**4.4. Cutaneous wounds**

sclerosis, bone marrow-derived MSCs were also found to reduce inflammatory MRI parameters, supporting their anti-inflammatory and immunomodulatory properties [187]. Moreover, autologous and allogeneic MSC therapy showed evidence of benefit in other autoimmune disorders such as refractory Crohn's disease [188–191] and systemic lupus erythematosus [14, 192, 193], respectively. Although there are no clinical trial results in patients with rheumatoid arthritis (clinical trials are ongoing; NCT01851070), in vitro studies show that allogeneic MSCs or MSCdifferentiated chondrocytes inhibit the proliferation and activation of collagen type II-stimulated T-cells and the secretion of proinflammatory cytokines, including IFN-gamma and TNF-alpha by CD4+ and CD8+ T cells, while increasing the secretion of IL-10 and restoring the secretion of IL-4 [194, 195]. These results suggest that the immunomodulatory and anti-inflammatory effects of MSCs offers an effective therapeutic modality for arthritic diseases [195], and several clinical

Transplanted MSCs exert a protective effect in type 1 diabetes mellitus [196]. MSCs localize to the pancreas after intravenous transplantation and lower blood sugar levels [197], similar to MSCs isolated from the Wharton's jelly of the umbilical cord, which differentiated into mature islet-like cell clusters and possessed insulin-producing ability in vitro and in vivo [198]. Transplanted MSCs lower blood sugar through secretion of trophic cytokines that promote endogenous pancreatic stem cells in the ductal epithelium to differentiate into new ß-cells and directly differentiate into functionally competent, new ß-cells [199]. Furthermore, MSCs produce a variety of cytokines and growth factors, which could promote survival of surrounding cells and improve the microenvironment of pancreas [200]. Based on these findings, clinical trials have been initiated to test safety and therapeutic efficacy. A pilot, randomized, controlled, and open-label trial investigated the potential benefits on metabolic control and safety of combined umbilical cord-derived MSCs and autologous bone marrow mononuclear cell transplantation without immunotherapy in patients with established type 1 diabetes [201]. The treatment was not only well tolerated, but at 1 year, metabolic measures, including hemoglobin A1C, fasting glycemia, and daily insulin requirements, improved in the treated patients, whereas it decreased in control subjects. In another clinical study, treatment with a single intravenous infusion of autologous MSCs was tested in new-onset type 1 diabetic patients and found to be safe and to show benefit in slowing disease progression and

A recent randomized, double-blinded, placebo-controlled study demonstrated the safety of systemic administration of allogeneic MSCs in patients with moderate to severe chronic obstructive pulmonary disease (COPD) [15], however, there were no differences in the frequency of COPD exacerbations, pulmonary function tests, or quality of life after 2 years of follow up. A significant decrease in levels of circulating C-reactive protein (CRP) was observed in MSC-treated patients who had elevated CRP levels at study entry, suggesting a beneficial

Idiopathic Pulmonary Fibrosis (IPF) is a lung disease characterized by progressive interstitial fibrosis leading to hypoxemic respiratory failure for which no effective treatment exists [203]. Histologically, there is evidence of alveolar epithelial cell injury, interstitial inflammation,

trials are ongoing evaluating bone marrow, adipose, and UC-derived MSCs.

160 Stromal Cells - Structure, Function, and Therapeutic Implications

preserving β-cell function [202].

effect of MSC infusion on systemic inflammation [15].

**4.3. Pulmonary diseases**

Chronic, non-healing cutaneous wounds are a major cause of morbidity. The ability of MSCs to differentiate into various cell types and their capacity to secrete factors important in accelerating wound healing have made cell therapy a promising strategy for tissue repair and regeneration [24, 205]. Although both autologous and allogeneic MSCs appear to be well suited as wound healing therapies, allogeneic MSCs derived from young healthy donors may have an advantage over autologous sources where age and systemic comorbidities, such as diabetes, chronic renal failure, and arterial or venous insufficiency, are a contributing factor. The effects of aging and systemic illness on MSCs include impaired cell migration, reduced growth factor production, and poor tissue remodeling [24]. A study evaluated MSCs and fibroblasts derived from normal donors and chronic wound patients to characterize the induction of mobilization when these cells are mixed as well as examine the effect of soluble factors on fibroblast migration [206]. These studies showed that MSCs participate in skin wound closure by affecting dermal fibroblast migration in a dose-dependent manner, but impairments were noted in chronic wound patient fibroblasts and MSCs as compared with those derived from normal donors. These results support the notion that allogeneic MSCs from "healthy" donors provide greater efficacy for wound healing compared to autologous MSCs. Such promising findings have supported the use of MSCs in animal models of burn wound healing [207–209]. Consequently, a clinical trial entitled "Stem Cell Therapy to Improve Burn Wound Healing" (NCT02104713) is currently underway and is examining the efficacy of allogeneic MSCs in burn wound closure for patients with a 2nd degree burn wounds of less than 20% total body surface area.
