Bone-Derived stem cells repair the heart after myocardial infarction through transdifferentiation and paracrine signaling mechanisms

Jason M. Duran, Catherine A. Makarewich, Thomas E. Sharp, Timothy Starosta, Fang Zhu, Nicholas E. Hoffman, Yumi Chiba, Muniswamy Madesh, Remus M. Berretta, Hajime Kubo, Steven R. Houser

Research output: Contribution to journalArticle

103 Scopus citations

Abstract

RATIONALE:: Autologous bone marrow-derived or cardiac-derived stem cell therapy for heart disease has demonstrated safety and efficacy in clinical trials, but functional improvements have been limited. Finding the optimal stem cell type best suited for cardiac regeneration is the key toward improving clinical outcomes. OBJECTIVE:: To determine the mechanism by which novel bone-derived stem cells support the injured heart. METHODS AND RESULTS:: Cortical bone-derived stem cells (CBSCs) and cardiac-derived stem cells were isolated from enhanced green fluorescent protein (EGFP+) transgenic mice and were shown to express c-kit and Sca-1 as well as 8 paracrine factors involved in cardioprotection, angiogenesis, and stem cell function. Wild-type C57BL/6 mice underwent sham operation (n=21) or myocardial infarction with injection of CBSCs (n=67), cardiac-derived stem cells (n=36), or saline (n=60). Cardiac function was monitored using echocardiography. Only 2/8 paracrine factors were detected in EGFP+ CBSCs in vivo (basic fibroblast growth factor and vascular endothelial growth factor), and this expression was associated with increased neovascularization of the infarct border zone. CBSC therapy improved survival, cardiac function, regional strain, attenuated remodeling, and decreased infarct size relative to cardiac-derived stem cells- or saline-treated myocardial infarction controls. By 6 weeks, EGFP+ cardiomyocytes, vascular smooth muscle, and endothelial cells could be identified in CBSC-treated, but not in cardiac-derived stem cells-treated, animals. EGFP+ CBSC-derived isolated myocytes were smaller and more frequently mononucleated, but were functionally indistinguishable from EGFP- myocytes. CONCLUSIONS:: CBSCs improve survival, cardiac function, and attenuate remodeling through the following 2 mechanisms: (1) secretion of proangiogenic factors that stimulate endogenous neovascularization, and (2) differentiation into functional adult myocytes and vascular cells.

Original languageEnglish (US)
Pages (from-to)539-552
Number of pages14
JournalCirculation research
Volume113
Issue number5
DOIs
StatePublished - Aug 16 2013

    Fingerprint

Keywords

  • differentiation
  • myocardial infarction
  • neovascularization
  • paracrine communication
  • stem cells

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Duran, J. M., Makarewich, C. A., Sharp, T. E., Starosta, T., Zhu, F., Hoffman, N. E., Chiba, Y., Madesh, M., Berretta, R. M., Kubo, H., & Houser, S. R. (2013). Bone-Derived stem cells repair the heart after myocardial infarction through transdifferentiation and paracrine signaling mechanisms. Circulation research, 113(5), 539-552. https://doi.org/10.1161/CIRCRESAHA.113.301202