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.
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.
Authors: Pearl Quijada; Haruhiro Toko; Kimberlee M Fischer; Brandi Bailey; Patrick Reilly; Kristin D Hunt; Natalie A Gude; Daniele Avitabile; Mark A Sussman Journal: Circ Res Date: 2012-05-22 Impact factor: 17.367
Authors: D Orlic; J Kajstura; S Chimenti; I Jakoniuk; S M Anderson; B Li; J Pickel; R McKay; B Nadal-Ginard; D M Bodine; A Leri; P Anversa Journal: Nature Date: 2001-04-05 Impact factor: 49.962
Authors: Sadia Mohsin; Mohsin Khan; Haruhiro Toko; Brandi Bailey; Christopher T Cottage; Kathleen Wallach; Divya Nag; Andrew Lee; Sailay Siddiqi; Feng Lan; Kimberlee M Fischer; Natalie Gude; Pearl Quijada; Daniele Avitabile; Silvia Truffa; Brett Collins; Walter Dembitsky; Joseph C Wu; Mark A Sussman Journal: J Am Coll Cardiol Date: 2012-07-26 Impact factor: 24.094
Authors: Jason M Duran; Sharven Taghavi; Remus M Berretta; Catherine A Makarewich; Thomas Sharp Iii; Tim Starosta; Foram Udeshi; Jon C George; Hajime Kubo; Steven R Houser Journal: Clin Transl Sci Date: 2012-06-26 Impact factor: 4.689
Authors: Atul R Chugh; Garth M Beache; John H Loughran; Nathan Mewton; Julius B Elmore; Jan Kajstura; Patroklos Pappas; Antone Tatooles; Marcus F Stoddard; Joao A C Lima; Mark S Slaughter; Piero Anversa; Roberto Bolli Journal: Circulation Date: 2012-09-11 Impact factor: 29.690
Authors: Raj R Makkar; Rachel R Smith; Ke Cheng; Konstantinos Malliaras; Louise Ej Thomson; Daniel Berman; Lawrence Sc Czer; Linda Marbán; Adam Mendizabal; Peter V Johnston; Stuart D Russell; Karl H Schuleri; Albert C Lardo; Gary Gerstenblith; Eduardo Marbán Journal: Lancet Date: 2012-02-14 Impact factor: 79.321
Authors: Kunhua Song; Young-Jae Nam; Xiang Luo; Xiaoxia Qi; Wei Tan; Guo N Huang; Asha Acharya; Christopher L Smith; Michelle D Tallquist; Eric G Neilson; Joseph A Hill; Rhonda Bassel-Duby; Eric N Olson Journal: Nature Date: 2012-05-13 Impact factor: 49.962
Authors: David D Ellison; Yasir Suhail; Junaid Afzal; Laura Woo; Onur Kilic; Jeffrey Spees; Andre Levchenko Journal: Proc Natl Acad Sci U S A Date: 2019-06-25 Impact factor: 11.205
Authors: Xueqin Gao; Arvydas Usas; Jonathan D Proto; Aiping Lu; James H Cummins; Alexander Proctor; Chien-Wen Chen; Johnny Huard Journal: FASEB J Date: 2014-05-19 Impact factor: 5.191
Authors: Markus Wallner; Jason M Duran; Sadia Mohsin; Constantine D Troupes; Davy Vanhoutte; Giulia Borghetti; Ronald J Vagnozzi; Polina Gross; Daohai Yu; Danielle M Trappanese; Hajime Kubo; Amir Toib; Thomas E Sharp; Shavonn C Harper; Michael A Volkert; Timothy Starosta; Eric A Feldsott; Remus M Berretta; Tao Wang; Mary F Barbe; Jeffrey D Molkentin; Steven R Houser Journal: Circ Res Date: 2016-07-26 Impact factor: 17.367