In vitro and in vivo effects of bone marrow stem cells on cardiac structure and function

Abstract

It is hypothesized that the protection of bone marrow stem cells (BMSCs) on ischemic myocardium might be related to the anti-apoptotic effect via paracrine mechanisms. In this study, a wide array of cytokines including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), stromal cell derived factor-1 (SDF-1) and insulin growth factor-1 (IGF-1) were detected in the BMSCs cultured medium by ELISA. Myocyte apoptosis was assayed by DNA fragmentation and annexin-V staining. Myocardial infarction model was produced by ligation of mouse left anterior descending coronary arteries (LAD). Before LAD ligation, mice were myoablated by irradiation and transplanted with bone marrow cells from transgenic green fluorescent protein (GFP) mice. After LAD ligation, animals were administered stem cell factor (SCF, 200 μg / day / kg, i.p.) or saline for 6 days. Animals were sacrificed on end of SCF treatment and four weeks later. Apoptotic cardiomyocytes were assayed after treatment finished by TUNEL. Myocardial function was analyzed by echocardiography and pressure-volume loop. Bcl-2 protein was analyzed by western blotting. Our results showed that cultured BMSCs released VEGF, bFGF, SDF-1 and IGF-1. Hypoxia induced cell apoptosis was diminished in cardiomyocytes co-cultured with BMSCs. Smaller LV dimension and increased LV ejection fraction were seen in SCF treated animals. SCF significantly reduced cardiomyocytes apoptosis within peri-infarct area and up-regulation expression of Bcl-2 in ischemic area. Moreover, conditioned medium from cultured BMSCs also induced up-regulation of Bcl-2 protein in cardiomyocytes. It is concluded that paracrine mediators secreted by BMSCs might be involved in early repair of ischemic heart by preventing cardiomyocytes apoptosis and improving cardiac function.

Over-expression of CXCR4 on mesenchymal stem cells augments myoangiogenesis in the infarcted myocardium

“…Bone marrow-derived MSCs are multipotent progenitor cells, which are increased in the peripheral circulation [14] and in the myocardium following myocardial infarction [15]. Although MSCs have been shown to participate in myocardial repair, their homing to infarcted area and their survival post transplantation are limited [16].…”

Current Research of the Renin-Angiotensin System Effect on Stem Cell Therapy

“…The supportive efects of vascular VEGF have been recognized in the migration, invasion of extracellular matrix, proliferation, survival of MSCs, and they contribute to MSCs' paracrine efects [64,65]. In this context, all pathways increasing VEGF would give rise to the function of MSCs.…”

The birth of ‘regenerative pharmacology’: a clinical perspective

“…The paracrine hypothesis relating to the mechanism of cell therapy has identified several factors that have therapeutic potential for myocardial repair (see Table 3) (Kinnaird et al, 2004;Xu et al, 2007;Burdon et al, 2011;Ratajczak et al, 2012). The production of what is a predominately cytokine-based catalogue of reparative factors has been demonstrated from several different cell types, suggesting that progenitor/stem cells possess the same basic mechanism that can lead to cardiac repair.…”

“…SDF-1 (stromal cell-derived factor-1) (Askari et al, 2003) Anti-apoptotic, cell migration, pro-angiogenic VEGF (Kamihata et al, 2001;Kinnaird et al, 2004) Pro-angiogenic, anti-apoptotic, cell proliferation and migration, contractility bFGF (basic fibroblast growth factor) (Kamihata et al, 2001, Kinnaird et al, 2004 Cell survival, pro-angiogenic, cell proliferation, contractility IGF-1 (insulin-like growth factor) (Xu et al, 2007) Cell survival, pro-angiogenic, cell proliferation and migration MCP-1 (monocyte chemoattractant protein) (Boomsma and Geenen, 2012) Cell migration, pro-angiogenic, differentiation, survival HGF (hepatocyte growth factor) (Kitta et al, 2003) Pro-angiogenic, cell survival, remodelling, differentiation IL-1b (Kobayashi et al, 2000) Pro-angiogenic IL-6 (Pricola et al, 2009) Cell proliferation, IL-10 (Chen et al, 2010) Remodelling, cell survival TGF-b (transforming growth factor-b) (Doyle et al, 2008) Cell hypertrophy, proliferation TNF-a (Corallini et al, 2010) Pro-angiogenic, migration MIP-1a (macrophage inflammatory protein-1a) (Boomsma and Geenen, 2012) Cell migration TIMP 1 and 2 (tissue inhibitor of metalloproteinase) (Singla and McDonald, 2007;Glass and Singla, 2012) Cell migration, remodelling SFRP-2 (secreted frizzled-related protein) (Alfaro et al, 2008) Cell survival…”

“…In order to reconcile these observations, several hypotheses have been proposed to explain cardiac repair in the absence of regeneration and are summarized in Figure 1 (Lovell and Mathur, 2010). Although all of the proposed mechanisms are based on associated evidence, the 'paracrine effect' appears to have the most data supporting it, irrespective of the cell type used (Kinnaird et al, 2004;Gnecchi et al, 2005;Xu et al, 2007;Korf-Klingebiel et al, 2008;Ratajczak et al, 2012). The paracrine effect proposes that cells delivered to the site of organ injury (in this case MI) secrete a factor or a combination of factors that have a beneficial effect on cardiac function that is achieved either by enhancing surviving myocyte function, by preventing cell loss as a result of the ischaemic insult (e.g.…”