Mesenchymal Stem Cell-Based Therapy for Cardiovascular Disease: Progress and Challenges

Abstract

Administration of mesenchymal stem cells (MSCs) to diseased hearts improves cardiac function and reduces scar size. These effects occur via the stimulation of endogenous repair mechanisms, including regulation of immune responses, tissue perfusion, inhibition of fibrosis, and proliferation of resident cardiac cells, although rare events of transdifferentiation into cardiomyocytes and vascular components are also described in animal models. While these improvements demonstrate the potential of stem cell therapy, the goal of full cardiac recovery has yet to be realized in either preclinical or clinical studies. To reach this goal, novel cell-based therapeutic approaches are needed. Ongoing studies include cell combinations, incorporation of MSCs into biomaterials, or pre-conditioning or genetic manipulation of MSCs to boost their release of paracrine factors, such as exosomes, growth factors, microRNAs, etc. All of these approaches can augment therapeutic efficacy. Further study of the optimal route of administration, the correct dose, the best cell population(s), and timing for treatment are parameters that still need to be addressed in order to achieve the goal of complete cardiac regeneration. Despite significant progress, many challenges remain.

Keywords: cardiovascular disease; mesenchymal stem cell; regenerative medicine.

Graphical abstract

Figure 1

Cell Combination Therapy (MSC + CSC) Reduces Scar Size and Promotes Mitosis of Endogenous Cells in a Swine Chronic Myocardial Infarction Model Delayed enhancement cardiac magnetic resonance short-axis representative images showing and quantifying the chronologic change of scar size in placebo and combination cell treatment groups pre- and post-transendocardial stem cell injection (TESI), from both allogeneic (A) and autologous (C) studies in swine MI. Graphs show that change in scar mass, as a percentage of left ventricular (LV) mass, decreased significantly following TESI of allogenic and autologous cell combination and mesenchymal stem cell therapies compared to placebo or cardiac stem cell therapy alone. *p < 0.05 within group, **p < 0.001 MSC + CSC versus placebo at all time points post-TESI, ***p < 0.0001 MSC + CSC or MSC versus placebo at all time points post-TESI, ^Ϯp < 0.05 MSC versus placebo at all time points post-TESI. MSC, mesenchymal stem cell; CSC, ckit⁺ cardiac stem cell. (B and D) Representative confocal microscopy images showing mitosis of cardiomyocytes in response to allogeneic (B) or autologous (D) combination stem cell treatment, using the mitosis-specific marker phospho-histone H3 (PHH3). Graphs represent PHH3 cardiomyocytes/slide in the remote (allogeneic) and border (autologous) zones. *p < 0.05 MSC + CSC versus placebo. Adapted from Natsumeda et al. (allogeneic cell study) and Karantalis et al. (autologous cell study).

Figure 2

MSCs Are a Particularly Attractive Cellular Platform for Cell-Based Cardiac Regenerative Medicine MSCs can be isolated from virtually all tissues, including bone marrow, adipose tissue, umbilical cord, and the heart itself, or they can be generated from pluripotent stem cells. Ongoing research, examining the relationship of MSCs to heart development and repair, will guide the development of more refined strategies, such as isolating bona fide cardiac MSC lineages, generating genetically engineered MSCs with better defined growth factor and exosome secretomes, and optimizing combination strategies of MSCs with cardiac progenitor cells and/or biomaterials more relevant to cardiac organogenesis. Translation of this research should address the most important clinical concerns, including feasibility, safety, and efficacy of utilizing MSCs as the basis for cell-based and novel cell-free, autologous and/or allogeneic regenerative medicine approaches. These approaches are designed to safely and effectively augment MSC repair of the damaged heart by delivering microvesicles/exosomes and growth factors and by cell-cell coupling that together activate anti-inflammatory and antifibrotic pathways and stimulate the proliferation of endogenous cardiac precursors, cardiomyocytes, and coronary vascular cells.