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Findings raise hope for new heart therapies from stem cells found in cortical, or compact, bone.
Many people who survive a heart attack find themselves back in the hospital with a failing heart just years later. And the outcome often is unfavorable, owing to limited treatment options. But scientists at Temple University School of Medicine's Cardiovascular Research Center (CVRC) recently found hope in an unlikely source – stem cells in cortical, or compact, bone. In a new study, they show that when it comes to the regeneration of heart tissue, these novel bone-derived cells do a better job than the heart's own stem cells.
According to the study's senior investigator, Steven R. Houser, Ph.D., FAHA, Chairperson of Temple's Department of Physiology and Director of the CVRC, it is early days for cortical bone-derived stem cells (CBSCs). Nonetheless, his team's findings, featured on the cover of the August 16th issue of Circulation Research, have considerable implications for stem cell therapy for the heart.
A major challenge in the treatment of heart attack is early intervention, which is key to reducing the chances for long-term complications, such as heart failure. When it comes to stem cells, Houser said, "The strategy is to inject the cells right after [a heart attack]." Currently, though, that approach works only in animal studies. To make it work in humans, Houser explained, "we need cells right off the rack and ready to go clinically."
CBSCs could be those cells.
To figure out how CBSCs might behave in the heart in the first place, Houser's team, led by Temple graduate student Jason Duran, began by collecting the cells from mouse tibias. The particular mice used had been engineered with green fluorescent protein (GFP), which meant that the CBSCs carried a green marker to allow for their later identification. The cells were then expanded in petri dishes in the laboratory before being injected directly into the hearts of non-GFP mice that had suffered heart attacks. Some mice received cardiac stem cells instead of CBSCs.
In the following weeks, as the team monitored the progress of the mice, they found that the youthfulness of the CBSCs had prevailed. The cells had triggered the growth of new blood vessels in the injured tissue, and six weeks after injection, they had differentiated, or matured, into heart muscle cells. While generally smaller than native heart cells, the new cells had the same functional capabilities, and overall they had improved survival and heart function. Similar improvements were not observed in the subset of mice treated with cardiac stem cells. Nor was there evidence in those mice that the cardiac cells had undergone differentiation.
The findings challenge the general assumption that cardiac stem cells, because they reside in the heart, are the cells most capable of repairing damaged heart tissue. For that reason, according to Houser, the new paper likely will be controversial.
Houser: "What we did generates as many questions as it does answers. Cell therapy attempts to repopulate the heart with new heart cells. But which cells should be used, and when they should be put into the heart are among many unanswered questions."
To address at least some of those questions, Houser's team plans next to investigate CBSCs in a large-animal heart attack model. If that study yields similar results as the first, the cells could be ushered into a small-scale clinical trial of human patients.
The cell therapy work by Houser's team represents just one of several forms of heart therapy being explored at Temple's CVRC. According to Houser, "Temple has made a commitment to cardiovascular research, with a clinical enterprise focused on treating patients. We're trying anything and everything to repair the heart [safely]." Other avenues of research include gene therapy, drug therapy, and the use of novel biomaterials to more effectively deliver drugs.
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.
Other researchers contributing to the work include Catherine A. Makarewich, Thomas E. Sharp, Timothy Starosta, Yumi Chiba, Remus M. Berretta, and Hajime Kubo, at the Cardiovascular Research Center at Temple; Nicholas E. Hoffman and Muniswamy Madesh, at the Center for Translational Medicine at Temple; and Fang Zhu, at the Biostatistics and Bioinformatics Facility, Fox Chase Cancer Center.
The research was supported in part by NIH grants R01HL089312, T32HL091804, P01HL091799, and R37HL033921.
About Temple Health
Temple University Health System (TUHS) is a $1.4 billion academic health system dedicated to providing access to quality patient care and supporting excellence in medical education and research. The Health System consists of Temple University Hospital (TUH), ranked among the "Best Hospitals" in the region by U.S. News & World Report; TUH-Episcopal Campus; TUH-Northeastern Campus; Fox Chase Cancer Center, an NCI-designated comprehensive cancer center; Jeanes Hospital, a community-based hospital offering medical, surgical and emergency services; Temple Transport Team, a ground and air-ambulance company; and Temple Physicians, Inc., a network of community-based specialty and primary-care physician practices. TUHS is affiliated with Temple University School of Medicine.
Temple University School of Medicine (TUSM), established in 1901, is one of the nation's leading medical schools. Each year, the School of Medicine educates approximately 840 medical students and 140 graduate students. Based on its level of funding from the National Institutes of Health, Temple University School of Medicine is the second-highest ranked medical school in Philadelphia and the third-highest in the Commonwealth of Pennsylvania. According to U.S. News & World Report, TUSM is among the top 10 most applied-to medical schools in the nation.
Original press release:http://www.templehealth.org/content/newsroom.htm?page_id=11&minor=