Abstract
The cardiogenesis of the fetal heart is absent in juveniles and adults. Cross-transplantation of decellularized extracellular matrix (dECM) can stimulate regeneration in myocardial infarct (MI) models. We have previously shown that dECM and tissue stiffness have cooperative regulation of heart regeneration in transiently regenerative day 1 neonatal mice. To investigate underlying mechanisms of mechano-signaling and dECM, we pharmacologically altered heart stiffness and administered dECM hydrogels in non-regenerative mice after MI. The dECM combined with softening exhibits preserved cardiac function, LV geometry, increased cardiomyocyte mitosis and lowered fibrosis while stiffening further aggravated ischemic damage. Transcriptome analysis identified a protein in cardiomyocytes, CLCA2, confirmed to be upregulated after MI and downregulated by dECM in a mechanosensitive manner. Synthetic knock-down of CLCA2 expression induced mitosis in primary rat cardiomyocytes in the dish. Together, our results indicate that therapeutic efficacy of extracellular molecules for heart regeneration can be modulated by heart microenvironment stiffness in vivo.
Highlights
Cardiovascular disease is the leading cause of death worldwide
We demonstrate that modulating heart microenvironment stiffness alters decellularized extracellular matrix (dECM)-induced cardiac regeneration in non-regenerative juvenile mice challenged with a myocardial infarction
We identify chloride channel accessory 2 (CLCA2) as a potential signaling pathway mediating dECM induced cardiomyocyte cell cycle activity
Summary
Cardiovascular disease is the leading cause of death worldwide. World Health Organization (WHO) estimates 17.9 million people will die from cardiovascular diseases each year [1]. Coronary heart disease (CHD) is the most common type of cardiovascular disease. Heart remodeling and irreversible scarring can permanently lower heart function in heart attack patients. The damage can develop to heart failure which currently can only be cured by heart transplantation. Because the therapies for myocardial infarction (MI) provide stabilization and partial recovery, the incidence of heart failure after an acute myocardial infarction is as high as 25% [2]. Promoting heart regeneration in post-ischemic hearts will benefit heart attack patients
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