Open AccessLeptin Signaling Is Required for Augmented Therapeutic Properties of Mesenchymal Stem Cells Conferred by Hypoxia Preconditioning
Author(s) -
Hu Xinyang,
Wu Rongrong,
Jiang Zhi,
Wang Lihan,
Chen Panpan,
Zhang Ling,
Yang Lu,
Wu Yan,
Chen Han,
Chen Huiqiang,
Xu Yinchuan,
Zhou Yu,
Huang Xin,
Webster Keith A.,
Yu Hong,
Wang Jian'an
Publication year - 2014
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1002/stem.1784
Subject(s) - mesenchymal stem cell , biology , hypoxia (environmental) , leptin , stem cell , cxcr4 , leptin receptor , microbiology and biotechnology , gene knockdown , cancer research , cell therapy , chemotaxis , bone marrow , immunology , receptor , endocrinology , inflammation , apoptosis , chemokine , chemistry , biochemistry , organic chemistry , oxygen , obesity
Hypoxia preconditioning enhances the therapeutic effect of mesenchymal stem cells (MSCs). However, the mechanism underlying hypoxia‐induced augmentation of the protective effect of MSCs on myocardial infarction (MI) is poorly understood. We show that hypoxia‐enhanced survival, mobility, and protection of cocultured cardiomyocytes were paralleled by increased expression of leptin and cell surface receptor CXCR4. The enhanced activities were abolished by either knockdown of leptin with a selective shRNA or by genetic deficiency of leptin or its receptor in MSCs derived, respectively, from ob/ob or db/db mice. To characterize the role of leptin in the regulation of MSC functions by hypoxia and its possible contribution to enhanced therapeutic efficacy, cell therapy using MSCs derived from wild‐type, ob/ob, or db/db mice was implemented in mouse models of acute MI. Augmented protection by hypoxia pretreatment was only seen with MSCs from wild‐type mice. Parameters that were differentially affected by hypoxia pretreatment included MSC engraftment, c‐Kit + cell recruitment to the infarct, vascular density, infarct size, and long‐term contractile function. These data show that leptin signaling is an early and essential step for the enhanced survival, chemotaxis, and therapeutic properties of MSCs conferred by preculture under hypoxia. Leptin may play a physiological role in priming MSCs resident in the bone marrow endosteum for optimal response to systemic signaling molecules and subsequent tissue repair. S tem C ells 2014;32:2702–2713