Author + information
- Emerson C. Perin, MD, PhD⁎ ( and )
- James T. Willerson, MD
- ↵⁎Reprint requests and correspondence:
Dr. Emerson C. Perin, Texas Heart Institute, 6624 Fannin, Suite 2220, Houston, Texas 77030
A classic legend immortalized by Goethe in 1808 tells of humanity's quest for the true essence of life. Through the allegory of Mephistopheles, Faust reaches for the supernatural to overcome his human limitations. Stem cell research has in a way brought us in touch with near supernatural powers as we begin to understand and explore the mechanisms imbuing these cells with the capacity for self-renewal. The question of aging is central to stem cell biology, and the harnessing of these powers, even in part, may change the way we deal with aging and disease.
Delivery of stem cells to the heart directly or via the use of a tissue-engineered platform is a clinically promising approach to improve clinical outcomes by enhancing the healing process after myocardial infarction (MI) or by facilitating functional gain in the setting of chronic ischemic heart disease. However, when considering autologous cell therapy, the benefits of this approach may be limited in one of the largest target groups for regenerative medicine—the elderly—because of age-related dysfunction in stem cells. Moreover, the use of autologous stem cells in patients with chronic heart disease is further hampered by the comorbidities common in this patient group, which also have a negative effect on the potency of bone marrow–derived stem cells (1,2).
Dysfunction of stem cells harvested from the bone marrow of aged patients has been clearly demonstrated (3) and verified in cell therapy trials of autologous bone marrow cells in patients with heart failure (4). In the FOCUS-HF (First Bone Marrow Mononuclear Cell United States Study in Heart Failure) trial, we showed that the regenerative capacity of the mesenchymal compartment of bone marrow cells was greater in younger patients than in older patients, and this improved proliferative ability translated into better clinical outcomes (4). In the largest study of cell therapy with autologous bone marrow cells in patients with chronic heart failure (5), better functional outcomes also were identified in younger patients and were associated with the presence of specific cell phenotypes.
In this issue of the Journal, Kang et al. (6) address the issue of function of aged cells in a rat model of surgical ventricular restoration after MI. They seeded human mesenchymal stromal cells (MSCs) onto collagen scaffolds and showed, not surprisingly, that MSCs from older donors proliferated in vitro on the scaffolds more slowly than did MSCs from younger donors. However, binding angiogenic cytokines to the scaffolds enabled the older MSCs to overcome this proliferation deficit. Of note, Kang et al. (6) showed that the salutary effects of cytokine exposure on older cells extended to the in vivo environment. After surgical ventricular restoration in rats with MI, the limited functional and vascular benefits of cardiac patches seeded with old cells improved, often to the level noted with patches that carried young cells, with the use of cytokine-enhanced patches (1).
Age-related changes in stem cells are the Achilles' heel of autologous cell therapy. We propose 4 different, sometimes overlapping, strategies for overcoming this problem. First, the most obvious way is to not use autologous cells in cell therapy. The initial clinical experience with the use of allogeneic bone marrow–derived mesenchymal stem cells in patients with MI (7) showed that the therapy was well tolerated and that immunosuppression was not required; the action of the mesenchymal cells may be in part immunomodulatory. In addition, we have shown that allogeneic mesenchymal precursor cells improved clinical outcomes and functional benefits in patients with heart failure (8). This approach, although promising, will require confirmation in larger studies.
Second, using stem cells from other tissue sources may circumvent the problem of age-related decline in potency seen in bone marrow cells. Adipose tissue seems to be a promising source of stem cells. In a preliminary study in patients with ischemic cardiomyopathy, we have shown that the transendocardial injection of adipose-derived regenerative cells was safe and feasible, with encouraging efficacy data (9). The resiliency of adipose tissue is evidenced by patients' ability to gain weight easily even in the presence of multiple comorbidities known to inhibit stem cell function. It may be that certain tissues are less exposed to the detrimental effects of disease and aging.
Third, we may be able to turn back the clock on senescent, dysfunctional stem cells by treating them with genetic factors before delivery to reverse or forestall the aging process. Experimental in vitro data suggest that the 2 nuclear proteins myocardin A and telomerase reverse transcriptase may interact to maintain the stem cell–like features of mesenchymal stem cells derived from adipose tissue (10). Telomerase helps ensure growth potency of the cells, whereas myocardin A promotes expression of promyogenic genes. Hypothetically then, increasing the expression of these 2 factors in aging mesenchymal cells may potentially enhance their myogenic regenerative properties contributing to their growth and differentiation into cardiovascular myocytes. Another significant molecular player in the aging process is the mammalian target of rapamycin pathway, which regulates cell growth and proliferation. Of note, the paradigm of glucose homeostasis seems to be linked to lifespan prolongation through the inhibition of mammalian target of rapamycin complex 1, which may provide protection from age-related diseases (11,12). Unraveling the molecular aspects of cellular aging is densely complex, and multiple genetic targets may emerge as applicable to clinical therapies.
Last, and most pertinent to the study of Kang et al. (6), is rejuvenation of the target tissue. Age-related changes in the tissue environment, or the stem cell niche, may affect the regenerative capacity of delivered stem cells and resident stem cells (3). Much research has focused on aging mechanisms within the cell, but providing a more youthful tissue environment for delivery of cells may improve the functional benefits associated with cell therapy, even in older patients. The effects of youthful rejuvenation of aged tissues have been studied in the setting of heterochronic parabiosis, in which 2 age-mismatched animals (old and young) are surgically connected via a large flap of skin, thereby joining circulatory systems and exposing the tissue of old animals to a younger systemic milieu. By using this ingenious approach, investigators have shown that exposure to a rejuvenated environment improves regenerative responses of aged cells to liver, muscle, and brain injuries (13,14).
The present study by Kang et al. (6) provides us with a platform on which to begin building a construct for making aged cells more effective in autologous therapy. Science is poised to make a great leap in the understanding of the mechanisms of senescence and regeneration and in applying that knowledge for advancing cellular therapies. This journey into discovery of the aging process at the cellular level may be one of the greatest endeavors of modern-day science. Much as Faust finds redemption from his transcendental quest, humankind, through more rational means, stands to find fundamental and rewarding answers from our observations of nature.
Both authors have reported they have no relationships relevant to the contents of this paper to disclose.
↵⁎ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
↵† Balch CE, Barbieri R, Maitland C, Wilson S. Buying New Soul. From Recordings. KScope Records; 2008.
- American College of Cardiology Foundation
- Heeschen C.,
- Lehmann R.,
- Honold J.,
- et al.
- Kissel C.K.,
- Lehmann R.,
- Assmus B.,
- et al.
- Dimmeler S.,
- Leri A.
- Kang K.,
- Sun L.,
- Xiao Y.,
- et al.
- Hare J.M.,
- Traverse J.H.,
- Henry T.D.,
- et al.
- Perin E.C.
- Madonna R.,
- Wu D.,
- Wassler M.,
- De Caterina R.,
- Willerson J.T.,
- Geng Y.J.
- Lamming D.W.,
- Ye L.,
- Katajisto P.,
- et al.