Mesenchymal Stem Cells Overexpressing CXCR4 Attenuate Remodeling of Postmyocardial Infarction by Releasing Matrix Metalloproteinase-9

Abstract

Myocardial infarction (MI) results in loss of myofibers in the ischemic zone of the heart, followed by scar formation. These factors increase barriers to mobilization of mesenchymal stem cells (MSC), thereby impeding their effectiveness in cardiac repair. This study examined MSC overexpressing CXCR4 (MSC CX4 ) to determine penetration into infarcted myocardium by releasing collagen degrading enzyme, matrix metalloproteinase-9 (MMP-9). In vitro, mouse MSC were utilized, including MSC using adenoviral transduction, to express CXCR4/ green fluorescent protein (GFP) (MSC CX4 ), Null/GFP (MSC Null ), MSC treated with siRNA targeting CXCR4 (MSC siR ), MSC treated with control siRNA(MSC Con-siR ), MSC CX4 treated with siRNA targeting MMP-9 (MSC CX4-siRMP9 ) and MMP-14 (MSC CX4-siRMP14 ), MSC derived from MMP-9 knockout mouse with adenoviral transduction for GFP (MSC MP9 -), or MSC MP9 -plus overexpressing CXCR4 (MSC MP9-CX4 ). The ability to cross the basement membrane was evaluated in all MSC using a trans-collagen gel invasion assay. The CXCR4 and MMP expression were analyzed by Western blot. In vivo, MSC with various treatments were infused into mice via tail vein injections 7 days after MI. Echocardiography was performed before harvesting hearts for analysis at 4 weeks after MSC injection. Both in vitro and in vivo studies demonstrated upregulation of MMP-9 induced by MSC CX4 , promoting increased GFP + cell migration into the infarcted area in comparison to control group. This enhanced response was associated with reduced left ventricular (LV) fibrosis, increased LV free wall thickness, angiogenesis, and improved LV function. Under hypoxic conditions, MMP-9 is upregulated in MSC CX4 , thus facilitating cross of the basement membrane, resulting in an improved remodeling of post-MI tissue.

Epithelial-to-Mesenchymal Transition Enhances the Cardioprotective Capacity of Human Amniotic Epithelial Cells

“…These findings are in line with our data, although EMT should not matter when MSCs are used as source cells. The extracellular matrix (ECM) and its components also play an important role in the postischemic heart, and somatic stem cells, naive or modified, have been shown to directly influence ECM turnover (11,16,19,31). The role of the matricellular protein periostin has been outlined during embryogenesis (4,14) as well as during pathological conditions (17,29).…”

“…AECs have been suggested to be useful for cellular therapy in the context of cardiovascular regeneration, but it is unclear whether this requires actual stemness or pluripotency-unrelated (i.e., secretory) mechanisms (7). Epithelial-to-mesenchymal transition (EMT) plays a role in embyrogenesis and in tumor metastasis and involves increased mobility of epithelial cells and modulation of extracellular matrix, phenomena that might be helpful for cell-based regeneration processes (2,11,16,19,31). We therefore assumed that, by forcing AECs to undergo EMT, their myocardial regeneration capacity could be augmented and tested this hypothesis in vitro as well as in a mouse model of myocardial infarction.…”

The CXCR4/SDF1 Axis Improves Muscle Regeneration Through MMP-10 Activity

“…In addition, the CXCR4/SDF1 signaling axis and MMPs have been shown to participate in some of the same cellular processes, including migration of musclederived cells during muscle repair [5,35,36]. This might suggest that these two systems functionally interact.…”

The effects of transplanted cells in stem cell therapy for myocardial ischemia

“…There, they divide and differentiate into heart cells and become involved in the process of new blood vessel formation (Bian et al, 2014;Hosoda et al, 2009;Tillmanns et al, 2008). CSC invasion to scar tissue is believed to be related to matrix metalloproteinase (MMP)-9 and -14 mediated regulation (Bax et al, 2012;Huang et al, 2011;Rota et al, 2008).…”