Cell therapy with bone marrow cells for myocardial regeneration

Abstract

Cell therapy has tremendous potential for the damaged heart, which has limited self-renewing capability. Bone marrow (BM) cells are attractive for cell therapy, as they contain diverse stem and progenitor cell populations that can give rise to various cell types, including cardiomyocytes, endothelial cells, and smooth muscle cells. Studies have shown BM cells to be safe and efficacious in the treatment of myocardial infarction. Possible therapeutic mechanisms mediated by both host and transplanted cells include cardiomyogenesis, neovascularization, and attenuation of adverse remodeling. In this review, different stem and progenitor cells in the bone marrow and their application in cell therapy are reviewed, and evidence for their therapeutic mechanisms is discussed.

FIG. 1.

A method to distinguish differentiation from fusion in coculture system. DiI-labeled bone marrow–derived multipotent stem cells (BMSCs) and carboxyfluorescein diacetate succinimidyl ester (CFDA-SE)-labeled neonatal rat cardiomyocytes (CFDA-SE-NRCM) are cocultured under direct contact and stained with cardiac troponin I (cTnI) to identify cardiomyocytes. Cells double-positive for DiI and cTnI are regarded to differentiate into cardiomyocytes without fusion, and those triple-positive for DiI, cTnI, and CFDA-SE are fused BMSCs with cardiomyocytes. D, differentiation; F, fusion. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article at www.liebertonline.com/ars).

FIG. 2.

Methods to determine cell fusion or transdifferentiation from BM cells. (A) Bone marrow (BM) cells are isolated from mice with constitutive Cre recombinase (Cre) and green fluorescent protein (GFP) protein expression and transplanted into lethally irradiated mice in which a stop cassette is floxed before the β-galactosidase (LacZ) reporter gene. Fused cells express LacZ via Cre-mediated recombination of floxed stop cassette and also express GFP, whereas transdifferentiated cells express only GFP. Donor cells express only GFP, whereas recipient cells express neither GFP nor LacZ. (B) BM cells are isolated from mice with constitutive GFP expression and transplanted into lethally irradiated mice with constitutive LacZ expression. Fused cells express both GFP and LacZ, and true transdifferentiation cells express only GFP. Donor cells express only GFP, and recipient cells express only LacZ. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article at www.liebertonline.com/ars).

FIG. 3.

The sustained upregulation of the humoral factors in ischemic myocardium after cell transplantation is attributable to host cells. To determine whether the upregulated cytokines after cell transplantation into infarcted myocardium were derived from injected donor cells or recipient host cells, human EPCs were transplanted into immunocompromised nude mice, and the levels of cytokines were measured by both human- and mouse-specific primers and probes for each cytokine, such as VEGF or FGF-2. The expression levels of cytokines from human EPCs (donor cells) were at their highest levels at day 1 and decreased to an undetectable range within 7 days. Most of the mouse (host)-specific cytokine levels continued to increase after day 1 and were maintained at higher than the baseline levels over a 14-day period (n = 5 per each time point). Individual values were normalized to GAPDH and shown as fold difference from the values at day 1. VEGF-A, vascular endothelial growth factor-A; FGF-2, fibroblast growth factor-2; Ang-1, angiopoietin-1; Ang-2, angiopoietin-2; PlGF; placental growth factor; HGF, hepatocyte growth factor; IGF-1, insulin-like growth factor-1; PDGF-B, platelet-derived growth factor, B polypeptide; SDF-1, stromal cell–derived factor-1. Originally published in Journal of Experimental Medicine (DOI: 10.1084/JEM20070166; ref. 15). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article at www.liebertonline.com/ars).

FIG. 4.

The role of host cells for sustained paracrine or humoral effects in ischemic myocardium after EPC transplantation. When endothelial progenitor cells (EPCs) are transplanted into ischemic myocardium, the transplanted cells release beneficial biologic factors in the beginning. However, over the 2-week period, the transplanted cells gradually disappeared, and thus the expression level of the factors decreased. In the later phase, the host cells that have been stimulated by the transplanted cells, secrete beneficial cytokines, and maintain the humoral effects >2 weeks. Yellow arrows, the secretion of beneficial cytokines. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article at www.liebertonline.com/ars).

FIG. 5.

BM cell therapy attenuates the adverse remodeling of the heart after myocardial infarction. Myocardial infarction is caused by occlusion of coronary arteries that supply oxygen and nutrients to the myocardium. In myocardial infarction without bone marrow (BM) cell transplantation, the damaged myocardium undergoes adverse remodeling, in which myocardial walls undergo thinning and the cardiac size expands over time, leading to dilative cardiac failure. When BM cells are applied, the ischemic myocardium in the border zone is partly salvaged by multiple cardioprotective effects of BM cells, which mitigate the thinning of infarcted wall and the expansion of the infarcted segment. This eventually attenuates cardiac-chamber dilatation and cardiac dysfunction. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article at www.liebertonline.com/ars).

FIG. 6.

Neovascularization induced by BM cells salvages the endangered cardiac cells in the ischemic area. Myocardial infarction is caused by occlusion of coronary arteries, which supply oxygen and nutrients to the myocardium. The core of the affected area undergoes acute necrosis due to severe deprivation of oxygen and nutrients such as glucose, whereas the surrounding area of the necrotic core has relatively mild, but chronic ischemia. Without cell therapy, progressive loss of the endangered cardiomyocytes of the surrounding area occurs over time. However, when bone marrow (BM) cells are applied to the affected myocardium, the endangered cardiac cells are salvaged from further loss. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article at www.liebertonline.com/ars).

FIG. 7.

Potential multimodal mechanisms underlying the therapeutic effect of BM cells in myocardial damage. After transplantation, the engrafted bone marrow (BM)-derived stem or progenitor cells may undergo differentiation into or fuse with endothelial cells or cardiomyocytes, leading to vasculogenesis or exogenous myogenesis. Moreover, the BM cells can exert humoral effects by secreting various biologic factors, which induce angiogenesis (growth of preexisting vessels), endogenous myogenesis (proliferation of host cardiomyocytes), and prevention of apoptosis of endangered myocardial cells. Furthermore, the engrafted BM cells may serve as cellular scaffolds. These multimodal effects (i.e., neovascularization, myogenesis, prevention of apoptosis, and cellular scaffolding) work together and induce favorable cardiac remodeling and improvement of cardiac function. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article at www.liebertonline.com/ars).