Introduction
Clinical applications of MSCs
MSCs infusion to treat GVHD
Year of publication | Patients (N) | MSC source | MSC dose | outcome |
---|---|---|---|---|
2007 [11] | 6 | haplo-identical family donors (n = 2), unrelated mismatched donors (n = 4) | 1.0x10(6)/kg | Acute GVHD disappeared completely in five of six patients, four of whom are alive after a median follow-up of 40 months (range, 18–90 months) after the initiation of AMSC therapy. All four surviving patients are in good clinical condition and in remission of their hematological malignancy. |
2008 [12] | 55 | HLA-identical sibling donors (n = 5), haploidentical donors (n = 18), third-party HLA-mismatched donors (n = 69). | 1.4x10 (6) (min-max range 0.4-9x10 (6)) cells per kg | 30 patients had a complete response and nine showed improvement. No patients had side-effects during or immediately after infusions of mesenchymal stem cells. Three patients had recurrent malignant disease and one developed de-novo acute myeloid leukaemia of recipient origin. Complete responders had lower transplantation-related mortality 1 year after infusion than did patients with partial or no response |
2008 [13] | 7 | hematopoietic stem cell donors (n = 5), third party parental donor (n = 2) | From 0.4x10(6) to 3.0x10(6) per kg based on availability | One out of three patients showed slight improvement of chronic GVHD. Two patients with severe acute GVHD did not progress to cGVHD. One patient received MSC to stabilize graft function after secondary haploidentical transplantation. One patient recovered from trilineage failure due to severe hemophagocytosis. |
2009[14] | 13 | Unrelated HLA disparate donors | A median dosage of 0.9 x 10(6)/kg (range 0.6-1.1). | Two patients (15%) responded and did not require any further escalation of immunosuppressive therapy. Eleven patients received additional salvage immunosuppressive therapy concomitant to further MSC transfusions, and after 28 days, five of them (45%) showed a response. Four patients (31%) are alive after a median follow-up of 257 days, including one patient who initially responded to MSC treatment. |
2009 [15] | 33 | PBSCT combined with MSCs | From 0.5x10 (5) to 1.7x10(6) per kg | Fifteen patients (45.5%) developed grade I–IV acute GVHD (aGVHD) and only 2 (6.1%) developed grade III to IVaGVHD. Nine (31%) of 29 evaluable patients experienced chronic GVHD (cGVHD). |
2009 [16] | 32 | Unrelated, unmatched donor | 2 or 8 million MSCs/kg in combination with corticosteroids | Ninety-four percent of patients had an initial response (77% complete response and 16% partial response). No infusional toxicities or ectopic tissue formations were reported. |
2010 [17] | 11 | Unrelated HLA disparate donors | Median dose was 1.2 x 10(6)/kg (range: 0.7-3.7 x 10(6)/kg). | Overall response was 71.4%, with complete response in 23.8% of cases. None patients presented GVHD progression upon MSC administration, but 4 patients presented GVHD recurrence 2 to 5 months after infusion. Two patients developed chronic limited GVHD. |
2011 [18] | 12 | premanufactured, universal donor | 8 x 10(6)cells/kg in 2 patients and 2 x 10(6)cells/kg in the rest | 7 (58%) patients had complete response, 2 (17%) partial response, and 3 (25%) mixed response. Complete resolution of GI symptoms occurred in 9 (75%) patients. The cumulative incidence of survival at 100 days from the initiation of therapy was 58%. |
MSCs for cardiovascular repair
Condition | Patients (N) | MSC source | Delivery route | Phase | Study design | ClinicalTrials.gov identifier |
---|---|---|---|---|---|---|
Myocardial Ischemia | 31 | Autologous MSC from bone marrow | intramyocardial injections | Phase I/II | Non-randomized, Single group assignment, Open label | NCT00260338 |
Acute Myocardial Infarction | 80 | Autologous MSC from bone marrow | intracoronary injection | Phase II/ III | Randomized, Parallel assignment, Open Label | NCT01392105 |
Ischemic Heart Disease | 48 | MSC from bone marrow | intracoronary injection | Phase I/II | Non-Randomized, Parallel Assignment, Open label | NCT00135850 |
Heart Failure | 10 | Not mentioned | intramyocardial injections | Phase II | Randomized, Parallel Assignment, Double blind (Subject, Caregiver, Investigator) | NCT00927784 |
MSCs for liver disease
Biological characteristics of MSCs associated with their therapeutic effects
Capacity to migrate and engraft
Differentiation
Secreting multiple bioactive molecules
Bioactive molecules | Functions |
---|---|
prostaglandin-E2 (PGE2) | anti-proliferative mediators [40] |
anti-inflammation [41] | |
Interleukin-10(IL-10) | |
transforming growth | suppress T-lymphocyte proliferation [44] |
factorβ-1(TGFβ1), hepatocyte growth factor(HGF) | |
Interleukin-1 receptor Antagonist | anti-inflammatory [45] |
human leukocyte antigen G isoform (HLA-G5) | anti-proliferative for naive |
T-cells [46] | |
LL-37 | anti-microbial peptide and reduce inflammation [47] |
angiopoietin-1 | restore epithelial protein permeability [48] |
MMP3, MMP9 | mediating neovascularization [49] |
Keratinocyte growth factor | Alveolar epithelial fluid transport [50] |
endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), placental growth factor (PlGF), and monocyte chemoattractant protein-1 (MCP-1) |
Immunomodulatory functions of MSCs
Immune cell type | MSCs’ effects |
---|---|
T lymphocyte | Suppress T cell proliferation induced by cellular or nonspecific mitogenic stimuli [44] |
Alter the cytokine secretion profile of naive and effector T cells [56] | |
Promote the expansion and function of Treg cells [57] | |
B lymphocyte | Inhibit proliferation of B lymphocyte [58] |
Affect the chemotactic properties of B cells [59] | |
Suppress B-cell terminal differentiation [60] | |
NK cell | |
Dendritic cells (DCs) | Influence differentiation, maturation and function of monocyte-derived dendritic cells [63] |
Suppress dendritic cell migration, maturation and antigen presentation [64] | |
Induce mature DCs into a novel Jagged-2-dependent regulatory DC population [65] |