The harsh microenvironment in infarcted heart accelerates transplanted bone marrow mesenchymal stem cells injury: the role of injured cardiomyocytes-derived exosomes

Abstract

Stem cell therapy can be used to repair and regenerate damaged hearts tissue; nevertheless, the low survival rate of transplanted cells limits their therapeutic efficacy. Recently, it has been proposed that exosomes regulate multiple cellular processes by mediating cell survival and communication among cells. The following study investigates whether injured cardiomyocytes-derived exosomes (cardiac exosomes) affect the survival of transplanted bone marrow mesenchymal stem cells (BMSCs) in infarcted heart. To mimic the harsh microenvironment in infarcted heart that the cardiomyocytes or transplanted BMSCs encounter in vivo, cardiomyocytes conditioned medium and cardiac exosomes collected from H2O2-treated cardiomyocytes culture medium were cultured with BMSCs under oxidative stress in vitro. Cardiomyocytes conditioned medium and cardiac exosomes significantly accelerated the injury of BMSCs induced by H2O2; increased cleaved caspase-3/caspase-3 and apoptotic percentage, and decreased the ratio of Bcl-2/Bax and cell viability in those cells. Next, we explored the role of cardiac exosomes in the survival of transplanted BMSCs in vivo by constructing a Rab27a knockout (KO) mice model by a transcription activator-like effector nuclease (TALEN) genome-editing technique; Rab27a is a family of GTPases, which has critical role in secretion of exosomes. Male mouse GFP-modified BMSCs were implanted into the viable myocardium bordering the infarction in Rab27a KO and wild-type female mice. The obtained results showed that the transplanted BMSCs survival in infarcted heart was increased in Rab27a KO mice by the higher level of Y-chromosome Sry DNA, GFP mRNA, and the GFP fluorescence signal intensity. To sum up, these findings revealed that the injured cardiomyocytes-derived exosomes accelerate transplanted BMSCs injury in infarcted heart, thus highlighting a new mechanism underlying the survival of transplanted cells after myocardial infarction.

Exosomes derived from pro‐inflammatory bone marrow‐derived mesenchymal stem cells reduce inflammation and myocardial injury via mediating macrophage polarization

“…In this study, 3~4‐week‐old male Sprague Dawley rats, weighing about 80‐100 g, were used for supplying peritoneal macrophages according to a method previously described . Cold PBS, containing 10% FBS, was injected into the rat peritoneal cavity.…”

Examining the Paracrine Effects of Exosomes in Cardiovascular Disease and Repair

“…After left anterior descending artery ligation in the Rab27a‐knockout mouse heart, mouse bone marrow–derived MSCs were injected into the border zone of the infarct. These transplanted bone marrow–derived MSCs showed 3‐fold increased survival after 4 days . The accumulative evidence suggests that EVs, including exosomes, when produced by cells under adverse conditions, not only contribute to the disease pathology but also may be detrimental toward cardiac regenerative therapies.…”

“…It has recently been shown that exosomes derived from injured cardiomyocytes may impede the survival of bone marrow-derived MSCs in the infarcted heart. 11 Exosomes isolated from cultured cardiomyocytes treated with H 2 O 2 could induce bone marrow-derived MSCs to undergo apoptosis in vitro. In corollary in vivo experiments, Ras-Related Protein Rab27a-knockout mice were engineered to have reduced exosome release from cardiac tissues.…”

“…These transplanted bone marrow-derived MSCs showed 3-fold increased survival after 4 days. 11 The accumulative evidence suggests that EVs, including exosomes, when produced by cells under adverse conditions, not only contribute to the disease pathology but also may be detrimental toward cardiac regenerative therapies. Nevertheless, the full extent of EV-mediated intracellular communication within the heart and how neighboring or distant cells can secrete EVs to influence the cardiac structure and function are largely unknown.…”

“…EVs also compose a critical component of intercellular signaling by transporting molecular cargo from donor cells to recipient cells, thereby modulating gene expression and influencing the phenotype of the recipient cell . Most studies have documented this intercellular communication in vitro, but emerging evidence suggests it also occurs in vivo . In this review, we focus on the role of exosomes, a subset of EVs, as mediators of intercellular signaling in the heart.…”