated With Endobronchial Valves in Emphysema

Pulmonary Emphysema

Procedure: Bronchoscopy

Mar-15

NCT01586312

Treatment of Knee Osteoarthritis With Allogenic Mesenchymal Stem Cells

Osteoarthritis, Knee|Arthritis of Knee|Knee Osteoarthritis

Other: Allogenic mesenchymal stromal cells injection|Drug: Hyaluronic Acid

Sep-15

NCT01860417

Treatment of Degenerative Disc Disease With Allogenic Mesenchymal Stem Cells (MSV)

Degenerative Disc Disease| Intervertebral Disc Disease|Low Back Pain

Biological: Allogenic Mesenchymal Stromal Cells| Drug: Mepivacaine

Sep-15

NCT02384018

Mesenchymal Stem Cell and Islet           Co-transplantation

Chronic Pancreatitis| Diabetes

Biological: autologous mesenchymal stromal cell

Dec-14

NCT01306513

Safety and Feasibility Study of Administration of Mesenchymal Stem Cells for Treatment of Emphysema

Emphysema

Biological: autologous bone marrow derived mesenchymal stromal cells

Nov-12

NCT02359929

BMT Auto MSCs GvHD Ph1

Graft Versus Host Disease|Acute Graft Versus Host Disease|Chronic Graft Versus Host Disease

Biological: Autologous mesenchymal stromal cells (MSCs)

Aug-15

NCT02585622

Novel Stromal Cell Therapy for Diabetic Kidney Disease

Diabetic Kidney Disease

Biological: Mesenchymal Stromal Cells| Other: Placebo

Oct-15

NCT02033525

Mesenchymal Stromal Cells for Degenerative Meniscus Injury

Chronic Meniscal Injury

Drug: XCEL-M-ALPHA and standard rehabilitation| Other: Rehabilitation

Jul-15

NCT02589119

Stem Cell Fistula Plug in Cryptoglandular Perianal Fistulas (MSC-AFP)

Perianal Fistula| Cryptoglandular Perianal Fistula

Drug: MSC-AFP

Oct-15

NCT02421484

Cellular Immunotherapy for Septic Shock: A Phase I Trial

Septic Shock

Biological: Allogeneic bone marrow derived mesenchymal stromal cells

Apr-15

NCT02055625

Mesenchymal Stem Cells as a Treatment for Oral Complications of Graft-versus-host Disease

Graft -Versus-host-disease

Biological: Mesenchymal stromal cells

Mar-15

NCT02408432

Intravenous Administration of Allogeneic Bone Marrow Derived Multipotent Mesenchymal Stromal Cells (MSCs) in Patients With Recent Onset Anthracycline-Associated Cardiomyopathy

Cardiomyopathy

Biological: Human Mesenchymal Stem Cells (hMSCs)|Other: Standard of Care

Jun-15

NCT02181478

Intra-Osseous Co-Transplant of UCB and hMSC

Acute Lymphoblastic Leukemia| Acute Myelogenous Leukemia| Myelodysplastic Syndromes| Myelofibrosis| Relapsed Non-Hodgkin Lymphoma| Refractory Non-Hodgkin Lymphoma| Hodgkin Lymphoma| Refractory Hodgkin Lymphoma| Relapsed Chronic Lymphocytic Leukemia| Refractory Chronic Lymphocytic Leukemia| Lymphoid Malignancies| Chronic Myelogenous Leukemia

Drug: cyclophosphamide| Drug: fludarabine phosphate| Radiation: total-body irradiation|Drug: cyclosporine|Drug: mycophenolate mofetil|Procedure: umbilical cord blood transplantation| Procedure: mesenchymal stem cell transplantation

Jul-15

NCT02351011

Human Autologous MSCs for the Treatment of Mid to Late Stage Knee OA

Osteoarthritis of Knee

Biological: 1 x 10^6 MSCs|Biological: 10 x 10^6 MSCs|Biological: 50 x 10^6 MSCs

Feb-15

NCT02270307

MSC and Cyclophosphamide for Acute Graft-Versus-Host Disease (aGVHD) Prophylaxis

Leukemia| Multiple Myeloma

Drug: Cyclophosphamide| Biological: Mesenchymal stromal cells

Oct-14

NCT01922908

Mesenchymal Stromal Cells for Ischemic Stroke

Ischemic Stroke

Biological: MSC Infusion|Biological: Placebo Comparator

May-15

NCT02145923

Effectiveness and Safety of MMSCs for Enhancing Hematopoietic Recovery and Prophylaxis of Neutropenic Enterocolitis

Neutropenic Enterocolitis| Myeloablative Chemotherapy Induced Bone Marrow Aplasia

Procedure: Peripheral blood stem cell mobilisation and collection|Drug: High-dose chemotherapy| Drug: Bone marrow derived allogeneic MMSCs infusion|Procedure: Autologous peripheral blood stem cells infusion

Jun-15

NCT01275612

Mesenchymal Stem Cells In Cisplatin-Induced Acute Renal Failure In Patients With Solid Organ Cancers

Solid Tumors| Acute Kidney Injury

Biological: Mesenchymal stromal cell infusion

Oct-15

NCT01909154

Safety Study of Local Administration of Autologous Bone Marrow Stromal Cells in Chronic Paraplegia

Spinal Cord Injury

Biological: Mesenchymal stromal cell therapy

Nov-13

NCT00395200

Mesenchymal Stem Cells in Multiple Sclerosis (MSCIMS)

Multiple Sclerosis

Procedure: MSC Treatment

Oct-11

NCT00260338

Stem Cell Therapy for Vasculogenesis in Patients With Severe Myocardial Ischemia

Myocardial Ischemia| Coronary Heart Disease

Biological: stem cell

May-13

NCT01659762

A Phase I Study Evaluating Autologous Bone Marrow Derived Mesenchymal Stromal for Crohn's Disease.

Crohn's Disease

Biological: autologous mesenchymal stromal cell

Jul-15

NCT02382874

Allogenic AD-MSC Transplantation in Idiopathic Nephrotic Syndrome (Focal Segmental Glomerulosclerosis)

Focal Segmental Glomerulosclerosis

Biological: Intravenous injection

Mar-15

NCT02448849

Autologous BM-MSC Transplantation in Combination With Platelet Lysate (PL) for Nonunion Treatment

Bone Fracture

Biological: Percutaneous injection| Other: Percutaneous injection

Sep-15

NCT01915927

Stem Cell Fistula Plug in Perianal Crohn's Disease

Perianal Crohn's Disease

Drug: MSC-AFP

Jun-15

NCT01686139

Safety Study of Stem Cells Treatment in Diabetic Foot Ulcers

Type I Diabetes Mellitus With Ulcer| Type II Diabetes Mellitus With Ulcer

Biological: ABMD-MSC

Jan-14

NCT02017912

Phase 2, Randomized, Double Blind, Placebo Controlled Multicenter Study of Autologous MSC-NTF Cells in Patients With ALS

Amyotrophic Lateral Sclerosis (ALS)

Biological: Autologous MSC-NTF cells

Jul-15

NCT01463475

University of Wisconsin hMSC Cell Bank: Bone Marrow Donor Protocol

Graft Versus Host Disease (GVHD)|Acute Myocardial Infarction (AMI)

Procedure: Bone marrow aspirate

Dec-14

NCT02195323

Autologous Bone Marrow Derived Mesenchymal Stromal Cells (BM-MSCs) in Patients With Chronic Kidney Disease (CKD)

Chronic Kidney Disease

Biological: Intravenous injection

Oct-13

NCT02409940

To Elucidate the Effect of Mesenchymal Stem Cells on the T Cell Repertoire of the Kidney Transplant Patients

Renal Transplant Rejection

Biological: Mesenchymal Stem Cells

Apr-15

NCT00908856

Autologous Cell Therapy After Stroke

Stroke

Biological: autologous bone marrow mononuclear cell transfusion| Biological: marrow stromal cells| Drug: placebo

Dec-14

NCT02247973

Mesenchymal Stem Cells Co-transplantation in Alternative Donor Transplantation of Severe Aplastic Anemia.

Severe Aplastic Anemia

Biological: mesenchymal stem cells| Biological: mesenchymal stem cells

Sep-14

NCT01446614

Mesenchymal Stem Cells Transplantation to Patients With Parkinson's Disease

Parkinson's Disease

Biological: bone marrow derived mesenchymal stem cells

Oct-11

NCT01446640

Mesenchymal Stem Cells Transplantation to Patients With Spinal Cord Injury

Spinal Cord Injury

Biological: bone marrow derived mesenchymal stem cells

Oct-11

NCT01305694

Mesenchymal Stem Cells Transplantation to Patients With Relapsed/Refractory Aplastic Anemia.

Aplastic Anemia

Biological: bone marrow derived mesenchymal stem cells

Feb-11

NCT01051882

Autologous Cultured Mesenchymal Bone Marrow Stromal Cells Secreting Neurotrophic Factors (MSC-NTF), in ALS Patients.

Amyotrophic Lateral Sclerosis

Biological: MSC-NTF cells transplantation (i.m.)| Biological: MSC-NTF cells transplantation (i.t.)

Aug-12

NCT01624701

Clinical Ex Vivo Expansion of Human Umbilical Cord Blood Stem and Progenitor Cells

Acute Leukemia| Chronic Leukemia| Myelodysplastic Syndrome| Lymphoma| Myeloma

Other: Ex-vivo expanded cord blood cells

Jun-12

NCT02336230

A Prospective Study of Remestemcel-L, Ex-vivo Cultured Adult Human Mesenchymal Stromal Cells, for the Treatment of Pediatric Patients Who Have Failed to Respond to Steroid Treatment for Acute GVHD

Grades B-D aGVHD

Drug: Remestemcel-L

Jan-15

NCT02525432

Autologous Stem Cell Study for Adult TBI (Phase 2b)

Brain Injuries, Traumatic| Brain Injuries, Acute| TBI (Traumatic Brain Injury)

Biological: Placebo Infusion| Biological: Autologous BMMNC Infusion| Device: Ultrasound

Oct-15

NCT02209311

Effectiveness and Safety of Method of Maxilla Alveolar Process Reconstruction Using Synthetic Tricalcium Phosphate and Autologous MMSCs

Partially Edentulous Maxilla| Alveolar Bone Atrophy| Alveolar Bone Loss

Procedure: Oral mucosa biopsy| Procedure: Sinus lift with implantation of tissue engineered construction| Device: Dental implant

Sep-15

NCT02379442

Early Treatment of Acute Graft Versus Host Disease With Bone Marrow-Derived Mesenchymal Stem Cells and Corticosteroids

Graft-Versus-Host Disease

Biological: MSC

Feb-15

NCT01144962

Dose-escalating Therapeutic Study of Allogeneic Bone Marrow Derived Mesenchymal Stem Cells for the Treatment of Fistulas in Patients With Refractory Perianal Crohn's Disease

Crohn's Disease| Fistula

Procedure: Localization, curettage of the fistulous tract and closure of the internal opening without MSC injection.| Procedure: Localization, curettage of the fistulous tract and closure of the internal opening with local MSC injection.

Dec-14

NCT02448121

Autologous Bone Marrow Stem Cell Transplantation for Hip Osteonecrosis in Sickle Cell Disease

Avascular Necrosis of Femur Head| Sickle Cell Disease

Procedure: Stem Cell Graft Group| Biological: Autologous bone marrow stem cell

Aug-15

NCT01892514

Randomized Clinical Trial for the Treatment of Osteonecrosis of the Femoral Head

Osteonecrosis

Procedure: core decompression

Apr-14

NCT02249676

Autologous Mesenchymal Stem Cells for the Treatment of Neuromyelitis Optica Spectrum Disorders

Devic's Syndrome| Devic's Neuromyelitis Optica| Devic Syndrome| Devic's Disease| Devic Disease

Biological: Autologous mesenchymal stem cells

Sep-14

NCT02482194

Autologous Mesenchymal Stem Cells Transplantation for Spinal Cord Injury- A Phase I Clinical Study

Spinal Cord Injury

Biological: mesenchymal stem cells

Jun-15

NCT00731744

Generation of Dendritic Cell Precursors From Cord Blood Stem Cells

Normal Full-Term Deliveries

Procedure: Normal full-term deliveries

Aug-08

NCT02037204

IMPACT: Safety and Feasibility of a Single-stage Procedure for Focal Cartilage Lesions of the Knee.

Foreign-Body Reaction| Inflammation| Effusion (L) Knee| Knee Pain Swelling

Other: Cartilage repair surgery

Jul-14

NCT01993368

Analysis of Osteoimmune Interactions Linking Inflammation and Bone Destruction in Aggressive Periodontitis

Aggressive Periodontitis| Chronic Periodontitis

Other: flow cytometry

Sep-15

NCT01777646

Autologous Cultured Mesenchymal Bone Marrow Stromal Cells Secreting Neurotrophic Factors (MSC-NTF), in Patients With Amyotrophic Lateral Sclerosis (ALS)

Amyotrophic Lateral Sclerosis

Biological: MSC_NTF cells transplantation by multiple intramuscular injections at 24 separate sites, in addition to a single intrathechal injection into the CSF

Jan-14

NCT01468064

Autologous Bone Marrow Stromal Cell and Endothelial Progenitor Cell Transplantation in Ischemic Stroke

Stroke| Infarction, Middle Cerebral Artery

Genetic: Autologous BMSCs transplantation| Genetic: Autologous EPCs transplantation| Genetic: IV infusion of placebo

Nov-15

NCT01071577

Collection of Bone Marrow From Healthy Volunteers and Patients for the Production of Clinical Bone Marrow Stromal Cell (BMSC) Products

Bone Marrow| Bone Marrow Stromal Cells| Mesenchymal Stem Cells| Blood Donors

 

Aug-15

NCT00186914

Stromal Therapy of Osteodysplasia After Allogeneic Bone Marrow Transplantation

Osteodysplasia

Biological: Marrow stromal cell infusion

Feb-08

NCT00781872

Mesenchymal Stem Cells for the Treatment of MS

Multiple Sclerosis

Biological: injection of autologous stem cells

Oct-08

NCT02467387

A Study to Assess the Effect of Intravenous Dose of (aMBMC) to Subjects With Non-ischemic Heart Failure

Non-Ischemic Heart Failure

Drug: Allogeneic Mesenchymal Bone Marrow Cells (aMBMC)| Drug: Lactated Ringer's Solution

Jun-15

NCT02442817

Linagliptin and Mesenchymal Stem Cells: A Pilot Study

Schizophrenia

Drug: Linagliptin

Apr-15

NCT02064062

Autologous Stem Cells in Achilles Tendinopathy

Achilles Tendinitis, Right Leg| Achilles Tendinitis| Achilles Degeneration| Achilles Tendon Thickening| Tendinopathy| Achilles Tendinitis, Left Leg

Biological: Autologous Mesenchymal Stem Cells

Feb-14

NCT01840540

MSC for Occlusive Disease of the Kidney

Atherosclerotic Renal Artery Stenosis| Ischemic Nephropathy| Renovascular Hypertension

Drug: Arterial infusion of autologous mesenchymal stem cells

Oct-15

NCT01795950

Safety Study of PLX-PAD Cells to Treat Pulmonary Arterial Hypertension (PAH)

Pulmonary Arterial Hypertension

Drug: PLX-PAD

Sep-15

NCT01377870

Evaluation of Autologous Mesenchymal Stem Cell Transplantation (Effects and Side Effects) in Multiple Sclerosis

Multiple Sclerosis

Biological: intravenous injection of mesenchymal stem cells| Biological: injection of cell free media

Aug-10

NCT01557543

Stem Cell Injection to Treat Heart Damage During Open Heart Surgery

Heart Disease| Ischemic Heart Disease| Coronary Artery Disease| Coronary Artery Disease (CAD)

Other: Cell Therapy

Nov-15

NCT00919958

Safety of Intramuscular Injection of Allogeneic PLX-PAD Cells for the Treatment of Critical Limb Ischemia

Peripheral Artery Disease| Peripheral Vascular Disease| Critical Limb Ischemia

Biological: PLX-PAD IM injection

Jun-12

NCT00951210

Safety of Intramuscular Injections (IM) of Allogeneic PLX-PAD Cells for the Treatment of Critical Limb Ischemia (CLI)

Peripheral Artery Disease| Peripheral Vascular Disease| Critical Limb Ischemia

Biological: PLX-PAD

Nov-11

NCT02323477

Human Umbilical Cord Stroma MSC in Myocardial Infarction

Chronic Ischemic Cardiomyopathy| Coronary Artery Bypass Surgery

Biological: stem cell transplantation

May-15

NCT01849159

Clinical Study of the Efficacy and Safety of the Application of Allogeneic Mesenchymal (Stromal) Cells of Bone Marrow, Cultured Under the Hypoxia in the Treatment of Patients With Severe Pulmonary Emphysema

Pulmonary Emphysema

Biological: Mesenchymal stem cells| Other: Reference therapy: 400 mL of 0.9% NaCl solution

Oct-15

NCT00821470

Treatment of Osteonecrosis of the Femoral Head by Bone Marrow Transplantation

Necrosis

Procedure: core decompression| Procedure: Bone marrow implantation into the necrotic lesion

Jan-09

NCT01172548

Safety and Efficacy Evaluation of Two Year Imatinib Treatment in Adjuvant Gastrointestinal Stromal Tumor (GIST)

Gastrointestinal Stromal Tumors

Drug: Imatinib mesylate

Mar-15

Table 2. Mesenchymal stromal/stem cells (MSCs) preclinical and clinical studies in RORM [53,55]

Organ/ system

RT

dose (Gy)

Normal Tissue Endpoint

Paradigm

Stem cell type
therapy
(preclinical studies)

Stem cell type
therapy (clinical trial)

Follow
up time

Bone marrow

12

Bone marrow aplasia

Hematopoietic stem cell/progenitor depletion and stem cell ‘‘niche’’ destruction

BM, hSC, bmMSC

BM (81)

30 years

Brain

>57

Brain radio-necrosis, cognitive dysfunction

Inflammation, vascular breakdown, disruption of BBB, CNS progenitor depletion, stem cell ‘‘niche’’ destruction, hypoxia, demyelination, necrosis

hESC, hNSC

No

_

Salivary glands

> 35

Xerostomia, salivary flow

Stem cell/progenitor depletion

BM, bmMSC, salivary gland stem cell

No

_

Bone

>60

Bone growth alteration, bone weakening, and osteo- radionecrosis

Hypocellularity, hypovascularization, hypoxia, and fibro-necrosis

BM, bmMSC

BM associated to biomaterial (Phase I)

Few months

Skin

>50

Skin radionecrosis, pain

Chronic inflammation, damage to the microvasculature, epidermis stem cell/ progenitor depletion, ischemia, fibroblast death, and fibro-necrosis

bmMSC, aMSCs, EPC

bmMSC (local injection, 2 x 106/kg, repetitive injections, curative startegy) (compatio-nnal treatment) and lipoaspira-te (PhaseI)

8 years and 13 months

Liver

>35

Radiation-induced liver disease, sinusoidal obstructive syndrome

Vascular (sinusoidal) breakdown, hepatocyte cell death, and inhibition of hepatocellular regeneration

Hepatocyte

Hepatocy-te (intraspel-nic transplan-tation,

6 x106 cells) (Phase I)

_

Heart

>30-40

Atheroscler-osis, cardiac attack

Inflammation, damage to the microvasculature, ischemia, myocardial cell death, and fibro-necrosis

_

No

_

Colon-rectum

>35

Pelvic radiation disease, colo-rectal ulceration, rectitis, cystitis, and fistulae

Chronic inflammation, damage to the microvasculature, epithelial stem cell/progenitor depletion, ischemia, myofibroblast death, and fibro-necrosis

bmMSC

bmMSC (i.v. injection, 2 x 106/kg, repetitive injections) (compass-ional treatment)

4 years

aMSCs = adipose-derived mesenchymal stromal cell, bmMSC = bone marrow MSCs; BBB = blood brain barrier; BM = bone marrow; CNS = central nervous system; EPC = endothelial progenitor cells; GFAP = glial fibrillary acidic protein; hESC = human embryonic stem cell; hSC = human stem cells; hNSC = human neural stem cell, RT = radiation.

Table 3. Adipose Mesenchymal stromal cells (aMSCs) clinical trials www.ClinicalTrials.gov by the national Institute of Health in RORM

NCT #

Title

Conditions

Interventions

Last Verified

NCT02603744

Autologous Adipose Derived Mesenchymal Stromal Cells (aMSCs) Transplantation in Women With Premature Ovarian Failure (POF)

Premature Ovarian Failure

Biological: Intraovarian injection of aMSCs

Nov-15

NCT01449032

MSCs Therapy in Patients With Chronic Myocardial Ischemia (MyStromalCell Trial)

Chronic Ischemic Heart Disease

Biological: MSCs|Biological: Saline

Jun-14

NCT01585857

ADIPOA - Clinical Study

Osteoarthritis

Biological: Autologous aMSCs administrated for intra-articular use|Biological: Autologous aMSCs administrated for intra-articular use

Dec-14

NCT02382874

Allogenic aMSCs Transplantation in Idiopathic Nephrotic Syndrome (Focal Segmental Glomerulosclerosis)

Focal Segmental Glomerulosclerosis

Biological: Intravenous injection

Mar-15

NCT02240823

Can Fat Derived Stem Cells (SVF) be Used in the Treatment of Erectile Dysfunction After Prostatectomy

Delayed Graft Function

Other: aMSCs

Oct-15

NCT02326935

Multi-Center Study Safety of aMSCs for the Treatment of Multiple Sclerosis

Multiple Sclerosis

Biological: Autologous aMSCs

Jan-15

NCT00913289

Liver Regeneration Therapy Using Autologous aMSCs

Liver Cirrhosis

Biological: aMSCs

Oct-12

NCT01062750

Liver Regeneration Therapy by Intrahepatic Arterial Administration of Autologous aMSCs

Liver Cirrhosis

Biological: aMSCs dosage

Sep-15

NCT02338271

Autologous aMSCs Therapy for Intervertebral Disc Degeneration

Low Back Pain

Other: autologous aMSCs

Jan-15

NCT01709279

Clinical Trial of Autologous aMSCs Therapy for Ischemic Heart Failure

Ischemic Heart Failure

Biological: aMSCs dosage

Oct-12

NCT01739504

Autologous aMSCs Delivered Intra-articularly in Patients With Osteoarthritis.

Osteoarthritis

Procedure: Autologous aMSCs harvesting through Liposuction for Intra-articular Injection

Oct-15

NCT02145897

To Evaluate the Safety and Efficacy of IM and IV Administration of Autologous aMSCs for Treatment of CLI

Critical Limb Ischemia

(CLI)

Biological: Autologous Stromal Vascular Fraction (SVF)|Biological: Autologous aMSCs| Other: Control

May-14

NCT01840540

MSC for Occlusive Disease of the Kidney

Atherosclerot-ic Renal Artery Stenosis| Ischemic Nephropathy|Renovascular Hypertension

Drug: Arterial infusion of autologous mesenchymal stem cells

Oct-15

NCT02135380

Evaluate Safety and Efficacy of Intravenous Autologous aMSC for Treatment of Idiopathic Pulmonary Fibrosis

Idiopathic Pulmonary Fibrosis

Biological: Autologous Stromal Vascular Fraction (SVF)|Biological: Autologous aMSCs |Other: Control

May-14

NCT01548092

Stromal Vascular Fraction (SVF) for Treatment of Recto-vaginal Fistula

Recto-vaginal Fistula

Drug: aMSCs without expanded

Mar-12

NCT01771913

Immunophenotyping of Fresh Stromal Vascular Fraction From aMSCs Enriched Fat Grafts

Breast Reconstruction|Contour Irregularities|Volume Insufficiency

Genetic: centrifuged fat graft| Genetic: aMSCs enriched fat graft

Jul-15

NCT01849159

Clinical Study of the Efficacy and Safety of the Application of Allogeneic Mesenchymal (Stromal) Cells of Bone Marrow, Cultured Under the Hypoxia in the Treatment of Patients With Severe Pulmonary Emphysema

Pulmonary Emphysema

Biological: Mesenchymal stem cells|Other: Reference therapy: 400 mL of 0.9% NaCl solution

Oct-15

NCT01532076

Effectiveness of aMSCs as Osteogenic Component in Composite Grafts

Osteoporotic Fractures

Procedure: Cellularized composite graft augmentation|Procedure: Acellular composite graft augmentation

Sep-14

NCT02387723

CSCC_ASC Therapy in Patients With Severe Heart Failure

Clinical Patient Safety of Allogeneic Stem Cell Therapy

Biological: Allogeneic aMSCs (CSCC_ASC)

Mar-15

NCT01730547

Mesenchymal Stem Cells for Multiple Sclerosis

Multiple Sclerosis

Biological: Autologous mesenchymal stem cells

Jan-15

NCT02492490

Effect of SVF-derived MSC in DCD Renal Transplantation

Uremia

Other: SVF-derived MSC transplantations|Drug: Basiliximab

Nov-14

NCT02492308

Induction With SVF Derived MSC in Living-related Kidney Transplantation

Living-relative Kidney Transplantation

Procedure: SVF-MSC induction|Drug: Basiliximab induction

Jul-15

Figure 1. MSCs anti-inflammatory properties

MSCs recruited to the radiation injury site secrete many cytokines and growth factors, e.g. prostaglandin-E2 (PGE2), nitric oxide (NO), hepatocyte growth factor (HGF), interleukin-10 (IL-10), tumor growth factor-beta (TGF-β), and indoleamine 2,3-dioxygenase (IDO). These soluble mediators inhibit the major components of the immune system and inflammation, e.g. dendritic cells, T-cells, B-cells, and natural killer cells (NK cells). The final result will be an increase in the secretion of the anti-inflammatory interleukin-10 (IL-10) together with lowering the availability of the pro-inflammatory mediators and cytokines, e.g. tumor necrosis factor-alpha (TNF-α), interferon-gamma (INF-γ), and interleukin -1-beta (IL-1β) [15].

Figure 2. MSCs radiobiological response

Double stranded DNA (dsDNA) breaks (DSB) resulting from the direct and indirect radiation injury stimulate the phosphorylation of Ataxia Telangectasia Mutated protein (ATM) which is the proximal step for cell cycle check points activation (G2/M arrest). The nuclear apoptotic factor P84 is up regulated, which participates in the apoptotic response of the cells. DSB stimulate the phosphorylation of histone-2AX through the Mre11, RAD50, NBS1 complex and p-ATM with a feedback loop amplification. Phosphorylated histone-2AX (γ-H2AX) stimulated both the homologous recombination repair (HR, active in S and G2 phases only) and the non-homologous end-joining repair (NHEJ, active in all cell cycle phases) of the DSB. Rad-51 is considered one of the mandatory proteins for HR to occur. DNA-PK is the major protein in the NHEJ repair pathway. Both proteins were up regulated in irradiated MSCs. P-ATM and p-DNA-PK activate the cell cycle check point kinases (Chk1 and Chk2) resulting in cyclin/Cdk-mediated G2/M cell cycle arrest by inhibiting the Cell division cycle phosphatase (Cdc25). P-ATM also stabilizes the tumor suppressor regulatory protein and transcription factor P53 which up-regulates the expression and enhances the stabilization of the inhibitory regulatory protein p21, which potently inhibits Cdks needed for the G1/S transition leading to inhibition of the entry into S phase.