Heat Shock Improves Sca-1+ Stem Cell Survival and Directs Ischemic Cardiomyocytes Toward a Prosurvival Phenotype Via Exosomal Transfer: A Critical Role for HSF1/miR-34a/HSP70 Pathway

Abstract

Stem cell based therapy is a promising intervention for ischemic heart diseases. However, the functional integrity of stem cells is impaired in an ischemic environment. Here, we report a novel finding that heat shock significantly improves Sca-1+stem cell survival in an ischemic environment by the regulation of the triangle: Heat Shock Factor 1(HSF1), HSF1/miR-34a, Heat Shock Protein 70(HSP70). Initially we prove that HSP70 is the key chaperone mediating cytoprotective effect of heat shock in Sca-1+cells and then we establish miR-34a as a direct repressor of HSP70. We found that HSP70 was down-regulated in heat shocked Sca-1+ stem cells (HSSca-1+ cells). Intriguingly, we demonstrate that the down-regulation of miR-34a is attributed to HSF1-mediated epigenetic repression through histone H3 Lys27 trimethylation (H3K27me3)on miR-34a promoter. Moreover, we show that heat shock induces exosomal transfer of HSF1 fromSca-1+ cells, which directs ischemic cardiomyocytes towards a prosurvival phenotype by epigenetic repression of miR-34a. In addition, our in vivo study demonstrates that transplantation of HSSca-1+ cells significantly reduces apoptosis, attenuates fibrosis and improves global heart functions in ischemic myocardium. Hence, our study not only provides novel insights into the effects of heat shock on stem cell survival and paracrine behavior but may have therapeutic values for stem cell therapy in ischemic heart diseases.

IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis

“…Besides p53, miR-34a can also be directly induced by ELK-1 and repressed by HSF-1 (44,45) and, as shown here, by STAT3. Once activated, the circuit can be permanently active through its positive feed-forward nature.…”

The mesmiRizing complexity of microRNAs for striated muscle tissue engineering

“…These observations partially match previous findings showing the exosomemediated beneficial effects of human mesenchymal cells on ischemia/ reperfusion injured myocardium [154]. Conversely, resident miRs can also be regulated by exosomal proteins/transcripts, as it has been reported for Sca-1 + CPCs shuttling Hsf-1 into ischemic cardiomyocytes, leading to epigenetic repression of miR-34a and improved survival [155].…”

Opportunities and Challenges: Stem Cell‐Based Therapy for the Treatment of Ischemic Stroke

“…H 2 O 2 pretreatment enhanced the survival of transplanted MSCs in mice with myocardial infarction, accompanied by better therapeutic effects [60]. Heat shock was reported to increase Sca1+ stem cells survival in ischemic heart [61]. BDNF pretreatment enhanced NSCs survival at the brain cortex in hypoxia-ischemia mice [62].…”