Mesenchymal stem cells: potential for therapy and treatment of chronic non-healing skin wounds

Figures & data

Figure 1. Mesenchymal stem cell therapy: role and function Depending on the microenvironment, MSCs are able to secrete several factors which may exert different functions via the release of different types of molecules involved in angiogenesis, immunomodelation, homing, ECM deposition and remodelling, proliferation, anti-apoptosis, and neuroprotection. ^26-28

Figure 2. SVF features SVF is composed of many mature, progenitor and stem cell types.

Table 1. Studies on preclinical efficacy of MSCs in animal models for autoimmune diseases

Investigators	MSC type	Animal disease model	Major findings after MSC transplantation	Ref.
Choi EW et al, 2012	Human ADSCs	Systemic lupus erythematosus	Significantly higher survival rate with improvement of histologic and serologic abnormalities and immunologic function, and decreased incidence of proteinuria	^103
Choi EW et al, 2015	Human ADSCs	Rheumatoid arthritis	Significantly lower anti-mouse collagen II autoantibody levels, cartilage damage, IL-6 and keratinocyte chemoattractant serum levels	^104
Park MJ et al, 2014	Human ADSCs	Systemic lupus erythematosus	Significantly reduction of ICOS(+)CD44(+) follicular helper T cells, Th1 cells and Th17 cells, increment of Foxp3-expressing regulatory T cells	^105
Gonzalez MA et al, 2009	Human ADSCs	Rheumatoid arthritis	Significantly reduced the incidence and severity of experimental arthritis by down-regulating the 2 deleterious disease components: the Th1-driven autoimmune and inflammatory responses.	^106
Zhou B et al, 2011	Human ADSCs	Rheumatoid arthritis	Prevention and treatment of collagen-induced arthritis by significantly reducing the incidence and severity of experimental arthritis, inhibiting the production of various inflammatory mediators, decreasing antigen-specific Th1/Th17 cell expansion, and inducing the production IL-10.	^107
Serratrice N et al, 2014	Human micro-fat	Systemic Sclerosis (SSc)	Significantly reversed dermal and epidermal sclerosis with a significant increase of the local vascularization	^108
Gonzalez MA et al, 2009	Human ADSCs	Crohn’s disease	Significantly amelioration of the clinical and histopathologic severity of colitis, abrogating body weight loss, diarrhea, and inflammation and increasing survival	^109
Gonzalez-Rey et al, 2009	Human ADSCs	Inflammatory bowel diseases	Down regulation of the Th1-driven inflammatory responses and a wide panel of inflammatory cytokines and chemokines and up-regulation of IL10, acting on macrophages. Protection from severe sepsis by reducing the infiltration of inflammatory cells in various target organs and by down regulating inflammatory mediator production.	^110
Goncalves Fda, C,et al, 2014	Murine ADSCs	Crohn’s disease	Histological evaluation demonstrated decreased colonic inflammation based on reduced crypt loss and reduced infiltration of inflammatory cells with down-regulation of IL-6 and TNF and by the up-regulation of IL-10 and IL-4, IFN, and apoptotic T cells	^111
Zhou Y et al, 2011	Human ADSCs	Autoimmune hearing loss	Significantly improved hearing function and protected hair cells, decreased the proliferation of antigen-specific Th1/Th17 cells and induced the production of IL-10 in splenocytes, and the generation of antigen-specific CD4(+) CD25(+) Foxp3(+) Treg cells with the capacity to suppress autoantigen-specific T-cell responses.	^112
Choi EW et al, 2011	Human ADSCs	Autoimmune thyroiditis	Significantly lower absorbance of thyroglobulin autoantibody; significant decrease in the proportion of CD3+ and CD11b; dramatically decreased of lymphocyte infiltration in the thyroid glands, and of the production of proinflammatory cytokines and down-regulation of Th1 cytokines.	^113
Choi EW et al, 2014	Human ADSCs	Autoimmune thyroiditis	Significantly reduction of canine thyroglobulin autoantibodies in serum and of the infiltration of T-lymphocytes between the follicles of the thyroid glands. significantly increment of FoxP3 expression in submandibular lymph nodes.	^114
Constantin G etal, 2009	Murine ADSCs	Autoimmune encephalomyelitis	Significantly amelioration of the disease course and reduction of both demyelination and axonal loss, and induction of Th2-type cytokine shift in T cells, secretion of bFGF-, BDNF-, PDGF-AB. with increased number of endogenous oligodendrocyte progenitors.	^115
Payne NL et al, 2013	Human ADSCs	Autoimmune encephalomyelitis (EAE)	Significantly reduction in peripheral T-cell proliferative responses, reduction in pro-inflammatory cytokine secretion as well as a preferential inhibition of Th17-mediated neuroinflammation. Inhibition of the phenotypic maturation, cytokine production and antigen presenting capacity of bone marrow-derived myeloid dendritic cells,	^116
Scruggs BA et al, 2013	Human ADSCs	Autoimmune encephalomyelitis	ADSCs from older donors failed to ameliorate the neurodegeneration associated with EAE, and mice treated with older donor cells had increased CNS inflammation, demyelination, and splenocyte proliferation in vitro compared with the mice receiving cells from younger donors. Therefore, donor age significantly affects the ability of human ADSCs to provide neuroprotection, immunomodulation, and/or remyelination in EAE mice.	^117
Yousefi, F et al, 2013	Human ADSCs	Autoimmune encephalomyelitis	Intraperitoneal route showed a more pronounced effect in maintaining the splenic CD4+CD25+FOXP3+ T cell population, increased of IL-4 secretion, decreased IFN-γ secretion and reduced cell infiltration in brain more effectively as compared to the intravenous. route.	^118
Semon JA et al, 2013	Murine SVF and ADSCs	Autoimmune encephalomyelitis (EAE)	Intraperitoneal administration of ADSCs significantly ameliorated the severity of disease course. SVF effectively inhibited disease severity and was statistically more effective than ADSCs. Both cell therapies also demonstrated a reduction in tissue damage, a decrease in inflammatory infiltrates, and a reduction in sera levels of IFN-γ and IL-12.	^119
Zhang X et al, 2014	Murine ADSCs	Autoimmune encephalomyelitis (EAE)	Significantly ameliorate the disease course, autoimmune mediated demyelination and cell infiltration through the regulation of the inflammatory responses, however, mice treated with autologous ADSCs showed no therapeutic improvement on the disease progression.	^120
Tafreshi AP et al, 2014	Murine ADSCs	Autoimmune encephalomyelitis (EAE)	Glycogen synthase kinase 3β (GSK3β) was absent in radial astrocytes and significantly lower in neurons of EAE animals. The loss of phosphorylated GSK3β in radial glia and neurons in EAE spinal cords was concurrent with radial glia migration and astrogliosis. This disturbance in the expression of inactive GSK3β was recovered in neurons, but not in the radial glia, after treatment of EAE mice with ADSCs capable of inducing a Th2 shift.	^121
Semon JA et al, 2014	Human ADSCs and BM-MSCs	Autoimmune encephalomyelitis (EAE)	Intraperitoneal administration of all cell types significantly ameliorates the severity of disease. SVF was as effective as the more commonly cultured BMSCs and ADSCs. All cell therapies demonstrated a similar reduction in tissue damage, inflammatory infiltrates, and sera levels of IFNγ and IL-12, with the latter significantly lower in SVF-treated than BMSC-treated or ASC-treated mice.	^122
Bassi EJ et al, 2012	Human ADSCs	Autoimmune diabetes	Down regulation of the CD4(+) Th1-biased immune response and expansion of regulatory T cells (Treg) in the pancreatic lymph nodes. Within the pancreas, inflammatory cell infiltration and IFN-γ levels were reduced, while insulin, pancreatic duodenal homeobox-1, and active TGF-β1 expression were increased.	^123
Xiao J et al, 2012	Human ADSCs	Immune thrombocytopenia (ITP)	Significantly increment of platelets level in the ITP mice. In the ADSC group, IFN-γ, IL-2, and IL-17 significantly decreased, while IL-4, IL-10, and TGF-β1 increased.	^124

Table 2. clinical studies from clinicaltrials.gov as of 20 November 2015

	Study	Condition	Status	Location	Phase	Identification number
1	Adipose Derived Regenerative Cellular Therapy of Chronic Wounds	Diabetic Foot; Venous Ulcer; Pressure Ulcer	Rank	Tower Outpatient Surgical Center, Los Angeles, California, USA	II	NCT02092870
2	Adipose-Derived Stromal Cells (ASC's) and Pressure Ulcers	Pressure Ulcer	Recruiting	Mayo Clinic in Florida, USA	I	NCT02375802
3	Autologous Adipose-Derived Stromal Cell Delivered Via Intramuscular Injections for the Treatment of Critical Limb Ischemia	Critical Limb Ischemia	Recruiting	Ageless Institute, Miami, Florida, USA	II	NCT02099500
4	Autologous Adipose-derived Stem Cells (ASCs) for the Treatment of Perianal Fistula in Crohn Disease: A Pilot Study	Perianal Fistula; Crohn Disease	Recruiting	Paolo Bertoli, Bergamo, Italy	II	NCT02403232
5	To Evaluate the Safety and Efficacy of IM and IV Administration of Autologous ADMSCs for Treatment of CLI	Critical Limb Ischemia	Recruiting	Kasiak Research Pvt Ltd, Thane, Maharashtra, India	I and II	NCT02145897
6	The Role of Lipoaspirate Injection in the Treatment of Diabetic Lower Extremity Wounds and Venous Stasis Ulcers	Diabetic Wounds Venous Stasis Wounds	Unknown ^†	Veterans Affairs Medical Center, Washington D.C, District of Columbia, USA	I	NCT00815217
7	Treatment of Hypertensive Leg Ulcer by Adipose Tissue Grafting	Skin Ulcer	Recruiting	University Hospital, Caen, France	I	NCT01932021
8	Feasibility Study of the TGI Adipose-derived Stromal Cell (ASC)-Coated ePTFE Vascular Graft	Lower Limb Ischemia	Active, not recruiting	University of Lousville Hospital, Kentucky, USA	I and II	NCT01305863
9	Safety of ALLO-ASC-DFU in the Patients With Diabetic Foot Ulcers	Diabetic Foot Ulcer	Completed	Asan Medical Center Seoul, Republic of Korea	I	NCT02394886
10	A Study to Evaluate the Safety of ALLO-ASC-DFU in the Subjects With Deep Second-degree Burn Wound	Burn	Recruiting	Hallym university Medical Center, Seoul, Republic of Korea	I	NCT02394873

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