TABLE 2.
A list of clinical trials using regenerative medicine applications. Each trial is identified by disease reference, patient gender, method of treatment, outcome, and International Society for Cellular Therapy Criteria Check (1, 2, 3). 1) MSC must be plastic-adherent when maintained in standard culture conditions. 2) MSC must express CD105, CD73 and CD90, and lack expression of CD45, CD34, CD14 or CD11b, CD79alpha or CD19 and HLA-DR surface molecules. 3) MSC must differentiate to osteoblasts, adipocytes and chondroblasts in vitro. Most clinical trials using MSC appeared to have the 1st and 2nd criteria mentioned, and a large difference was noted between the trials regarding cell number, type, from of transplantation, and culture conditions. Such variation allows for the identification of different forms of effect per experimental group but shows little consistency in the trials performed. Thus, it would be beneficial if clinical trials followed a clearer guideline with minor changes per experimental group to understand better the applicability and efficacy of cellular and tissue engineered therapies.
| Diseases reference | Patients male/Female | Treatment | Outcomes | International society for cellular therapy criteria check (1,2, 3) |
|---|---|---|---|---|
| Atherosclerotic renovascular disease (Saad et al. (2017)) | n = 14 (9/5) | Investigational new drug (IND) #15082 and intra-arterial injection of low dose (1.0 × 105 cells/kg) or higher dose (2.5 × 105 cells/kg) autologous adipose-derived MSCs | No side effects. Stimulated angiogenesis and modified immune function. Increased renal tissue oxygenation and cortical blood flow | 1) Plastic-adherent, 2) Specific surface antigen (Ag) expression |
| Newly diagnosed Type 1 Diabetes (Ye et al. (2017)) | n = 8 3/5 | Insulin and intravenous injection of autologous hematopoietic stem cell conditioning with cyclophosphamide (200 mg/kg) and rabbit anti-thymocyte globulin (4.5 mg/kg) | Improved residual C-peptide secretion lowered anti-GAD titers and reduced exogenous insulin dosages. Decreased expansion and function of Th1 and Th17 cells | NA: Cells mobilized with cyclophosphamide (2.0 g/m2) and granulocyte colony stimulating factor (10 mg/kg/day), and then collected from peripheral blood by leukapheresis and cryopreserved |
| Systemic sclerosis (Zhang et al. (2017)) | n = 8 3/5 | Plasmapheresis and infusion of 1 × 106 cells/kg allogeneic umbilical cord mesenchymal stem cells | Improved mean modified Rodnan skin score, lung function and computed tomography (CT). Decreased anti-Scl70 autoantibody titer and serum transforming growth factor-β and vascular endothelial growth factor | 1) Plastic-adherent, 2) Specific surface antigen (Ag) expression, and 3) multipotent differentiation potential |
| Steroid-resistant acute graft versus host disease (Bloor et al. (2020)) | n = 15 8/7 | Intravenous infusion of CYP-001 (induced pluripotent stem cells-derived mesenchymal stromal cells) two dose 1 × 106 to108 cells/kg or 2 × 106 to 2 × 108 cells/kg | Safe and well tolerated, no adverse side effects | 1) Plastic-adherent, 2) Specific surface antigen (Ag) expression, and 3) multipotent differentiation potential |
| Symptomatic ischemic heart failure (Bartunek et al. (2017)) | n = 107 males | Endomyocardial infusion with a retention-enhanced catheter of 2.4 × 107 bone marrow mesenchymal stem cells expanded and differentiated to cardiopoietic cells | Safe with neutral results. Future clinical trials should consider patient selection based on disease severity markers | 1) Plastic-adherent, 2) Specific surface antigen (Ag) expression |
| Nonischemic Cardiomyopathy (Butler et al. (2017)) | n = 22 males | Intravenous infusion of ischemia-tolerant human donor allogeneic bone marrow MSCs dosed at 1.5 ×106 cells/kg | Safe, caused immunomodulatory effects, and was associated with improvements in health status and functional capacity | 1) Plastic-adherent, 2) Some specific surface antigen (Ag) expression |
| Ischemic cardiomyopathy (Florea et al., 2017) | n = 30 27/3 | Transendocardial injection of 2 × 107 or 1 × 108 allogeneic bone marrow-derived human mesenchymal stem cells | Both cell doses reduced scar size, only the 1 × 108 dose increased ejection fraction. Optimal dose and delivery crucial for beneficial results | 1) Plastic-adherent |
| Chronic kidney disease (Nassar et al. (2016)) | n = 18 9/9 | Intravenous and intra-renal arteries injection of 1 × 1010 p/g EVs derived from human cord blood mesenchymal stem cells | Safe and can ameliorate the inflammatory immune reaction and improve the overall kidney function in grade III-IV CKD patients | 1) Plastic-adherent, 2) Some specific surface antigen (Ag) expression |
| Moderate to severe COVID-19 (Meng et al. (2020)) | n = 9 | Three cycles of intravenous infusion of 3 × 107 allogeneic umbilical cord-derived mesenchymal stem cells (manufactured by Vcanbio Cell & Gene Engineering Ltd.) | Safe and well tolerated, reduced IL6 | 1) Plastic-adherent, 2) Specific surface antigen (Ag) expression, and 3) multipotent differentiation potential |
| Severe COVID-19 (Shu et al. (2020)) | n = 12 8/4 | Intravenous administration 2 × 106 cells/kg allogeneic umbilical cord-derived mesenchymal stem cells (manufactured by The Jiangsu Cell Tech Medical Research Institute and The Jiangsu Cell Tech Biotechnology Co.) | No adverse reactions, C-reactive protein and IL-6 levels were significantly decreased, lymphocyte count returned to normal range and observed reduced lung inflammation | 1) Plastic-adherent, 2) Specific surface antigen (Ag) expression |
| Severe COVID-19 (Shi et al. (2021)) | n = 65 | Infusion of three doses of 4 × 107 umbilical cord-mesenchymal stem cells (by VCANBIO Cell & Gene Engineering Corp, Tianjin, China) | Safe and showed improvement in whole lung lesion volume | 1) Plastic-adherent, 2) Specific surface antigen (Ag) expression, and 3) multipotent differentiation potential |
| COVID-19-induced acute respiratory distress syndrome (Hashemian et al. (2021)) | n = 11 8/3 | Three intravenous infusions 2 × 108 cells umbilical cord MSCs (UC-MSCs; 6 cases) or placental MSCs (PL-MSCs; 5 cases) | Improved respiratory distress and reduce inflammatory biomarkers in some. Patients with sepsis or multiorgan failure poor candidates | 1) Plastic-adherent, 2) Specific surface antigen (Ag) expression |
| COVID-19-induced pneumonia (Liang et al. (2020)) | n = 1 female | Three intravenous infusions of 5 × 107 umbilical cord mesenchymal stem cells with thymosin α1 and antibiotics daily injection | Safe and well tolerated, showed remission of inflammation symptom | 1) Plastic-adherent, 2) Specific surface antigen (Ag) expression, and 3) multipotent differentiation potential |
| Severe COVID-19-induced pneumonia (Leng et al. (2020)) | n = 7 4/3 | Intravenous drip of 1 × 106 cells/kg mesenchymal stem cells suspended in 100 ml of saline | Safe and well tolerated, reduced inflammatory response, promoted tissue repair and regeneration | NA: No information classified as clinical grade MSCs |
| Severe COVID-19 (Sengupta et al. (2020)) | n = 27 17/10 | Intravenous drip of 15 ml of exosomes (ExoFlo™) derived from allogeneic bone marrow mesenchymal stem cells | Safe and well tolerated, restored oxygenation, downregulated cytokine storm, and reconstituted immunity | NA |
| COVID-19 pulmonary fibrosis (Wu et al. (2020)) | n = 27 19/8 | 1 or 2 or 3 intravenous transfusion of 3 × 106 cells/kg embryonic stem cell–derived immunity- and matrix-regulatory cells | Safe and well tolerated, with improved clinical symptoms and reduced pulmonary fibrosis | NA |
| Nonacute stroke ischemic or hemorrhagic (Chernykh et al. (2016)) | n = 13 12/1 | Intrathecally injection of 2.19 × 107 macrophage type 2 generated from autologous peripheral blood mononuclear cells in 2 ml of saline | Safe and improved neurological recovery possibly by immunomodulatory activity | NA |
| Living donor kidney transplant recipients (Mathew et al. (2018)) | n = 9 6/3 | Infusion of 0.5, 1, or 5 × 109 CD4+CD25+ Tregs isolated from patient’s cryopreserved leukopheresis and expanded in vitro | Safe and showed no adverse infusion related side effects, infections or rejection events up to 2 years post-transplant | NA |
| Urethral stricture recurrences urethroplasty (Ram-Liebig et al. (2017)) | n = 99 male | Tissue-engineered oral mucosa graft generated from oral mucosa biopsy and manufactured by MukoCell® | Safe and efficient in urethroplasty | NA |
| Chronic nonhealing venous leg ulcers (Stone et al. (2017)) | n = 15 13/2 | FDA-approved bilayered living cell construct consists of human foreskin-derived neonatal fibroblasts in a bovine type I collagen matrix below a layer of human foreskin-derived neonatal epidermal keratinocytes | Safe and well tolerated, changed inflammation to acute healing process | NA |
| Chronic myocardial scar (Bayes-Genis et al. (2016)) | n = 5 | Autologous pericardial adipose graft (adipose tissue taken from the left or the right side of the pericardium) | Safe procedure that may be efficacious in selected patients | NA |
| Severe ischemic left ventricular dysfunction (Menasche et al. (2018)) | n = 6 5/1 | Embryonic stem cell differentiated toward cardiovascular lineage than mixed with fibrinogen and thrombin to form a gel | Safe and showed low risk in short- and medium-term adverse events | NA |
| Chronic non-ischemic dilated cardiomyopathy (Hare et al. (2017)) | n = 34 24/10 | Transendocardial injection in ten left ventricular sites by NOGA Catheter of 1 × 108 allogeneic or autologous bone marrow-derived mesenchymal stem cells | Allogeneic MSCs safe and efficacious alternative to autologous MSCs. Therapeutic effects driven by immunomodulation and endothelial restoration | 1) Plastic-adherent |
| Type 2 Diabetes Mellitus (Bhansali et al. (2017)) | n = 20 15/5 | Superior pancreatico-duodenal artery injection of 1 × 106 cells/kg of in vitro expanded autologous bone marrow-derived mesenchymal stem cells or 1 × 109 autologous bone marrow- derived mononuclear cells (separated by centrifugation) | Both cell types resulted in sustained reduction in insulin doses. MSC showed better improvement in insulin sensitivity while MNC showed an increase in C-peptide response | 1) Plastic-adherent, 2) Specific surface antigen (Ag) expression |
| Dilated cardiomyopathy (Xiao et al. (2017)) | n = 33 21/12 | Intracoronary administration of (5.1 ± 2.0) × 108 bone marrow mononuclear cells or (4.9 ± 1.7) × 108 mesenchymal stem cells | Safe and both show comparable effectiveness. BMSC showed further improvements at 12-month but not BMMC. | 1) Plastic-adherent, 2) Specific surface antigen (Ag) expression |
| Autosomal dominant polycystic kidney disease (Makhlough et al. (2017)) | n = 6 3/3 | Infusion through the cubital vein of 2 × 106 cells/kg autologous cultured bone marrow mesenchymal stromal cells | Safe and well tolerated | 1) Plastic-adherent, 2) Specific surface antigen (Ag) expression |
| Alcoholic hepatitis (Lanthier et al. (2017)) | n = 28 14/14 | Hepatic artery infusion of 0.47 ± 0.15 × 108 cells/kg bone marrow derived CD34+ stem cells and mesenchymal stem cells | No clinical efficacy detected | NA: cells mobilized with 5-day course of lenograstim and centrifuged over a Ficoll-Hypaque plus gradient |
| End-stage liver disease (Rajaram et al. (2017)) | n = 1 male | Two intrahepatic arterial infusion of 1.2 × 106 autologous bone marrow derived mesenchymal stem cells expanded in vitro | Safe with only short-term clinical benefit | 1) Plastic-adherent, 2) Some specific surface antigen (Ag) expression |
| Decompensated liver cirrhosis (Kim et al. (2017)) | n = 19 9/10 | Peripheral vein infusion of 1 × 108/kg bone marrow mononuclear cells | Short term improvement of liver function and volume. High incidence of hepatocellular carcinoma | NA |