Mesenchymal stem cells: biology, pathophysiology, translational findings, and therapeutic implications for cardiac disease

Abstract

Mesenchymal stem cells (MSCs) are a prototypical adult stem cell with capacity for self-renewal and differentiation with a broad tissue distribution. Initially described in bone marrow, MSCs have the capacity to differentiate into mesoderm- and nonmesoderm-derived tissues. The endogenous role for MSCs is maintenance of stem cell niches (classically the hematopoietic), and as such, MSCs participate in organ homeostasis, wound healing, and successful aging. From a therapeutic perspective, and facilitated by the ease of preparation and immunologic privilege, MSCs are emerging as an extremely promising therapeutic agent for tissue regeneration. Studies in animal models of myocardial infarction have demonstrated the ability of transplanted MSCs to engraft and differentiate into cardiomyocytes and vasculature cells, recruit endogenous cardiac stem cells, and secrete a wide array of paracrine factors. Together, these properties can be harnessed to both prevent and reverse remodeling in the ischemically injured ventricle. In proof-of-concept and phase I clinical trials, MSC therapy improved left ventricular function, induced reverse remodeling, and decreased scar size. This article reviews the current understanding of MSC biology, mechanism of action in cardiac repair, translational findings, and early clinical trial data of MSC therapy for cardiac disease.

Figure 1. Delivery and potential effects of MSC therapy in cardiac disease

Figure 2. Isolation of mesenchymal stem cells from a bone marrow biopsy

Many stem cells and maturing cells exist in the bone marrow cavity. The mononuclear cells are isolated from red blood cells using Ficoll density centrifugation and the MSCs are separated from the MNCs by plastic adherence in culture.

Figure 3. MSC interactions with immune cells

MSCs are immunoprivileged cells inhibit both innate (neutrophils, dendritic cells, natural killer cells) and adaptive (T cells and B cells) immune cells.

Figure 4. Molecular regulation of MSC differentiation

Wnt signaling and TGF-β induce intracellular signaling regulate differentiation of MSCs.

Figure 5. Impact of allogeneic MSC therapy on infarct size

DE-MRI images of swine with chronic ischemic cardiomyopathy (A) injected with 200M allogeneic MSCs before and 3 months after therapy showing a 17% reduction in scar size; and (B) a control animal showing no change in scar size (red arrows indicate gadolinium enhanced scar).

Figure 6. Intramyocardial injection of autologous MSCs improves regional contractility

Tagged CMR strain maps (A) before MSC injection showing a lateral infarct (white arrows) with decreased contractility (red) and (B) post-injection showing improved contractility (green/blue). Corresponding DE-CMR 16 segment model of infarct size (A) before MSC injection and (D) 1 year after injection (less transmularity depicted by decreased orange/yellow). (Panels A and B are reproduced from Williams et al. Circ Res. 2011;108:792–796, courtesy of the American Heart Association)