title: Leptin signaling is required for augmented therapeutic properties of mesenchymal stem cells conferred by hypoxia preconditioning.
abstract: 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.
authors.affiliation: Department of Cardiology, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China; Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, China.
authors.forename: Xinyang
authors.initials: X
authors.lastname: Hu
authors.forename: Rongrong
authors.initials: R
authors.lastname: Wu
authors.forename: Zhi
authors.initials: Z
authors.lastname: Jiang
authors.forename: Lihan
authors.initials: L
authors.lastname: Wang
authors.forename: Panpan
authors.initials: P
authors.lastname: Chen
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.forename: Lu
authors.initials: L
authors.lastname: Yang
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.forename: Han
authors.initials: H
authors.lastname: Chen
authors.forename: Huiqiang
authors.initials: H
authors.lastname: Chen
authors.forename: Yinchuan
authors.initials: Y
authors.lastname: Xu
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhou
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.forename: Keith A
authors.initials: KA
authors.lastname: Webster
authors.forename: Hong
authors.initials: H
authors.lastname: Yu
authors.forename: Jian'an
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D019610:Cytoprotection; D006334:Heart Function Tests; D006801:Humans; D000860:Hypoxia / Q000473:pathology*; D019157:Ischemic Preconditioning, Myocardial; D020738:Leptin / Q000378:metabolism*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic; D019899:Paracrine Communication; D019718:Receptors, CXCR4 / Q000378:metabolism; D015203:Reproducibility of Results; D015398:Signal Transduction
chemical_list: D020738:Leptin; D019718:Receptors, CXCR4
keywords: CXCR4; Hypoxic preconditioning; Leptin; Mesenchymal stem cells; Myocardial infarction