**5. Conclusions**

neuroprotective effect of MSCs is mediated by the production of various trophic factors, including brain-derived neurotrophic factors, nerve growth factor, and insulin-like growth factor-1, which contribute to recovering neurobehavioral function and stimulating endogenous regeneration [210, 212, 221]. In addition, MSCs home to injured brain tissues and exert immunoregulatory properties, reduce apoptosis, and improve neuronal cell survival [215, 217, 221]. However,

The anti-fibrotic properties of MSCs may exert therapeutic effects in liver regeneration and disease. MSCs inhibit activated fibrogenic cells such as hepatic stellate cells [222]. Numerous preclinical studies on bone marrow [223–225]. adipose tissue [226], and UC-derived [227] MSC treatment for improvement of liver fibrosis have been conducted and have reported reductions in liver fibrosis as well as improvements in hepatic function. Indeed, MSC based therapies for patients with end-stage liver disease, have shown promise in phaseIand II clinical trials [19, 20, 228]. MSC transplantation was safe and well-tolerated and hepatic function improved in patients with liver fibrosis [20]. Moreover, the biochemical hepatic index and model for end-stage liver disease (MELD) score were markedly improved from 2 to 3 weeks post transplantation [19]. However, the long-term hepatic function was not significantly enhanced in patients with liver failure caused by hepatitis B [19]. Notably, many of these clinical trials differ in MSC source, and liver pathology [229–232] and perhaps certain type of MSCs may serve as better therapeutic options for specific liver pathologies. These early stage studies and more recent clinical trials suggest that MSC transplantation is safe and may confer

benefit to patients with liver cirrhosis and various kinds of liver diseases [233].

Frailty is a medical syndrome that increases in prevalence with age and augments the risk for adverse health outcomes, including mortality, hospitalization, fall, and institutionalization. Markers of frailty include age-associated declines in lean body mass, strength, endurance, balance, walking performance, and activity; and are accompanied by declines in physiologic reserve in most organ systems. Together, these symptoms lead to the loss of homeostasis and the capability to withstand stressors and resulting vulnerabilities. Notably, there is a robust correlation between frailty and biomarkers of inflammation. There is also evidence that endogenous stem cell production decreases with age, likely contributing to reduce ability to regenerate and repair organs and tissues. Therefore, a regenerative treatment strategy could ameliorate signs and symptoms of aging frailty. Currently, there are no approved treatments for frail patients and therefore no established standard of care. There are specific features of the frailty syndrome that support the hypothesis that MSCs will also ameliorate or improve frailty. Indeed, in a pilot study and subsequently in a randomized, double-blind, dose-finding study, we demonstrated safety of intravenous infusion of allogeneic MSCs into elderly, frail individuals and found significant improvements in physical performance measures and inflammatory biomarkers [6, 234–235]. These findings suggest that frailty can ultimately be prevented or attenuated, and the link between

frailty and inflammation offers a potential therapeutic target, addressable by cell therapy

it is unclear if MSCs differentiate into neural cells in vivo [210, 212].

162 Stromal Cells - Structure, Function, and Therapeutic Implications

**4.6. Liver diseases**

**4.7. Aging frailty**

The promising cell-based therapy field has exploded in the past decade and currently, MSCs from various sources, mainly bone marrow and adipose-derived, are being evaluated in phase I and II trials for a myriad of chronic, disabling disorders with no currently effective therapies. Although preclinical studies provide mechanistic insights into therapeutic effects of MSCs and phase I/II studies provide evidence of safety in the short-term, questions regarding most effective dose, route of administration, interaction with other concurrent therapies, sustainability/durability of effect, and adverse effects, including opportunistic infections and tumor development or progression, remain to be resolved. Addressing these questions will require rigorously conducted, multicenter clinical trials with well-defined clinical outcomes, longer duration of follow up, and more patients [151, 236].
