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Strategies to Enhance the Effectiveness of Adult Stem Cell Therapy for Ischemic Heart Diseases Affecting the Elderly Patients

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Abstract

Myocardial infarctions and chronic ischemic heart disease both commonly and disproportionately affect elderly patients more than any other patient population. Despite available treatments, heart tissue is often permanently damaged as a result of cardiac injury. This review aims to summarize recent literature proposing the use of modified autologous adult stem cells to promote healing of post-infarct cardiac tissue. This novel cellular treatment involves isolation of adult stem cells from the patient, in vitro manipulation of these stem cells, and subsequent transplantation back into the patient’s own heart to accelerate healing. One of the hindrances affecting this process is that cardiac issues are increasingly common in elderly patients, and stem cells recovered from their tissues tend to be pre-senescent or already in senescence. As a result, harsh in vitro manipulations can cause the aged stem cells to undergo massive in vivo apoptosis after transplantation. The consensus in literature is that inhibition or reversal of senescence onset in adult stem cells would be of utmost benefit. In fact, it is believed that this strategy may lower stem cell mortality and coerce aged stem cells into adopting more resilient phenotypes similar to that of their younger counterparts. This review will discuss a selection of the most efficient and most-recent strategies used experimentally to enhance the effectiveness of current stem cell therapies for ischemic heart diseases.

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References

  1. Dong, L., Hao, H., Han, W., and Fu, X. (2015). The role of the microenvironment on the fate of adult stem cells. Science China. Life Sciences

  2. Segers, V. F., & Lee, R. T. (2008). Stem-cell therapy for cardiac disease. Nature, 451, 937–942.

    Article  CAS  PubMed  Google Scholar 

  3. Mohsin, S., Siddiqi, S., Collins, B., & Sussman, M. A. (2011). Empowering adult stem cells for myocardial regeneration. Circulation Research, 109, 1415–1428.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Sanada, F., Kim, J., Czarna, A., Chan, N. Y., Signore, S., Ogorek, B., Isobe, K., Wybieralska, E., Borghetti, G., Pesapane, A., Sorrentino, A., Mangano, E., Cappetta, D., Mangiaracina, C., Ricciardi, M., Cimini, M., Ifedigbo, E., Perrella, M. A., Goichberg, P., Choi, A. M., Kajstura, J., Hosoda, T., Rota, M., Anversa, P., & Leri, A. (2014). c-Kit-positive cardiac stem cells nested in hypoxic niches are activated by stem cell factor reversing the aging myopathy. Circulation Research, 114, 41–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Conboy, I. M., Conboy, M. J., Wagers, A. J., Girma, E. R., Weissman, I. L., & Rando, T. A. (2005). Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature, 433, 760–764.

    Article  CAS  PubMed  Google Scholar 

  6. Cutts, J., Nikkhah, M., & Brafman, D. A. (2015). Biomaterial approaches for stem cell-based myocardial tissue engineering. Biomarker Insights, 10, 77–90.

    PubMed  PubMed Central  Google Scholar 

  7. Finan, A., & Richard, S. (2015). Stimulating endogenous cardiac repair. Frontiers in Cell and Developmental Biology, 3, 57.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Nadal-Ginard, B., Ellison, G. M., & Torella, D. (2014). The cardiac stem cell compartment is indispensable for myocardial cell homeostasis, repair and regeneration in the adult. Stem Cell Research, 13, 615–630.

    Article  CAS  PubMed  Google Scholar 

  9. Liang, Y., Van Zant, G., & Szilvassy, S. J. (2005). Effects of aging on the homing and engraftment of murine hematopoietic stem and progenitor cells. Blood, 106, 1479–1487.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kubo, M., Li, T. S., Kurazumi, H., Takemoto, Y., Ohshima, M., Murata, T., Katsura, S., Morikage, N., Furutani, A., & Hamano, K. (2012). Hypoxic preconditioning enhances angiogenic potential of bone marrow cells with aging-related functional impairment. Circulation Journal : Official Journal of the Japanese Circulation Society, 76, 986–994.

    Article  CAS  Google Scholar 

  11. Hu, S., Yan, G., Xu, H., He, W., Liu, Z., & Ma, G. (2014). Hypoxic preconditioning increases survival of cardiac progenitor cells via the pim-1 kinase-mediated anti-apoptotic effect. Circulation Journal : Official Journal of the Japanese Circulation Society, 78, 724–731.

    Article  CAS  Google Scholar 

  12. Lee, S. H., Lee, J. H., Yoo, S. Y., Hur, J., Kim, H. S., & Kwon, S. M. (2013). Hypoxia inhibits cellular senescence to restore the therapeutic potential of old human endothelial progenitor cells via the hypoxia-inducible factor-1alpha-TWIST-p21 axis. Arteriosclerosis, Thrombosis, and Vascular Biology, 33, 2407–2414.

    Article  CAS  PubMed  Google Scholar 

  13. Haider, H., & Ashraf, M. (2008). Strategies to promote donor cell survival: combining preconditioning approach with stem cell transplantation. Journal of Molecular and Cellular Cardiology, 45, 554–566.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Haider, H., & Ashraf, M. (2010). Preconditioning and stem cell survival. Journal of Cardiovascular Translational Research, 3, 89–102.

    Article  PubMed  Google Scholar 

  15. Rosova, I., Dao, M., Capoccia, B., Link, D., & Nolta, J. A. (2008). Hypoxic preconditioning results in increased motility and improved therapeutic potential of human mesenchymal stem cells. Stem Cells, 26, 2173–2182.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Liu, X. B., Wang, J. A., Ji, X. Y., Yu, S. P., & Wei, L. (2014). Preconditioning of bone marrow mesenchymal stem cells by prolyl hydroxylase inhibition enhances cell survival and angiogenesis in vitro and after transplantation into the ischemic heart of rats. Stem Cell Research & Therapy, 5, 111.

    Article  Google Scholar 

  17. Cai, C., Teng, L., Vu, D., He, J. Q., Guo, Y., Li, Q., Tang, X. L., Rokosh, G., Bhatnagar, A., & Bolli, R. (2012). The heme oxygenase 1 inducer (CoPP) protects human cardiac stem cells against apoptosis through activation of the extracellular signal-regulated kinase (ERK)/NRF2 signaling pathway and cytokine release. The Journal of Biological Chemistry, 287, 33720–33732.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Cai, C., Guo, Y., Teng, L., Nong, Y., Tan, M., Book, M. J., Zhu, X., Wang, X. L., Du, J., Wu, W. J., Xie, W., Hong, K. U., Li, Q., and Bolli, R. (2015). Preconditioning human cardiac stem cells with an HO-1 inducer exerts beneficial effects after cell transplantation in the infarcted murine heart. Stem cells.

  19. Issan, Y., Kornowski, R., Aravot, D., Shainberg, A., Laniado-Schwartzman, M., Sodhi, K., Abraham, N. G., & Hochhauser, E. (2014). Heme oxygenase-1 induction improves cardiac function following myocardial ischemia by reducing oxidative stress. PLoS One, 9, e92246.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Sheng, Z., Yao, Y., Li, Y., Yan, F., Huang, J., & Ma, G. (2013). Bradykinin preconditioning improves therapeutic potential of human endothelial progenitor cells in infarcted myocardium. PLoS One, 8, e81505.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Akao, M., Teshima, Y., & Marban, E. (2002). Antiapoptotic effect of nicorandil mediated by mitochondrial atp-sensitive potassium channels in cultured cardiac myocytes. Journal of the American College of Cardiology, 40, 803–810.

    Article  CAS  PubMed  Google Scholar 

  22. Hoke, N. N., Salloum, F. N., Kass, D. A., Das, A., & Kukreja, R. C. (2012). Preconditioning by phosphodiesterase-5 inhibition improves therapeutic efficacy of adipose-derived stem cells following myocardial infarction in mice. Stem Cells, 30, 326–335.

    Article  CAS  PubMed  Google Scholar 

  23. Zhang, L., Qin, X., Zhao, Y., Fast, L., Zhuang, S., Liu, P., Cheng, G., & Zhao, T. C. (2012). Inhibition of histone deacetylases preserves myocardial performance and prevents cardiac remodeling through stimulation of endogenous angiomyogenesis. Journal of Pharmacology and Experimental Therapeutics, 341, 285–293.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Veis, D. J., Sorenson, C. M., Shutter, J. R., & Korsmeyer, S. J. (1993). Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Cell, 75, 229–240.

    Article  CAS  PubMed  Google Scholar 

  25. Nunez, G., Benedict, M. A., Hu, Y., & Inohara, N. (1998). Caspases: the proteases of the apoptotic pathway. Oncogene, 17, 3237–3245.

    Article  PubMed  Google Scholar 

  26. Kutschka, I., Kofidis, T., Chen, I. Y., von Degenfeld, G., Zwierzchoniewska, M., Hoyt, G., Arai, T., Lebl, D. R., Hendry, S. L., Sheikh, A. Y., Cooke, D. T., Connolly, A., Blau, H. M., Gambhir, S. S., & Robbins, R. C. (2006). Adenoviral human BCL-2 transgene expression attenuates early donor cell death after cardiomyoblast transplantation into ischemic rat hearts. Circulation, 114, I174–I180.

    PubMed  Google Scholar 

  27. Murphy, A. N., Bredesen, D. E., Cortopassi, G., Wang, E., & Fiskum, G. (1996). Bcl-2 potentiates the maximal calcium uptake capacity of neural cell mitochondria. Proceedings of the National Academy of Sciences of the United States of America, 93, 9893–9898.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Li, W., Ma, N., Ong, L. L., Nesselmann, C., Klopsch, C., Ladilov, Y., Furlani, D., Piechaczek, C., Moebius, J. M., Lutzow, K., Lendlein, A., Stamm, C., Li, R. K., & Steinhoff, G. (2007). Bcl-2 engineered MSCs inhibited apoptosis and improved heart function. Stem Cells, 25, 2118–2127.

    Article  CAS  PubMed  Google Scholar 

  29. Shintani, S., Kusano, K., Ii, M., Iwakura, A., Heyd, L., Curry, C., Wecker, A., Gavin, M., Ma, H., Kearney, M., Silver, M., Thorne, T., Murohara, T., & Losordo, D. W. (2006). Synergistic effect of combined intramyocardial CD34+ cells and VEGF2 gene therapy after MI. Nature Clinical Practice. Cardiovascular Medicine, 3(Suppl 1), S123–S128.

    Article  CAS  PubMed  Google Scholar 

  30. Ohtani, N., Yamakoshi, K., Takahashi, A., & Hara, E. (2004). The p16INK4a-RB pathway : molecular link between cellular senescence and tumor suppression. The Journal of Medical Investigation, 51, 146–153.

    Article  PubMed  Google Scholar 

  31. Brookes, S., Rowe, J., Gutierrez Del Arroyo, A., Bond, J., & Peters, G. (2004). Contribution of p16(INK4a) to replicative senescence of human fibroblasts. Experimental Cell Research, 298, 549–559.

    Article  CAS  PubMed  Google Scholar 

  32. Janzen, V., Forkert, R., Fleming, H. E., Saito, Y., Waring, M. T., Dombkowski, D. M., Cheng, T., DePinho, R. A., Sharpless, N. E., & Scadden, D. T. (2006). Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a. Nature, 443, 421–426.

    CAS  PubMed  Google Scholar 

  33. Morrison, S. J., Wandycz, A. M., Akashi, K., Globerson, A., & Weissman, I. L. (1996). The aging of hematopoietic stem cells. Nature Medicine, 2, 1011–1016.

    Article  CAS  PubMed  Google Scholar 

  34. Sack, M. N. (2012). The role of SIRT3 in mitochondrial homeostasis and cardiac adaptation to hypertrophy and aging. Journal of Molecular and Cellular Cardiology, 52, 520–525.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Jing, E., Emanuelli, B., Hirschey, M. D., Boucher, J., Lee, K. Y., Lombard, D., Verdin, E. M., & Kahn, C. R. (2011). Sirtuin-3 (Sirt3) regulates skeletal muscle metabolism and insulin signaling via altered mitochondrial oxidation and reactive oxygen species production. Proceedings of the National Academy of Sciences of the United States of America, 108, 14608–14613.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Stolzing, A., Coleman, N., & Scutt, A. (2006). Glucose-induced replicative senescence in mesenchymal stem cells. Rejuvenation Research, 9, 31–35.

    Article  CAS  PubMed  Google Scholar 

  37. Lee, J. H., Jung, K. J., Kim, J. W., Kim, H. J., Yu, B. P., & Chung, H. Y. (2004). Suppression of apoptosis by calorie restriction in aged kidney. Experimental Gerontology, 39, 1361–1368.

    Article  CAS  PubMed  Google Scholar 

  38. Quagliaro, L., Piconi, L., Assaloni, R., Martinelli, L., Motz, E., & Ceriello, A. (2003). Intermittent high glucose enhances apoptosis related to oxidative stress in human umbilical vein endothelial cells: the role of protein kinase C and NAD(P)H-oxidase activation. Diabetes, 52, 2795–2804.

    Article  CAS  PubMed  Google Scholar 

  39. Klotz, B., Mentrup, B., Regensburger, M., Zeck, S., Schneidereit, J., Schupp, N., Linden, C., Merz, C., Ebert, R., & Jakob, F. (2012). 1,25-dihydroxyvitamin D3 treatment delays cellular aging in human mesenchymal stem cells while maintaining their multipotent capacity. PLoS One, 7, e29959.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Chakkalakal, J. V., Jones, K. M., Basson, M. A., & Brack, A. S. (2012). The aged niche disrupts muscle stem cell quiescence. Nature, 490, 355–360.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Li, L., & Clevers, H. (2010). Coexistence of quiescent and active adult stem cells in mammals. Science, 327, 542–545.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Katsimpardi, L., Litterman, N. K., Schein, P. A., Miller, C. M., Loffredo, F. S., Wojtkiewicz, G. R., Chen, J. W., Lee, R. T., Wagers, A. J., & Rubin, L. L. (2014). Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science, 344, 630–634.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Sinha, M., Jang, Y. C., Oh, J., Khong, D., Wu, E. Y., Manohar, R., Miller, C., Regalado, S. G., Loffredo, F. S., Pancoast, J. R., Hirshman, M. F., Lebowitz, J., Shadrach, J. L., Cerletti, M., Kim, M. J., Serwold, T., Goodyear, L. J., Rosner, B., Lee, R. T., & Wagers, A. J. (2014). Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle. Science, 344, 649–652.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Mohsin, S., Khan, M., Nguyen, J., Alkatib, M., Siddiqi, S., Hariharan, N., Wallach, K., Monsanto, M., Gude, N., Dembitsky, W., & Sussman, M. A. (2013). Rejuvenation of human cardiac progenitor cells with Pim-1 kinase. Circulation Research, 113, 1169–1179.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Zhou, X. (2014). Role of Notch signaling in the mammalian. 47, 1–10

  46. Carlson, M. E., Hsu, M., & Conboy, I. M. (2008). Imbalance between pSmad3 and Notch induces CDK inhibitors in old muscle stem cells. Nature, 454, 528–532.

    Article  CAS  PubMed  Google Scholar 

  47. Yoshida, Y., Hayashi, Y., Suda, M., Tateno, K., Okada, S., Moriya, J., Yokoyama, M., Nojima, A., Yamashita, M., Kobayashi, Y., Shimizu, I., & Minamino, T. (2014). Notch signaling regulates the lifespan of vascular endothelial cells via a p16-dependent pathway. PLoS One, 9, e100359.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Fischer, K. M., Cottage, C. T., Wu, W., Din, S., Gude, N. A., Avitabile, D., Quijada, P., Collins, B. L., Fransioli, J., & Sussman, M. A. (2009). Enhancement of myocardial regeneration through genetic engineering of cardiac progenitor cells expressing Pim-1 kinase. Circulation, 120, 2077–2087.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Zippo, A., De Robertis, A., Bardelli, M., Galvagni, F., & Oliviero, S. (2004). Identification of Flk-1 target genes in vasculogenesis: Pim-1 is required for endothelial and mural cell differentiation in vitro. Blood, 103, 4536–4544.

    Article  CAS  PubMed  Google Scholar 

  50. Mohsin, S., Khan, M., Toko, H., Bailey, B., Cottage, C. T., Wallach, K., Nag, D., Lee, A., Siddiqi, S., Lan, F., Fischer, K. M., Gude, N., Quijada, P., Avitabile, D., Truffa, S., Collins, B., Dembitsky, W., Wu, J. C., & Sussman, M. A. (2012). Human cardiac progenitor cells engineered with Pim-I kinase enhance myocardial repair. Journal of the American College of Cardiology, 60, 1278–1287.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Blagosklonny, M. V. (2008). Aging, stem cells, and mammalian target of rapamycin: a prospect of pharmacologic rejuvenation of aging stem cells. Rejuvenation Research, 11, 801–808.

    Article  CAS  PubMed  Google Scholar 

  52. Gao, X. M., Wong, G., Wang, B., Kiriazis, H., Moore, X. L., Su, Y. D., Dart, A., & Du, X. J. (2006). Inhibition of mTOR reduces chronic pressure-overload cardiac hypertrophy and fibrosis. Journal of Hypertension, 24, 1663–1670.

    Article  CAS  PubMed  Google Scholar 

  53. Blagosklonny, M. V. (2012). Cell cycle arrest is not yet senescence, which is not just cell cycle arrest: terminology for TOR-driven aging. Aging, 4, 159–165.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Menendez, J. A., Vellon, L., Oliveras-Ferraros, C., Cufi, S., & Vazquez-Martin, A. (2011). mTOR-regulated senescence and autophagy during reprogramming of somatic cells to pluripotency: a roadmap from energy metabolism to stem cell renewal and aging. Cell Cycle, 10, 3658–3677.

    Article  CAS  PubMed  Google Scholar 

  55. Chen, C., Liu, Y., Liu, Y., & Zheng, P. (2009). mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Science Signaling, 2, ra75.

    PubMed  PubMed Central  Google Scholar 

  56. Avolio, E., Gianfranceschi, G., Cesselli, D., Caragnano, A., Athanasakis, E., Katare, R., Meloni, M., Palma, A., Barchiesi, A., Vascotto, C., Toffoletto, B., Mazzega, E., Finato, N., Aresu, G., Livi, U., Emanueli, C., Scoles, G., Beltrami, C. A., Madeddu, P., & Beltrami, A. P. (2014). Ex vivo molecular rejuvenation improves the therapeutic activity of senescent human cardiac stem cells in a mouse model of myocardial infarction. Stem Cells, 32, 2373–2385.

    Article  PubMed  Google Scholar 

  57. Cesselli, D., Beltrami, A. P., D'Aurizio, F., Marcon, P., Bergamin, N., Toffoletto, B., Pandolfi, M., Puppato, E., Marino, L., Signore, S., Livi, U., Verardo, R., Piazza, S., Marchionni, L., Fiorini, C., Schneider, C., Hosoda, T., Rota, M., Kajstura, J., Anversa, P., Beltrami, C. A., & Leri, A. (2011). Effects of age and heart failure on human cardiac stem cell function. The American Journal of Pathology, 179, 349–366.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Frey, N., Linke, A., Suselbeck, T., Muller-Ehmsen, J., Vermeersch, P., Schoors, D., Rosenberg, M., Bea, F., Tuvia, S., & Leor, J. (2014). Intracoronary delivery of injectable bioabsorbable scaffold (IK-5001) to treat left ventricular remodeling after ST-elevation myocardial infarction: a first-in-man study. Circulation. Cardiovascular Interventions, 7, 806–812.

    Article  PubMed  Google Scholar 

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Acknowledgments

This study was supported by NIH Grants R01HL114951 (to C.C.) from the National Institutes of Health, and Research Grant 12BGIA9090005 (to C.C.) from the American Heart Association.

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  1. Center for Cardiovascular Sciences, Albany Medical College, Albany, NY, 12208, USA

    Roshni Khatiwala & Chuanxi Cai

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Correspondence to Chuanxi Cai.

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Khatiwala, R., Cai, C. Strategies to Enhance the Effectiveness of Adult Stem Cell Therapy for Ischemic Heart Diseases Affecting the Elderly Patients. Stem Cell Rev and Rep 12, 214–223 (2016). https://doi.org/10.1007/s12015-016-9642-z

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