Blood-Forming Stem Cells Fail to Repair Heart Muscle in Stanford Study
Sunday March 21, 1:00 pm ET
STANFORD, Calif.--(BUSINESS WIRE)--March 21, 2004--A new study adds a twist to the ongoing debate over using blood-forming stem cells to repair heart muscle. In the March 21 online issue of Nature, researchers at the Stanford University School of Medicine report that the cells are unable to replace heart muscle after a heart attack, which refutes earlier findings.
During the past three years, several groups had reported that stem cells found in bone marrow could lodge in the heart and repair muscle damaged by a heart attack. These stem cells normally reside in the bone marrow, where they constantly replenish red blood cells and immune cells. If the earlier findings were correct and the blood-forming stem cells switched their fates, that could reveal an exciting new path for treating heart attack patients.
"We started out attempting to validate and extend those findings," said Leora Balsam, MD, a research fellow working with Robert Robbins, MD, associate professor of cardiothoracic surgery.
Instead of supporting previous findings, however, her experiments contradicted them. She found that in mice, blood-forming stem cells lodge in damaged hearts but retain the form of blood cells rather than transforming into muscle cells. A paper by another research group in the same issue of Nature supports Balsam's findings using slightly different methods.
The question now is why some studies have found that blood-forming stem cells can repair the heart while others show that those adult stem cells retain their blood-forming fate. The question is particularly timely given that human trials are already under way based on the strength of earlier findings refuted by the new research.
"If we are delivering bone marrow to patients with the expectation that it will regenerate the heart, that may not be realistic," Balsam said.
One difference between Balsam's study and previous experiments is the type of bone marrow cells she used. Amy Wagers, PhD, a postdoctoral scholar in the lab of Irving Weissman, MD, the Karel and Avice Beekhuis Professor of Cancer Biology, took whole bone marrow from mice then isolated several purified groups of cells, including a highly purified subset of stem cells that can go on to form all blood cell types. Previous experiments had only used less purified cells.
Balsam injected those cells directly into the heart muscle of 23 mice in which she had induced a heart attack. The injected cells produced a green protein that is easily visible under a microscope. She then examined the heart muscles of those mice 10 days and 30 days after the injection to search for signs of transplanted blood-forming stem cells.
At 10 days she saw clusters of green cells, but none of them made proteins typical of heart muscle. However, the green cells did produce proteins commonly made by blood cells. By 30 days, very few green cells remained in the heart, and those that did still produced blood proteins rather than heart muscle proteins.
Balsam found that 30 days after injecting the blood-forming stem cells, the mice died at the same rate as those in another group that received only water after their induced heart attacks. Even though the transplanted stem cells didn't help the mice survive, the stem cell-injected group did have slight improvements in how well their hearts pumped blood.
Robbins, who is lead author of the study, said even with these results, adult stem cells may offer some potential for treating damaged hearts. "Maybe these cells don't need to differentiate," he said.
Robbins said the transplanted blood-forming cells may recruit new blood vessels to the damaged tissues. These new blood vessels may keep heart muscle cells alive that would otherwise have died, thus indirectly rescuing the heart. By genetically engineering those cells to make additional factors to recruit blood vessels, they may become part of a successful therapy, Robbins said.
Researchers are also examining embryonic stem cells and immature skeletal muscle cells as possible candidates for repairing heart muscle. Robbins and other members of his lab are looking into these alternative ways of repairing heart muscle.
"We're all interested in finding ways of regenerating the heart," Balsam said. "I think what this study points out is that it's not easy."
Stanford University Medical Center integrates research, medical education and patient care at its three institutions -- Stanford University School of Medicine, Stanford Hospital & Clinics and Lucile Packard Children's Hospital at Stanford. For more information, please visit the Web site of the medical center's Office of Communication & Public Affairs at mednews.stanford.edu.
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Stanford University Medical Center
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amyadams@stanford.edu
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Nature AOP, published online 21 March 2004; doi:10.1038/nature02460
Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium
LEORA B. BALSAM1, AMY J. WAGERS2,3, JULIE L. CHRISTENSEN2,3, THEO KOFIDIS1, IRVING L. WEISSMAN2,3 & ROBERT C. ROBBINS1
1 Departments of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, California 94305, USA
2 Pathology, Stanford University School of Medicine, Stanford, California 94305, USA
3 Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA
Correspondence and requests for materials should be addressed to R.C.R. (robbins@stanford.edu).
Under conditions of tissue injury, myocardial replication and regeneration have been reported. A growing number of investigators have implicated adult bone marrow (BM) in this process, suggesting that marrow serves as a reservoir for cardiac precursor cells. It remains unclear which BM cell(s) can contribute to myocardium, and whether they do so by transdifferentiation or cell fusion. Here, we studied the ability of c-kit-enriched BM cells, Lin- c-kit+ BM cells and c-kit+ Thy1.1lo Lin- Sca-1+ long-term reconstituting haematopoietic stem cells to regenerate myocardium in an infarct model. Cells were isolated from transgenic mice expressing green fluorescent protein (GFP) and injected directly into ischaemic myocardium of wild-type mice. Abundant GFP+ cells were detected in the myocardium after 10 days, but by 30 days, few cells were detectable. These GFP+ cells did not express cardiac tissue-specific markers, but rather, most of them expressed the haematopoietic marker CD45 and myeloid marker Gr-1. We also studied the role of circulating cells in the repair of ischaemic myocardium using GFP+–GFP- parabiotic mice. Again, we found no evidence of myocardial regeneration from blood-borne partner-derived cells. Our data suggest that even in the microenvironment of the injured heart, c-kit-enriched BM cells, Lin- c-kit+ BM cells and c-kit+ Thy1.1lo Lin- Sca-1+ long-term reconstituting haematopoietic stem cells adopt only traditional haematopoietic fates.
Nature AOP, published online 21 March 2004; doi:10.1038/nature02446
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Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts
CHARLES E. MURRY1, MARK H. SOONPAA2, HANS REINECKE1, HIDEHIRO NAKAJIMA2, HISAKO O. NAKAJIMA2, MICHAEL RUBART2, KISHORE B. S. PASUMARTHI2,*, JITKA ISMAIL VIRAG1, STEPHEN H. BARTELMEZ3, VERONICA POPPA1, GILLIAN BRADFORD2, JOSHUA D. DOWELL2, DAVID A. WILLIAMS2,* & LOREN J. FIELD2
1 Department of Pathology, Box 357470, Room D-514 HSB, University of Washington, Seattle, Washington 98195, USA
2 Wells Center for Pediatric Research, Indiana University, 1044 West Walnut Street, R4 Bldg, Room W376, Indianapolis 46202-5225, USA
3 Department of Pathobiology, University of Washington, Seattle, Washington 98195, USA
* Present addresses: Department of Pharmacology Dalhousie University, Sir Charles Tupper Medical Bldg, Room 6-F1, 5850 College Street, Halifax B3H 1X5, Canada (K.B.S.P.); Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229-3039, USA (D.A.W.)
Correspondence and requests for materials should be addressed to C.E.M. (murry@u.washington.edu) or L.J.F. (ljfield@iupui.edu).
The mammalian heart has a very limited regenerative capacity and, hence, heals by scar formation. Recent reports suggest that haematopoietic stem cells can transdifferentiate into unexpected phenotypes such as skeletal muscle, hepatocytes, epithelial cells, neurons, endothelial cells and cardiomyocytes, in response to tissue injury or placement in a new environment. Furthermore, transplanted human hearts contain myocytes derived from extra-cardiac progenitor cells, which may have originated from bone marrow. Although most studies suggest that transdifferentiation is extremely rare under physiological conditions, extensive regeneration of myocardial infarcts was reported recently after direct stem cell injection, prompting several clinical trials. Here, we used both cardiomyocyte-restricted and ubiquitously expressed reporter transgenes to track the fate of haematopoietic stem cells after 145 transplants into normal and injured adult mouse hearts. No transdifferentiation into cardiomyocytes was detectable when using these genetic techniques to follow cell fate, and stem-cell-engrafted hearts showed no overt increase in cardiomyocytes compared to sham-engrafted hearts. These results indicate that haematopoietic stem cells do not readily acquire a cardiac phenotype, and raise a cautionary note for clinical studies of infarct repair. |
