title: 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, and 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 miR-34a was downregulated in heat shocked Sca-11 stem cells (HSSca-11 cells) [corrected]. Intriguingly, we demonstrate that the downregulation 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 from Sca-1(+) cells, which directs ischemic cardiomyocytes toward a prosurvival phenotype by epigenetic repression of miR-34a. In addition, our in vivo study demonstrates that transplantation of (HS) Sca-1(+) cells significantly reduces apoptosis, attenuates fibrosis, and improves global heart functions in ischemic myocardium. Hence, our study provides not only novel insights into the effects of heat shock on stem cell survival and paracrine behavior but also may have therapeutic values for stem cell therapy in ischemic heart diseases.
authors.affiliation: Medical Research Center of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangdong Provincial Cardiovascular Institute, Southern Medical University, Guangzhou, China; Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: Yuliang
authors.initials: Y
authors.lastname: Feng
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.forename: Wei
authors.initials: W
authors.lastname: Meng
authors.forename: Anil G
authors.initials: AG
authors.lastname: Jegga
authors.forename: Yigang
authors.initials: Y
authors.lastname: Wang
authors.forename: Wenfeng
authors.initials: W
authors.lastname: Cai
authors.forename: Ha Won
authors.initials: HW
authors.lastname: Kim
authors.forename: Zeeshan
authors.initials: Z
authors.lastname: Pasha
authors.forename: Zhili
authors.initials: Z
authors.lastname: Wen
authors.forename: Fang
authors.initials: F
authors.lastname: Rao
authors.forename: Rohan M
authors.initials: RM
authors.lastname: Modi
authors.forename: Xiyong
authors.initials: X
authors.lastname: Yu
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ashraf
mesh_terms: D000950:Antigens, Ly / Q000235:genetics* / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D055354:Exosomes / Q000235:genetics; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D018869:Heat-Shock Response / Q000235:genetics; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D000950:Antigens, Ly; D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; C074650:Ly6a protein, mouse; C522425:MIRN34 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; D014157:Transcription Factors
keywords: Cardiac; Chaperone; Exosome; Histone modification; Hypoxia; Sca-1; Stem cell transplantation; miR-34a