We found that allogeneic MSCs restored endothelial function

We found that allogeneic MSCs restored endothelial function in patients to a degree greatly exceeding that of autologous MSCs. One possible explanation for this may be the age of the cells. Recent studies highlight that MSC\'s therapeutic function declines as a result of aging (Efimenko et al., 2013; Asumda, 2013). Efimenko et al. showed that adipose-derived MSCs from aged patients with coronary artery disease have impaired angiogenic potential (Efimenko et al., 2013). Similarly, Kasper et al. demonstrated that MSC function is altered and diminished with age, specifically showing lower mek inhibitors turnover and therefore decreased motility, decreased antioxidant power, decreased responsiveness to chemical and mechanical signaling, and increased senescence (Kasper et al., 2009). Stolzing et al. also reported a decline in “fitness” as a result of aging, as evidenced by a decline in colony-forming unit-fibroblasts and increase in reactive oxygen species levels and oxidative stress (Stolzing et al., 2008). In our study, all allogeneic stem cell donors were healthy, young donors between the ages of 20 and 35. Patients receiving their own stem cells not only had underlying chronic diseases, but also were older (between the ages of 45 and 75). MSC aging may impair the survival, differentiation, and ability to recruit EPCs to areas of damage, ultimately reducing their therapeutic efficacy (Asumda, 2013). Additionally, due to underlying patient comorbidities, the autologous MSC microenvironment may be negatively altered due to systematic inflammation. Consistent with this notion, Teraa et al. showed that systemic inflammation affects the bone marrow microenvironment, disturbing EPC function (Teraa et al., 2013). Although more studies are necessary to validate that the advantage evident here is due to the health and age of MSCs, this study supports the encouraging idea of using “off the shelf” allogeneic MSCs over autologous MSCs. In this study, we report positive systemic effects from local, cardiac transendocardial MSC injections. We have previously shown that MSC engraftment after intramyocardial injection is approximately 10 to 20%, suggesting that these cells migrate and circulate systemically (Quevedo et al., 2009). MSCs are known to secrete anti-inflammatory factors and cytokines (such as IL-2, TGF-β1, hepatocyte growth factor, NO, prostaglandin 2, and stromal cell derived factor-1), which can modulate the mobilization of EPCs from bone marrow (Williams and Hare, 2011; Iyer and Rojas, 2008). Additionally, MSCs have been shown to secrete paracrine factors that stimulate resident cells (Williams and Hare, 2011). Thus, we propose a potential mechanism whereby allogeneic MSCs injected into cardiac tissue respond to local microenvironment cues, thereby secreting anti-inflammatory and EPC mobilizing factors that ultimately improve endothelial function alleviating cardiac stress.
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