Ablation of MMP9 induces survival and differentiation of cardiac stem cells into cardiomyocytes in the heart of diabetics: a role of extracellular matrix

Abstract

The contribution of extracellular matrix (ECM) to stem cell survival and differentiation is unequivocal, and matrix metalloproteinase-9 (MMP9) induces ECM turn over; however, the role of MMP9 in the survival and differentiation of cardiac stem cells is unclear. We hypothesize that ablation of MMP9 enhances the survival and differentiation of cardiac stem cells into cardiomyocytes in diabetics. To test our hypothesis, Ins2(+/-) Akita, C57 BL/6J, and double knock out (DKO: Ins2(+/-)/MMP9(-/-)) mice were used. We created the DKO mice by deleting the MMP9 gene from Ins2(+/-). The above 3 groups of mice were genotyped. The activity and expression of MMP9 in the 3 groups were determined by in-gel gelatin zymography, Western blotting, and confocal microscopy. To determine the role of MMP9 in ECM stiffness (fibrosis), we measured collagen deposition in the histological sections of hearts using Masson's trichrome staining. The role of MMP9 in cardiac stem cell survival and differentiation was determined by co-immunoprecipitation (co-IP) of MMP9 with c-kit (a marker of stem cells) and measuring the level of troponin I (a marker of cardiomyocytes) by confocal microscopy in the 3 groups. Our results revealed that ablation of MMP9 (i) reduces the stiffness of ECM by decreasing collagen accumulation (fibrosis), and (ii) enhances the survival (elevated c-kit level) and differentiation of cardiac stem cells into cardiomyocytes (increased troponin I) in diabetes. We conclude that inhibition of MMP9 ameliorates stem cell survival and their differentiation into cardiomyocytes in diabetes.

Dysregulation of Mfn2 and Drp-1 proteins in heart failure

“…A recent report noted that pharmacological activation of angiotensin receptor resulted in protection from MI in mouse models through reduced expression of MMP-9 (Lauer et al 2014). In support of a pathological role for MMP-9 in dilated cardiomyopathies, broad spectrum pharmacological inhibition of MMPs or specific ablation of MMP-9 were observed to enhance the heart function in different heart failure scenarios as well as survival of cardiac stem cells (Mishra et al 2012). The cardio-protective effects from the naturally occurring flavonol glycoside icariin, involve down-regulation of MMP-9 activity during the amelioration of left ventricular dysfunction (Song et al 2011).…”

Advanced Interfere Treatment of Diabetic Cardiomyopathy Rats by aFGF-Loaded Heparin-Modified Microbubbles and UTMD Technique

“…DCM results in cardiac functional and structural changes, independent of hypertension, coronary artery disease, or any other known cardiac disease. The structural changes include fibrosis, apoptosis, hypertrophy of myocytes and the functional changes include systolic and diastolic dysfunction [2][3][4][5][6][7]. DCM patients do not show special clinical symptoms in the early stage which makes it difficult for early clinical diagnosis and effective treatment.…”

Cardiac Stem Cell Niche, MMP9, and Culture and Differentiation of Embryonic Stem Cells

“…In diabetic condition, MMP9 is activated ( 24,25 ) . To understand the effect of hyperglycemia on differentiation of ESC, we treated differentiating ESC with 5mm (physiological dose: CT) and 25mM (high dose) of D-glucose for 24 hrs.…”

“…The stiffness of ECM determines the contractility of cardiomyocytes and cardiac tissue repair ( 22,23 ) . One of the important enzymes involved in induction of stiffness of ECM is matrix metalloproteinase-9 (MMP9) that induces cardiac fibrosis ( 24,25 ) . Although clinical studies revealed that MMP9 plays crucial role in diastolic dysfunction ( 26 ) , protects against ischemia-reperfusion ( 27 ) and acts as biomarker for heart failure ( 28 ) , its role in stem cell differentiation was not clear.…”

“…Although clinical studies revealed that MMP9 plays crucial role in diastolic dysfunction ( 26 ) , protects against ischemia-reperfusion ( 27 ) and acts as biomarker for heart failure ( 28 ) , its role in stem cell differentiation was not clear. Recently, we have reported that MMP9 is involved in regulation of survival and differentiation of cardiac stem cells by inducing stiffness of ECM ( 25 ) . Since ablation of MMP9 differentially regulate miRNAs ( 29 ) and miRNAs play key role in differentiation of stem cells ( 8,30-34 ) , it is also expected that MMP9 may inhibit differentiation of stem cells by regulating miRNAs.…”