Abstract
The onset of cardiac fibrosis post myocardial infarction greatly impairs the function of heart. Recent advances of cell transplantation showed great benefits to restore myocardial function, among which the mesenchymal stem cells (MSCs) has gained much attention. However, the underlying cellular mechanisms of MSC therapy are still not fully understood. Although paracrine effects of MSCs on residual cardiomyocytes have been discussed, the amelioration of fibrosis was rarely studied as the hostile environment cannot support the survival of most cell populations and impairs the diffusion of soluble factors. Here in order to decipher the potential mechanism of MSC therapy for cardiac fibrosis, we investigated the interplay between MSCs and cardiac myofibroblasts (mFBs) using interactive co-culture method, with comparison to paracrine approaches, namely treatment by MSC conditioned medium and gap co-culture method. Various fibrotic features of mFBs were analyzed and the most prominent anti-fibrosis effects were always obtained using direct co-culture that allowed cell-to-cell contacts. Hepatocyte growth factor (HGF), a well-known anti-fibrosis factor, was demonstrated to be a major contributor for MSCs’ anti-fibrosis function. Moreover, physical contacts and tube-like structures between MSCs and mFBs were observed by live cell imaging and TEM which demonstrate the direct cellular interactions.Electronic supplementary materialThe online version of this article (doi:10.1007/s13238-015-0196-7) contains supplementary material, which is available to authorized users.
Highlights
Myocardial infarction accounts for over 40% of cardiovascular diseases (CVD) related human mortality, as reported by the World Health Organization (WHO, 2013)
In order to decipher the potential mechanism of mesenchymal stem cells (MSCs) therapy for cardiac fibrosis, we investigated the interplay between MSCs and cardiac myofibroblasts using interactive co-culture method, with comparison to paracrine approaches, namely treatment by MSC conditioned medium and gap co-culture method
Histological characterization revealed that an excessive deposition of fibrillar collagen was accumulated within the infarcted myocardium and an altered cell population which was positive for alpha-smooth muscle actin (α-SMA) replaced the lost cardiomyocytes, namely myofibroblasts (Rohr, 2009). mFBs were believed to mainly originate from interstitial cardiac fibroblasts (Brown et al, 2005; Czubryt, 2012) which are responsible for the stability of extracellular matrix in heart and its dynamic balance with cardiomyocytes (Fan et al, 2012; Weber et al, 2013)
Summary
Myocardial infarction accounts for over 40% of cardiovascular diseases (CVD) related human mortality, as reported by the World Health Organization (WHO, 2013). The paracrine activity of MSCs was reported to activate the quiescent cardiac progenitor cells or stimulate the residual cardiomyocytes to re-enter proliferative phase (Ranganath et al, 2012) Few of these studies have provided solid explanation on how MSCs attenuate the fibrosis condition within the infarcted myocardium, since the hostile avascular and hypoxic environment could not support cell survival and factor diffusion to help remuscularization of the diseased heart. To elucidate the dominant role of intercellular communications for MSC therapy, the direct cell co-culture model using adipose-derived MSCs and cardiac mFBs was introduced in vitro and multiple pathological features of mFBs, including cellular viability, biomarker expression (α-SMA, collagen), cellular contractility and motility were analyzed in the model, which were compared to the treatment of MSC conditioned medium in parallel. The system comprised two chambers separated by varying distances of cell-repellent gap, which would only allow communication by paracrine factors and no direct contact could be formed
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