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

Authors

  • Yuliang Feng,

    1. Medical Research Center of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangdong Provincial Cardiovascular Institute, Southern Medical University, Guangzhou, China
    2. Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio, USA
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  • Wei Huang,

    1. Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio, USA
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  • Wei Meng,

    1. Division of Liver Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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  • Anil G. Jegga,

    1. Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
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  • Yigang Wang,

    1. Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio, USA
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  • Wenfeng Cai,

    1. Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio, USA
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  • Ha Won Kim,

    1. Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio, USA
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  • Zeeshan Pasha,

    1. Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio, USA
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  • Zhili Wen,

    1. Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio, USA
    2. Affiliated Hospital of Infectious Diseases, Nan Chang University, Nanchang, China
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  • Fang Rao,

    1. Medical Research Center of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangdong Provincial Cardiovascular Institute, Southern Medical University, Guangzhou, China
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  • Rohan M. Modi,

    1. Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio, USA
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  • Xiyong Yu,

    Corresponding author
    1. Medical Research Center of Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangdong Provincial Cardiovascular Institute, Southern Medical University, Guangzhou, China
    • Correspondence: Muhammad Ashraf, Ph.D., Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, 231 Albert Sabin Way, Cincinnati, Ohio 45267-0529, USA. Telephone: 513-234-4485; Fax: 513-558-2141; e-mail: ashrafm251@gmail.com; or Xi-Yong Yu, M.D., Ph.D., Medical Research Center of Guangdong, General Hospital, Guangdong Academy, of Medical Sciences, 96 Dongchuan Road, WeilunBldg, Guangzhou 510080, China. Telephone: 8620-83827812-51155; Fax: 8620-83769487; e-mail: yuxycn@hotmail.com

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  • Muhammad Ashraf

    Corresponding author
    1. Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio, USA
    • Correspondence: Muhammad Ashraf, Ph.D., Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, 231 Albert Sabin Way, Cincinnati, Ohio 45267-0529, USA. Telephone: 513-234-4485; Fax: 513-558-2141; e-mail: ashrafm251@gmail.com; or Xi-Yong Yu, M.D., Ph.D., Medical Research Center of Guangdong, General Hospital, Guangdong Academy, of Medical Sciences, 96 Dongchuan Road, WeilunBldg, Guangzhou 510080, China. Telephone: 8620-83827812-51155; Fax: 8620-83769487; e-mail: yuxycn@hotmail.com

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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 HSP70 was downregulated in heat shocked Sca-1+ stem cells (HSSca-1+ cells). 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 HSSca-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. Stem Cells 2014;32:462–472

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