Stem cell stimulation of endogenous myocyte regeneration

Abstract

Cell-based therapy has emerged as a promising approach to combat the myocyte loss and cardiac remodelling that characterize the progression of left ventricular dysfunction to heart failure. Several clinical trials conducted over the past decade have shown that a variety of autologous bone-marrow- and peripheral-blood-derived stem and progenitor cell populations can be safely administered to patients with ischaemic heart disease and yield modest improvements in cardiac function. Concurrently, rapid progress has been made at the pre-clinical level to identify novel therapeutic cell populations, delineate the mechanisms underlying cell-mediated cardiac repair and optimize cell-based approaches for clinical use. The following review summarizes the progress that has been made in this rapidly evolving field over the past decade and examines how our current understanding of the mechanisms involved in successful cardiac regeneration should direct future investigation in this area. Particular emphasis is placed on discussion of the general hypothesis that the benefits of cell therapy primarily result from stimulation of endogenous cardiac repair processes that have only recently been identified in the adult mammalian heart, rather than direct differentiation of exogenous cells. Continued scientific investigation in this area will guide the optimization of cell-based approaches for myocardial regeneration, with the ultimate goal of clinical implementation and substantial improvement in our ability to restore cardiac function in ischaemic heart disease patients.

Figure 1. Intracoronary mesenchymal stem cells elicit myocardial regeneration that arises from mobilization of endogenous progenitor cells and stimulation of myocyte proliferation

Autologous bone marrow-derived MSCs (44×10⁶) were administered via intracoronary injection to swine with chronic hibernating myocardium (n=10). Animals were studied either 2-weeks (n=6) or 6-weeks later (n=4) and compared with untreated animals with hibernating myocardium (n=7) or sham-normal animals receiving MSCs (n=6). (A) Myocardial c-kit+ cells were increased two-weeks after MSC treatment and remained elevated six-weeks after injection. In addition, intracoronary MSC administration resulted in persistent elevations in (B) Ki-67⁺ and (C) phospho-histone H3 (pHH3)⁺ myocytes, indicating that cell therapy stimulated myocyte proliferation. (D) Untreated hibernating myocardium was characterized by a reduction in myocyte nuclear density and compensatory myocyte hypertrophy. MSC-treated animals exhibited a progressive increase in myocyte nuclear density and a concomitant reduction in myocyte diameter, consistent with significant myocardial regeneration. (Modified from [60]).

Figure 2. Proposed paradigm of cell therapy-mediated cardiac repair via stimulation of endogenous repair processes

Although the initial application of cell-based therapies for myocardial repair was motivated by the idea that the delivery of exogenous stem and/or progenitor cells could promote myocyte regeneration via direct differentiation to cardiac cells, studies to date suggest that this rarely occurs, if at all. Instead, it appears that cell administration stimulates endogenous cardiac repair processes, possibly via paracrine signaling, direct cell-to-cell interactions, and/or transfer of micro-RNAs that influence the transcriptional activity of host cells. Data from experimental studies in our laboratory indicate that the repair process involves mobilization of c-kit⁺ resident cardiac stem cells in both healthy (sham control) and diseased hearts. However, only animals with viable, dysfunctional (hibernating) myocardium exhibit increased markers of cell cycle activation (such as Ki-67 and phospho-histone H3), indicative of myocyte proliferation. Collectively, the mobilization of endogenous progenitors and stimulation of myocyte cell cycle re-entry result in myocardial regeneration, characterized by an increased density of myocyte nuclei and a reduction in mean myocyte diameter.