**4.2. Autoimmune diseases**

**4.1. Transplantation**

158 Stromal Cells - Structure, Function, and Therapeutic Implications

Le Blanc *et al.* first reported the clinical immunoregulatory response to MSCs in a case of severe, treatment-resistant grade IV acute graft-vs-host disease (GVHD) [13]. A multicenter phase 2 trials for steroid-resistant, severe acute GVHD confirmed this observation [12] and MSCs obtained from HLA-identical siblings, haploidentical third-party donors, or HLAmismatched third-party donors were similarly effective. Recently, infusion of MSCs the day of hematopoietic cell transplantation (HCT) promotes engraftment and improves outcomes. A pilot study of allogeneic MSC infusion before nonmyeloablative HCT from HLA-mismatched donors showed sustained engraftment in 19 out of 20 patients, and the 1 year incidence of nonrelapse mortality, relapse, overall survival, progression-free survival, and death from GVHD was favorable compared to a historic control group [176]. In another pilot study evaluated the effect of infusion of MSCs at the time of dual transplant of cord blood and third-party donor mobilized hematopoietic stem cells regarding tolerance, cord blood engraftment, and effects on acute GVHD, both preventive and therapeutic [177]. MSC infusions were effective for treating severe acute GVHD, but no significant differences in cord blood engraftment and incidence of severe acute GVHD were observed. Although there is accumulating evidence of safety from these small pilot studies [96], randomized trials are necessary to establish efficacy.

**Figure 8.** Immunomodulatory effects of mesenchymal stem cells. MSCs are immunoprivileged cells that inhibit both

innate (neutrophils, dendritic cells, and natural killer cells) and adaptive (T cells and B cells) immune cells.

Autologous MSC transplantation evaluated in clinical trials of amyotrophic lateral sclerosis [18] and multiple sclerosis [17, 186] is safe and associated with increased proportion of CD4+ CD25+ regulatory T cells, decreased proliferative responses of lymphocytes, and lower expression of costimulatory molecules (CD40+ , CD83+ , and CD86+ ), and HLA-DR on myeloid dendritic cells within 24 hours of transplantation [17]. In a randomized, placebo-controlled, phase 2 trial of multiple 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 trials are ongoing evaluating bone marrow, adipose, and UC-derived MSCs.

fibroblast proliferation, and extracellular matrix collagen deposition. Because MSCs home to sites of injury, inhibit inflammation and contribute to epithelial tissue repair, they offer a potential therapy for IPF [203]. The phase 1 clinical trial entitled allogeneic human mesenchymal stem cells in patients with IPF via intravenous delivery (AETHER) demonstrated the safety of bone marrow-derived MSCs in nine patients with mild to moderate IPF [10]. A 3.0% mean decline in percent predicted forced vital capacity, and 5.4% mean decline in percent predicted diffusing capacity of the lungs for carbon monoxide was observed by 60 weeks

Mesenchymal Stromal Cells as a Therapeutic Intervention

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Of note, a study has provided evidence of a resident c-kit+ multi-potent stem cell in the human lung [204]. These lung c-kit+ stem cells were shown to have the capacity to develop into bronchioles, alveoli, and pulmonary vessels, supporting the notion that they play an important role in lung homeostasis and tissue regeneration after injury. Although the therapeutic implications of these findings have not been investigated, we can infer from findings in ischemic heart disease models that there is the potential for MSCs to stimulate endogenous c-kit+ lung stem cell proliferation and differentiation, thereby facilitating lung tissue repair and regeneration.

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.

MSCs are also considered a promising therapeutic strategy for acute injury and progressive degenerative diseases of the central nervous system [210], such as spinal cord injury [211, 212] ischemic stroke [21, 22, 213, 214] Parkinson's disease [215, 216] traumatic brain injury [217, 218] multiple sclerosis [17, 186, 219, 220] and multiple system atrophy [23]. Studies suggest that the

post-MSC infusion, suggesting potential for efficacy.

**4.4. Cutaneous wounds**

**4.5. Neurological diseases**

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 preserving β-cell function [202].

#### **4.3. Pulmonary diseases**

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 effect of MSC infusion on systemic inflammation [15].

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, fibroblast proliferation, and extracellular matrix collagen deposition. Because MSCs home to sites of injury, inhibit inflammation and contribute to epithelial tissue repair, they offer a potential therapy for IPF [203]. The phase 1 clinical trial entitled allogeneic human mesenchymal stem cells in patients with IPF via intravenous delivery (AETHER) demonstrated the safety of bone marrow-derived MSCs in nine patients with mild to moderate IPF [10]. A 3.0% mean decline in percent predicted forced vital capacity, and 5.4% mean decline in percent predicted diffusing capacity of the lungs for carbon monoxide was observed by 60 weeks post-MSC infusion, suggesting potential for efficacy.

Of note, a study has provided evidence of a resident c-kit+ multi-potent stem cell in the human lung [204]. These lung c-kit+ stem cells were shown to have the capacity to develop into bronchioles, alveoli, and pulmonary vessels, supporting the notion that they play an important role in lung homeostasis and tissue regeneration after injury. Although the therapeutic implications of these findings have not been investigated, we can infer from findings in ischemic heart disease models that there is the potential for MSCs to stimulate endogenous c-kit+ lung stem cell proliferation and differentiation, thereby facilitating lung tissue repair and regeneration.
