Leptin signaling is required for augmented therapeutic properties of mesenchymal stem cells conferred by hypoxia preconditioning

Xinyang Hu, Rongrong Wu, Zhi Jiang, Lihan Wang, Panpan Chen, Ling Zhang, Lu Yang, Yan Wu, Han Chen, Huiqiang Chen, Yinchuan Xu, Yu Zhou, Xin Huang, Keith A. Webster, Hong Yu, Jian'an Wang

Research output: Contribution to journalArticle

45 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2702-2713
Number of pages12
JournalStem Cells
Volume32
Issue number10
DOIs
StatePublished - Jan 1 2014

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Keywords

  • CXCR4
  • Hypoxic preconditioning
  • Leptin
  • Mesenchymal stem cells
  • Myocardial infarction

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Molecular Medicine

Cite this

Hu, X., Wu, R., Jiang, Z., Wang, L., Chen, P., Zhang, L., Yang, L., Wu, Y., Chen, H., Chen, H., Xu, Y., Zhou, Y., Huang, X., Webster, K. A., Yu, H., & Wang, J. (2014). Leptin signaling is required for augmented therapeutic properties of mesenchymal stem cells conferred by hypoxia preconditioning. Stem Cells, 32(10), 2702-2713. https://doi.org/10.1002/stem.1784