Human umbilical cord tissue-derived mesenchymal stromal cells attenuate remodeling after myocardial infarction by proangiogenic, antiapoptotic, and endogenous cell-activation mechanisms

Abstract

IntroductionAmong the plethora of cells under investigation to restore a functional myocardium, mesenchymal stromal cells (MSCs) have been granted considerable interest. However, whereas the beneficial effects of bone marrow MSCs (BM-MSCs) in the context of the diseased heart are widely reported, data are still scarce on MSCs from the umbilical cord matrix (UCM-MSCs). Herein we report on the effect of UCM-MSC transplantation to the infarcted murine heart, seconded by the dissection of the molecular mechanisms at play.MethodsHuman umbilical cord tissue-derived MSCs (UCX®), obtained by using a proprietary technology developed by ECBio, were delivered via intramyocardial injection to C57BL/6 females subjected to permanent ligation of the left descending coronary artery. Moreover, medium produced by cultured UCX® preconditioned under normoxia (CM) or hypoxia (CMH) was collected for subsequent in vitro assays.ResultsEvaluation of the effects upon intramyocardial transplantation shows that UCX® preserved cardiac function and attenuated cardiac remodeling subsequent to myocardial infarction (MI). UCX® further led to increased capillary density and decreased apoptosis in the injured tissue. In vitro, UCX®-conditioned medium displayed (a) proangiogenic activity by promoting the formation of capillary-like structures by human umbilical vein endothelial cells (HUVECs), and (b) antiapoptotic activity in HL-1 cardiomyocytes subjected to hypoxia. Moreover, in adult murine cardiac Sca-1+ progenitor cells (CPCs), conditioned medium enhanced mitogenic activity while activating a gene program characteristic of cardiomyogenic differentiation.ConclusionsUCX® preserve cardiac function after intramyocardial transplantation in a MI murine model. The cardioprotective effects of UCX® were attributed to paracrine mechanisms that appear to enhance angiogenesis, limit the extent of the apoptosis, augment proliferation, and activate a pool of resident CPCs. Overall, these results suggest that UCX® should be considered an alternative cell source when designing new therapeutic approaches to treat MI.

Paracrine Factors Secreted by Umbilical Cord-Derived Mesenchymal Stem Cells Induce Angiogenesis In Vitro by a VEGF-Independent Pathway

“…Kim et al had shown that the transplantation of UCMSCs in patients with Buerger's disease showed improvement in the symptoms along with increase in the number and size of capillaries [36]. Other similar studies have implicated paracrine factors secreted by UCMSCs to be responsible for improved angiogenesis [37,38]. In these reported studies, the paracrine factors responsible for the angiogenic response have not been elucidated.…”

Trimetazidine Protects Umbilical Cord Mesenchymal Stem Cells Against Hypoxia and Serum Deprivation Induced Apoptosis by Activation of Akt

“…Numerous studies have demonstrated that MSC therapy has great promise for regenerating damaged myocardium [15,16]. However, the efficacy of the therapy is limited by the poor viability of MSCs transplanted into the infracted heart [17,18].…”

Sca-1+Cardiac Progenitor Cells and Heart-Making: A Critical Synopsis

“…It is also conceivable that growth factors and cytokines produced by transplanted cells in general might play a role in the proliferation, mobilization, differentiation, and/or survival of endogenous CPCs. We have recently demonstrated that noncardiac Wharton's jelly mesenchymal stem/stromal cells are able to stimulate Sca-1 + CPCs proliferation and to activate a cardiomyogenic program through secreted factors [63]. Comprehensive investigations are also lacking on the ability of Sca-1 + CPCs to modulate their nesting microenvironment.…”