Mesenchymal Stem Cells for Cardiac Therapy: Practical Challenges and Potential Mechanisms

Abstract

Cell based treatments for myocardial infarction have demonstrated efficacy in the laboratory and in phase I clinical trials, but the understanding of such therapies remains incomplete. Mesenchymal stem cells (MSCs) are classically defined as maintaining the ability to generate mesenchyme-derived cell types, namely adipocytes, chondrocytes and osteocytes. Recent evidence suggests these cells may in fact harbor much greater potency than originally realized, as several groups have found that MSCs can form cardiac lineage cells in vitro. Additionally, experimental coculture of MSCs with cardiomyocytes appears to improve contractile function of the latter. Bolstered by such findings, several clinical trials have begun to test MSC transplantation for improving post-infarct cardiac function in human patients. The results of these trials have been mixed, underscoring the need to develop a deeper understanding of the underlying stem cell biology. To help synthesize the breadth of studies on the topic, this paper discusses current challenges in the field of MSC cellular therapies for cardiac repair, including methods of cell delivery and the identification of molecular markers that accurately specify the therapeutically relevant mesenchymal cell types. The various possible mechanisms of MSC mediated cardiac improvement, including somatic reprogramming, transdifferentiation, paracrine signaling, and direct electrophysiological coupling are also reviewed. Finally, we consider the traditional cell culture microenvironment, and the promise of cardiac tissue engineering to provide biomimetic in vitro model systems to more faithfully investigate MSC biology, helping to safely and effectively translate exciting discoveries in the laboratory to meaningful therapies in the clinic.

Allogenicity of Human Cardiac Stem/Progenitor Cells Orchestrated by Programmed Death Ligand 1

“…Although animal studies clearly indicated that the engraftment and differentiation specify the regenerative mechanism, 35,36 the paracrine effect is today also recognized as part of the overall regenerative process. 2,[37][38][39][40][41][42] In this context, our present study underscores the capacity of allogeneic hCPC to elicit Treg response as an indirect paracrine effect that would promote cardiac repair and suggests that the presumed functional benefit of allogeneic CPC could be also linked to their inherent immune properties. This notion is reinforced by our results showing that in allogeneic settings hCPC can inhibit an ongoing inflammatory T-cell response.…”

Mesenchymal stem cells: Potential role in corneal wound repair and transplantation

“…Despite corneal transplantation is the most successful solid organ transplantation, immune rejection is still the major cause of graft failure. Over the last decade, mesenchymal stem cell (MSC) therapy has been proposed and used as a possible treatment strategy for cardiovascular diseases, renal wound repair, diabetes, systemic lupus erythematosus, and solid organ transplantation [4][5][6][7] . MSCs are a promising stem cell population because of their self-renewal, pluripotential capability, low immunogenicity properties, and notable immunomodulatory and anti-inflammatory activities [8] .…”

Selective Isolation of Nanog-Positive Human Amniotic Mesenchymal Cells and Differentiation into Cardiomyocytes

“…The MSC population offers an exciting possibility for cellular-based therapies due to their unique attributes of multipotency and presence in the adult. Although recent findings of MSC-mediated cardiac repair are very encouraging, the understanding of MSC biology remains incomplete, partly reflecting limitations of available in vitro culture systems (Cashman et al, 2012). Each cell type has its own advantages, but there are still numerous issues to consider, such as cell number, ability to differentiation, immune rejection, teratoma formation, and ethical issues (Gnecchi et al, 2012).…”