Ann Thorac Surg 2009;87:819. doi:10.1016/j.athoracsur.2008.12.089
© 2009 The Society of Thoracic Surgeons
Original Articles: Adult Cardiac
Invited Commentary
Craig Selzman, MD
Division of Cardiothoracic Surgery, University of Utah, 30 N 1900 E, 3C 127 SOM, Salt Lake City, UT 84132
(Email: craig.selzman{at}hsc.utah.edu).
In the last 5 years, significant enthusiasm (both experimentally and clinically) exists to apply progenitor cells to modify the myocardial response to injury. In many ways, the popular appeal of stem cell therapy, as well as its vast potential, has led to the quick adoption of these approaches into human clinical trials. Meanwhile, much remains to be learned about individual cell types and their mechanism of action. In the article by Zeller and colleagues [1], the group from Indiana continues their investigation of the effects of mesenchymal stem cells (MSCs) to provide myocardial protection from ischemia-reperfusion. When delivered through the coronary circulation, we know that few MSCs actually can be identified in the heart. As with other groups, this group believes that many of the positive effects of MSCs are related to their paracrine effects. This group has a long history of studying cytokine biology, and the gender effect of cytokines and myocardial injury in particular. They have previously demonstrated that MSCs from female donors produce less pro-inflammatory cytokines and more growth factors than their male counterparts. They have shown further that this observation may be related to activation of the tumor necrosis factor receptor 1 (TNFR1), whereby male mice deficient in this receptor manifest a more favorable cytokine profile, and females are unaffected by TNFR1 ablation.
In the current report, the authors extend their observations of MSCs in culture (hypoxia and lipopolysaccharide) to a standard ex-vivo Langendorff preparation. They demonstrate that MSCs from either gender, but moreso with female MSCs, appropriately improve post-ischemic functional recovery. The MSCs from male TNFR1-deficient animals improved cardioprotection, whereas those from females were no different than their wild-type mates. This effect from the male knock-out cells was even more pronounced than the baseline protection afforded by the wild-type female MSCs.
The implied implications potentially relevant to human use of this form of therapy are: (1) female donor MSCs might be a preferred source of cells, especially because one of the advantages of MSCs in their relative immune tolerance, and (2) manipulation of the TNFR1 receptor in male donor cells might provide even a better source of MSCs. Of course, the appeal of the current study is not so much in its direct clinical relevance, but in its continued search for understanding how these cells actually work. Although the authors use transgenic animals to hint of mechanism, this report is only observational and leaves the reader wondering why TNFR1 ablation in females MSCs makes no difference, whereas it dramatically increases cardioprotection induced by male MSCs. Because this is a functional Langendorff study, many questions remain related to cellular infiltration, cytokine and growth factor production, and cell viability. Admittedly, the authors acknowledge several potential targets for further mechanistic study, which we will be interested in seeing as this line of investigation evolves.
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- Zeller CN, Wang Y, Markel TA. Role of tumor necrosis factor receptor 1 in sex differences of stem cell mediated cardioprotection Ann Thorac Surg 2009;87:812-819.[Abstract/Free Full Text]
Related Article
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Role of Tumor Necrosis Factor Receptor 1 in Sex Differences of Stem Cell Mediated Cardioprotection
- Courtney N. Zeller, Yue Wang, Troy A. Markel, Brent Weil, Aaron Abarbanell, Jeremy L. Herrmann, Megan L. Kelly, Arthur Coffey, and Daniel R. Meldrum
Ann. Thorac. Surg. 2009 87: 812-819.
[Abstract]
[Full Text]
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