Cell-based therapy for prevention and reversal of myocardial remodeling

Abstract

Although pharmacological and interventional advances have reduced the morbidity and mortality of ischemic heart disease, there is an ongoing need for novel therapeutic strategies that prevent or reverse progressive ventricular remodeling following myocardial infarction, the process that forms the substrate for ventricular failure. The development of cell-based therapy as a strategy to repair or regenerate injured tissue offers extraordinary promise for a powerful anti-remodeling therapy. In this regard, the field of cell therapy has made major advancements in the past decade. Accumulating data from preclinical studies have provided novel insights into stem cell engraftment, differentiation, and interactions with host cellular elements, as well as the effectiveness of various methods of cell delivery and accuracy of diverse imaging modalities to assess therapeutic efficacy. These findings have in turn guided rationally designed translational clinical investigations. Collectively, there is a growing understanding of the parameters that underlie successful cell-based approaches for improving heart structure and function in ischemic and other cardiomyopathies.

Fig. 1.

Ongoing clinical trial activity evaluating cell-based therapy for heart disease. A: topographic representation of ongoing clinical trials currently registered with ClinicalTrials.gov employing stem cell therapy for myocardial infarction (map adapted from ClinicalTrials.gov). B: types of delivery systems. IC, intracoronary infusion; IM, intramyocardial injection; IV, intravenous infusion. C: number of patients enrolled in clinical trials of different phases. BMC, bone marrow-derived stem cells; MSC, mesenchymal stem cells; CSC, cardiac stem cells.

Fig. 2.

Mechanisms of cardiac regeneration. Mammalian myocyte renewal may result from stem cell differentiation and/or myocyte mitosis. These processes are likely linked in that CSCs become mature myocytes by becoming transient amplifying cells, a process enhanced by MSCs. A: Masson's trichrome (Masson's Tri) histological stain obtained from the border zone between infarcted and viable myocardium in the porcine heart. In this image viable new myocytes are shown in red and scarred myocardium in blue. Immunohistochemical analysis for the mitotic marker serine 10 phosphorylated histone H3 (PH3; white nucleus) in B and c-kit (green) in C suggests regeneration of new myocardium from replicating myocytes and adult c-kit⁺ CSCs, respectively. The relative contribution of CSCs or adult dedifferentiation to myocyte entry into the cell cycle is not definitively defined. The spatial and temporal colocalization of c-kit cells and the PH3 myocytes in an animal treated with MSCs is suggestive that the mitotic cells represent transient amplifying cells (61, 94).

Fig. 3.

MSCs stimulate endogenous cardiomyocyte cell (CM) cycling. A and B: quantification of newly formed myocytes of both host (red bar graph, phospho-H3+) and donor (green bar graph, Y chromosome⁺) origin 2- and 8-wk postinjection, respectively. MSCs stimulated host cardiomyocytes to amplify during the first 2 wk following transendocardial injection. The new CMs were mainly distributed at the ischemic zone (IZ) and border zone (BZ) of the treated hearts, indicating active regeneration of injured myocardium. By 8 wk, endogenous cycling CMs levels had returned to normal values. C and D: mitotic features in endogenous CMs from the BZ of an MSC-treated and cell-conditioned media (CCM)-treated heart, respectively. MLC, myosin light chain; DAPI, 4,6-diamidino-2-phenylindole. Values are means ± SE (n = 3 hearts, each). *P < 0.05, †P ≤ 0.005 between groups; ‡P = 0.05 between groups. Reproduced with permission from Hatzistergos et al., Circulation Research, 2010 (61).

Fig. 4.

Mechanisms underlying cardiac regeneration due to cell-based therapy. The improvement in myocardial function and ventricular geometry after transplantation of stem results from multiple coordinated actions of cells used as a therapeutic. Successful cell-base therapy, as observed as a result of MSC and CSC therapy, likely arises from the actions of both administered cells and host cellular elements. Notably, MSCs both have the capacity for trilineage differentiation, as well as stimulating the recruitment, survival, and differentiation of host CSCs. This action of MSCs results from both secretion of cytokines and growth factors [vascular endothelial growth factor (VEGF), stromal-derived factor 1 (SDF1), insulin-growth factor 1 (IGF1), angiopoietin 1] and antifibrotic mediators that together promote neovascularization and reduce fibrosis. Together these actions and the recruitment of endogenous CSCs could represent the reconstitution of stem cell niches in the myocardium.

Fig. 5.

Dose responsiveness of cardiac functional recovery to intramyocardial MSCs. Plots depict peak circumferential shortening (peak Ecc) in the infarct, border, and remote zones. Peak negative Ecc values represent myocardial shortening and increased contractility, whereas increasingly positive values indicate myocardial dysfunction. Ecc improves after cell therapy in both low- and high-dose cell groups in border zones. In contrast, Ecc improves in infarct zones only in the high- and not the low-dose MSC group, consistent with a dose-response effect to MSC therapy in that zone. *P < 0.05 vs. placebo; †P < 0.05 week 12 vs. week 24. Reproduced with permission from Schuleri et al, European Heart Journal, 2009 (146).