Human Umbilical Cord Perivascular Cells Exhibit Enhanced Cardiomyocyte Reprogramming and Cardiac Function after Experimental Acute Myocardial Infarction

Abstract

We were interested in evaluating the ability of the mesenchymal stromal cell (MSC) population, human umbilical cord perivascular cells (HUCPVCs), to undergo cardiomyocyte reprogramming in an established coculture system with rat embryonic cardiomyocytes. Results were compared with human bone marrow-derived (BM) MSCs. The transcription factors GATA4 and Mef 2c were expressed in HUCPVCs but not BM-MSCs at baseline and, at 7 days, increased 7.6- and 3.5-fold, respectively, compared with BM-MSCs. Although cardiac-specific gene expression increased in both cell types in coculture, upregulation was more significant in HUCPVCs, consistent with Mef 2c-GATA4 synergism. Using a lentivector with eGFP transcribed from the α-myosin heavy chain (α-MHC) promoter, we found that cardiac gene expression was greater in HUCPVCs than BM-MSCs after 14 days coculture (52±17% vs. 29±6%, respectively). A higher frequency of HUCPVCs expressed α-MHC protein compared with BM-MSCs (11.6±0.9% vs. 5.3±0.3%); however, both cell types retained MSC-associated determinants. We also assessed the ability of the MSC types to mediate cardiac regeneration in a NOD/SCID γ mouse model of acute myocardial infarction (AMI). Fourteen days after AMI, cardiac function was significantly better in cell-treated mice compared with control animals and HUCPVCs exhibited greater improvement. Although human cells persisted in the infarct area, the frequency of α-MHC expression was low. Our results indicate that HUCPVCs exhibit a greater degree of cardiomyocyte reprogramming but that differentiation for both cell types is partial. We conclude that HUCPVCs may be preferable to BM-MSCs in the cell therapy of AMI.

Discovering cardiac pericyte biology: From physiopathological mechanisms to potential therapeutic applications in ischemic heart disease

“…In the same year, Yannarelli and colleagues evaluated the reparative ability of human umbilical cord perivascular cells in an immunodeficient mouse model of MI [66]. Similarly to the previous studies, pericytes improved indexes of cardiac contractility; however, no improvement was observable with regard to infarct size in comparison with control mice [66].…”

“…Intramyocardial transplantation of CD146 pos , CD34/CD45/CD56 neg pericytes improved left ventricular function and angiogenesis, while attenuating myocardial fibrosis and the infiltration of inflammatory cells into the site of injury, compared to controls [65]. In the same year, Yannarelli and colleagues evaluated the reparative ability of human umbilical cord perivascular cells in an immunodeficient mouse model of MI [66]. Similarly to the previous studies, pericytes improved indexes of cardiac contractility; however, no improvement was observable with regard to infarct size in comparison with control mice [66].…”

Mesenchymal Stromal Cell Therapy for Respiratory Complications of Extreme Prematurity

“…In addition, accumulating evidence suggests that perinatal-derived MSCs may have superior healing capabilities than the more widely used adult bone marrow MSCs. [21][22][23] Human cord blood and Wharton's jelly derived MSCs demonstrated their therapeutic efficacy in neonatal rodents by preventing oxygen-induced impairment in alveolar and lung vascular growth as well as improving lung function. 24,25 The therapeutic benefit of MSC therapy in the neonatal period persisted up to 6 months with normal lung structure and exercise capacity compared with untreated controls without evidence of tumor formation.…”

Therapeutic Potential of Stem Cells Strategy for Cardiovascular Diseases

“…Umbilical-cord-blood-derived MSCs (UCB-MSCs) are a new xenogeneic stem cell therapy source for CVDs [19]. The newly proposed cell source may be optimum for CVDs because they have a low immunogenicity and a large change of cardiomyocyte reprogramming of UCB-MSCs in comparison with xenogeneic stem cells [19, 69–71]. In addition, UCB-MSCs are easily obtained through low-invasive surgery without raising ethical issues, demonstrating their promising clinical application [19].…”