Human hearts have limited regenerative ability, which presents significant challenges in healing after damage. Unlike certain animals, such as fish, that can regenerate their heart tissue effectively, humans typically respond to heart injuries by forming scar tissue, which can impair heart function. To understand why this occurs and what can be done to address it, it's important to explore both the biological processes involved and current research in regenerative medicine.
During human development, hearts grow through two main mechanisms: the differentiation of special cells called progenitor cells into heart muscle cells (cardiomyocytes) and the division of existing heart cells. This process, known as hyperplasia, continues through early life (Günthel et al., 2018). However, as humans mature, heart cells (cardiomyocytes) stop dividing and instead grow larger in a process called hypertrophy (Porrello et al., 2011; Porrello et al., 2013). This shift means that in adults, the heart is unable to repair itself by producing new cells after an injury.
After heart damage, such as during a heart attack, the body's response involves creating scar tissue. Scar tissue helps quickly patch up the damaged area, but it cannot contract like normal heart muscle. As a result, the heart's pumping ability is reduced, which can lead to heart failure. Proteins like TGF-β play a crucial role in this scarring process by stimulating fibroblasts to produce collagen (Liu et al., 2017). Although this process stabilizes the heart structure, excessive scarring can prevent proper healing and reduce the heart's efficiency (Ongstad & Gourdie, 2016).
Although adult human hearts show very limited natural regeneration, some studies indicate a minimal ability to produce new heart cells. For example, research involving carbon-14 dating found that a small number of new cardiomyocytes are generated each year, but this is not sufficient to repair significant damage, such as from a heart attack (Bergmann et al., 2009).
To enhance heart regeneration, scientists are focusing on various methods to encourage adult cardiomyocytes to re-enter the cell cycle and divide. One promising strategy involves blocking the Hippo pathway, which normally prevents cells from dividing (Zhou et al., 2015). By inhibiting this pathway, researchers have found that adult heart cells can resume division, adopt a more flexible structure, and help repair damaged heart tissue. Similarly, stimulating certain growth signals, such as those involving the proteins ErbB2 and Yap, has been shown to activate heart cell proliferation and reprogramming (Wadugu & Kühn, 2012; Xin et al., 2013).
Another approach involves manipulating specific genes. For instance, the Meis1 gene is known to suppress cell division in cardiomyocytes. Reducing its activity can extend the period during which heart cells are capable of dividing, promoting cell growth without affecting the heart's normal size or function (Mahmoud et al., 2013). Additionally, the overexpression of genes like Tbx20, which play roles in heart development and cellular signaling, can lead to increased cardiomyocyte division and improved heart repair after injury (Xiang et al., 2016). Tbx20's effects are linked to the activation of pathways that promote cell growth and the inhibition of those that restrict it (Chen et al., 2021).
Stem cells also play an important role in research focused on heart regeneration. Endogenous stem cells, which are naturally present in the body, have the potential to differentiate into various cardiac cell types and self-renew (Cho et al., 2014). For example, cardiac progenitor cells (CPCs) and cardiac stem cells (CSCs) can produce signals that encourage tissue repair, new blood vessel formation, and reduced inflammation. These cells help promote the proliferation of existing heart cells and can activate the body's own repair mechanisms. However, the availability of endogenous stem cells may be limited, particularly in cases of extensive damage or in older individuals, as their regenerative capacity tends to decline with age (Cianflone et al., 2019).
Exogenous stem cell transplantation involves introducing stem cells from outside the body to support heart repair. Cardiac progenitor cells can be sourced from heart tissue and expanded in the lab before being reintroduced into the damaged heart (Davis et al., 2010). Myoblasts from skeletal muscle have also been tested for their ability to support heart function, although they do not become cardiomyocytes and may not synchronize well with heart tissue (Vunjak-Novakovic et al., 2010). Bone marrow-derived stem cells, including c-kit+ cells and mesenchymal stem cells (MSCs), have been shown to support heart repair through paracrine effects—releasing beneficial factors rather than directly turning into heart cells (Baraniak & McDevitt, 2010).
Pluripotent stem cells, such as induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs), offer high potential for heart regeneration due to their ability to develop into genuine cardiomyocytes with normal heart muscle properties. iPSCs, which are reprogrammed from adult cells, bypass some ethical concerns associated with ESCs (Moradi et al., 2019). However, they must be thoroughly purified to avoid the risk of forming tumors (Blazeski et al., 2012). Advances in using small molecules and growth factors to direct iPSCs into heart cells have improved safety and effectiveness (Willems et al., 2011). Despite this, the immature nature of these cells can sometimes cause irregular heart rhythms when transplanted (Mazzola & Di Pasquale, 2020).
Endogenous stem cells have advantages, including their natural presence in the body, the ability to migrate to injury sites, and reduced risk of immune rejection (Zhu et al., 2021). However, their numbers and regenerative potential may be insufficient, especially in older patients. On the other hand, exogenous cells can be grown and modified in the lab to enhance their properties, allowing for tailored treatments. The main challenges with exogenous cells include the risk of immune rejection, potential tumor formation, and ethical considerations (Chehelgerdi et al., 2023).
Given the controllability and ability to modify exogenous stem cells, prioritizing research in this area could yield promising results. By optimizing cell culture and transplantation methods, researchers aim to overcome the limitations of endogenous cell regeneration, address age-related declines in healing, and develop scalable therapies that improve outcomes for people with heart damage (Mancuso et al., 2020).
References
Abeyrathna, P., & Su, Y. (2015). The Critical Role of Akt in Cardiovascular Function. Vascular Pharmacology, 74, 38–48. https://doi.org/10.1016/j.vph.2015.05.008
Baraniak, P. R., & McDevitt, T. C. (2010). Stem cell paracrine actions and tissue regeneration. Regenerative Medicine, 5(1), 121–143. https://doi.org/10.2217/rme.09.74
Barreto, S., Hamel, L., Schiatti, T., Yang, Y., & George, V. (2019). Cardiac Progenitor Cells from Stem Cells: Learning from Genetics and Biomaterials. Cells, 8(12), 1536. https://doi.org/10.3390/cells8121536
Barron, M., Gao, M., & Lough, J. (2000). Requirement for BMP and FGF signaling during cardiogenic induction in non-precardiac mesoderm is specific, transient, and cooperative. Developmental Dynamics: An Official Publication of the American Association of Anatomists, 218(2), 383–393. https://doi.org/10.1002/(SICI)1097-0177(200006)218:2<383::AID-DVDY11>3.0.CO;2-P
Bergmann, O., Bhardwaj, R. D., Bernard, S., Zdunek, S., Barnabé-Heider, F., Walsh, S., Zupicich, J., Alkass, K., Buchholz, B. A., Druid, H., Jovinge, S., & Frisén, J. (2009). Evidence for cardiomyocyte renewal in humans. Science (New York, N.Y.), 324(5923), 98–102. https://doi.org/10.1126/science.1164680
Blazeski, A., Zhu, R., Hunter, D. W., Weinberg, S. H., Boheler, K. R., Zambidis, E. T., & Tung, L. (2012). Electrophysiological and contractile function of cardiomyocytes derived from human embryonic stem cells. Progress in Biophysics and Molecular Biology, 110(0), 178–195. https://doi.org/10.1016/j.pbiomolbio.2012.07.012
Bryl, R., Kulus, M., Bryja, A., Domagała, D., Mozdziak, P., Antosik, P., Bukowska, D., Zabel, M., Dzięgiel, P., & Kempisty, B. (2024). Cardiac progenitor cell therapy: Mechanisms of action. Cell & Bioscience, 14, 30. https://doi.org/10.1186/s13578-024-01211-x
Chehelgerdi, M., Behdarvand Dehkordi, F., Chehelgerdi, M., Kabiri, H., Salehian-Dehkordi, H., Abdolvand, M., Salmanizadeh, S., Rashidi, M., Niazmand, A., Ahmadi, S., Feizbakhshan, S., Kabiri, S., Vatandoost, N., & Ranjbarnejad, T. (2023). Exploring the promising potential of induced pluripotent stem cells in cancer research and therapy. Molecular Cancer, 22(1), 189. https://doi.org/10.1186/s12943-023-01873-0
Chen, Y., Xiao, D., Zhang, L., Cai, C.-L., Li, B.-Y., & Liu, Y. (2021). The Role of Tbx20 in Cardiovascular Development and Function. Frontiers in Cell and Developmental Biology, 9, 638542. https://doi.org/10.3389/fcell.2021.638542
Cho, G.-S., Fernandez, L., & Kwon, C. (2014). Regenerative Medicine for the Heart: Perspectives on Stem-Cell Therapy. Antioxidants & Redox Signaling, 21(14), 2018–2031. https://doi.org/10.1089/ars.2014.6063
Cianflone, E., Torella, M., Chimenti, C., De Angelis, A., Beltrami, A. P., Urbanek, K., Rota, M., & Torella, D. (2019). Adult Cardiac Stem Cell Aging: A Reversible Stochastic Phenomenon? Oxidative Medicine and Cellular Longevity, 2019, 5813147. https://doi.org/10.1155/2019/5813147
Davis, D. R., Kizana, E., Terrovitis, J., Barth, A. S., Zhang, Y., Smith, R. R., Miake, J., & Marbán, E. (2010). Isolation and expansion of functionally-competent cardiac progenitor cells directly from heart biopsies. Journal of Molecular and Cellular Cardiology, 49(2), 312–321. https://doi.org/10.1016/j.yjmcc.2010.02.019
Durrani, S., Konoplyannikov, M., Ashraf, M., & Haider, K. H. (2010). Skeletal myoblasts for cardiac repair. Regenerative Medicine, 5(6), 919–932. https://doi.org/10.2217/rme.10.65
Esmaeili, R., Sadeghpour, A., Darbandi-Azar, A., Majidzadeh-A, K., Vajhi, A., & Sadeghizadeh, M. (2017). Echocardiographic assessment of myocardial infarction: Comparison of a rat model in two strains. Iranian Journal of Veterinary Research, 18(1), 30–35.
Evans, T. (2008). Embryonic Stem Cells as a Model for Cardiac Development and Disease. Drug Discovery Today. Disease Models, 5(3), 147–155. https://doi.org/10.1016/j.ddmod.2009.03.004
Fathi, E., Valipour, B., Vietor, I., & Farahzadi, R. (2020). An overview of the myocardial regeneration potential of cardiac c-Kit+ progenitor cells via PI3K and MAPK signaling pathways. Future Cardiology, 16(3), 199–209. https://doi.org/10.2217/fca-2018-0049
Günthel, M., Barnett, P., & Christoffels, V. M. (2018). Development, Proliferation, and Growth of the Mammalian Heart. Molecular Therapy, 26(7), 1599–1609. https://doi.org/10.1016/j.ymthe.2018.05.022
Jia, G., Mitra, A. K., Gangahar, D. M., & Agrawal, D. K. (2010). Insulin-like Growth factor-1 Induces Phosphorylation of PI3K-Akt/PKB to Potentiate Proliferation of Smooth Muscle Cells in Human Saphenous Vein. Experimental and Molecular Pathology, 89(1), 20–26. https://doi.org/10.1016/j.yexmp.2010.04.002
Lafontant, P. (2006). The cardiomyocyte cell cycle. Biology Faculty Publications. https://scholarship.depauw.edu/bio_facpubs/6
Lafontant, P. J., Burns, A. R., Grivas, J. A., Lesch, M. A., Lala, T. D., Reuter, S. P., Field, L. J., & Frounfelter, T. D. (2012). The Giant Danio (D. Aequipinnatus) as A Model of Cardiac Remodeling and Regeneration. The Anatomical Record, 295(2), 234–248. https://doi.org/10.1002/ar.21492
Liu, G., Ma, C., Yang, H., & Zhang, P.-Y. (2017). Transforming growth factor β and its role in heart disease. Experimental and Therapeutic Medicine, 13(5), 2123–2128. https://doi.org/10.3892/etm.2017.4246
Mahmoud, A. I., Kocabas, F., Muralidhar, S. A., Kimura, W., Koura, A. S., Thet, S., Porrello, E. R., & Sadek, H. A. (2013). Meis1 regulates postnatal cardiomyocyte cell cycle arrest. Nature, 497(7448), 249–253. https://doi.org/10.1038/nature12054
Mancuso, A., Barone, A., Cristiano, M. C., Cianflone, E., Fresta, M., & Paolino, D. (2020). Cardiac Stem Cell-Loaded Delivery Systems: A New Challenge for Myocardial Tissue Regeneration. International Journal of Molecular Sciences, 21(20), 7701. https://doi.org/10.3390/ijms21207701
Mazzola, M., & Di Pasquale, E. (2020). Toward Cardiac Regeneration: Combination of Pluripotent Stem Cell-Based Therapies and Bioengineering Strategies. Frontiers in Bioengineering and Biotechnology, 8, 455. https://doi.org/10.3389/fbioe.2020.00455
Menasché, P., Vanneaux, V., Hagège, A., Bel, A., Cholley, B., Parouchev, A., Cacciapuoti, I., Al-Daccak, R., Benhamouda, N., Blons, H., Agbulut, O., Tosca, L., Trouvin, J.-H., Fabreguettes, J.-R., Bellamy, V., Charron, D., Tartour, E., Tachdjian, G., Desnos, M., & Larghero, J. (2018). Transplantation of Human Embryonic Stem Cell–Derived Cardiovascular Progenitors for Severe Ischemic Left Ventricular Dysfunction. Journal of the American College of Cardiology, 71(4), 429–438. https://doi.org/10.1016/j.jacc.2017.11.047
Moradi, S., Mahdizadeh, H., Šarić, T., Kim, J., Harati, J., Shahsavarani, H., Greber, B., & Moore, J. B. (2019a). Research and therapy with induced pluripotent stem cells (iPSCs): Social, legal, and ethical considerations. Stem Cell Research & Therapy, 10, 341. https://doi.org/10.1186/s13287-019-1455-y
Moradi, S., Mahdizadeh, H., Šarić, T., Kim, J., Harati, J., Shahsavarani, H., Greber, B., & Moore, J. B. (2019b). Research and therapy with induced pluripotent stem cells (iPSCs): Social, legal, and ethical considerations. Stem Cell Research & Therapy, 10, 341. https://doi.org/10.1186/s13287-019-1455-y
Mousaei Ghasroldasht, M., Seok, J., Park, H.-S., Liakath Ali, F. B., & Al-Hendy, A. (2022). Stem Cell Therapy: From Idea to Clinical Practice. International Journal of Molecular Sciences, 23(5), 2850. https://doi.org/10.3390/ijms23052850
Naqvi, N., Iismaa, S. E., Graham, R. M., & Husain, A. (2021). Mechanism-Based Cardiac Regeneration Strategies in Mammals. Frontiers in Cell and Developmental Biology, 9, 747842. https://doi.org/10.3389/fcell.2021.747842
Ongstad, E. L., & Gourdie, R. G. (2016). Can Heart Function Lost To Disease Be Regenerated By Therapeutic Targeting Of Cardiac Scar Tissue? Seminars in Cell & Developmental Biology, 58, 41–54. https://doi.org/10.1016/j.semcdb.2016.05.020
Rheault-Henry, M., White, I., Grover, D., & Atoui, R. (2021). Stem cell therapy for heart failure: Medical breakthrough, or dead end? World Journal of Stem Cells, 13(4), 236–259. https://doi.org/10.4252/wjsc.v13.i4.236
Taylor, C. J., Bolton, E. M., & Bradley, J. A. (2011). Immunological considerations for embryonic and induced pluripotent stem cell banking. Philosophical Transactions of the Royal Society B: Biological Sciences, 366(1575), 2312–2322. https://doi.org/10.1098/rstb.2011.0030
Velikic, G., Maric, D. M., Maric, D. L., Supic, G., Puletic, M., Dulic, O., & Vojvodic, D. (2024). Harnessing the Stem Cell Niche in Regenerative Medicine: Innovative Avenue to Combat Neurodegenerative Diseases. International Journal of Molecular Sciences, 25(2), 993. https://doi.org/10.3390/ijms25020993
Vunjak-Novakovic, G., Tandon, N., Godier, A., Maidhof, R., Marsano, A., Martens, T. P., & Radisic, M. (2010). Challenges in Cardiac Tissue Engineering. Tissue Engineering. Part B, Reviews, 16(2), 169–187. https://doi.org/10.1089/ten.teb.2009.0352
Wadugu, B., & Kühn, B. (2012). The role of neuregulin/ErbB2/ErbB4 signaling in the heart with special focus on effects on cardiomyocyte proliferation. American Journal of Physiology - Heart and Circulatory Physiology, 302(11), H2139–H2147. https://doi.org/10.1152/ajpheart.00063.2012
Wanjare, M., & Huang, N. F. (2017). Regulation of the microenvironment for cardiac tissue engineering. Regenerative Medicine, 12(2), 187–201. https://doi.org/10.2217/rme-2016-0132
Willems, E., Spiering, S., Davidovics, H., Lanier, M., Xia, Z., Dawson, M., Cashman, J., & Mercola, M. (2011). Small molecule inhibitors of the Wnt pathway potently promote cardiomyocytes from human embryonic stem cell derived mesoderm. Circulation Research, 109(4), 360–364. https://doi.org/10.1161/CIRCRESAHA.111.249540
Xiang, F.-L., Guo, M., & Yutzey, K. E. (2016). Overexpression of Tbx20 in Adult Cardiomyocytes Promotes Proliferation and Improves Cardiac Function After Myocardial Infarction. Circulation, 133(11), 1081–1092. https://doi.org/10.1161/CIRCULATIONAHA.115.019357
Xin, M., Kim, Y., Sutherland, L. B., Murakami, M., Qi, X., McAnally, J., Porrello, E. R., Mahmoud, A. I., Tan, W., Shelton, J. M., Richardson, J. A., Sadek, H. A., Bassel-Duby, R., & Olson, E. N. (2013). Hippo pathway effector Yap promotes cardiac regeneration. Proceedings of the National Academy of Sciences, 110(34), 13839–13844. https://doi.org/10.1073/pnas.1313192110
Zhou, P., Yu, S., Zhang, H., Wang, Y., Tao, P., Tan, Y., & Wang, H. (2023). C-kit+VEGFR-2+ Mesenchymal Stem Cells Differentiate into Cardiovascular Cells and Repair Infarcted Myocardium after Transplantation. Stem Cell Reviews and Reports, 19(1), 230–247. https://doi.org/10.1007/s12015-022-10430-z
Zhou, Q., Li, L., Zhao, B., & Guan, K.-L. (2015). The Hippo pathway in heart development, regeneration, and diseases. Circulation Research, 116(8), 1431–1447. https://doi.org/10.1161/CIRCRESAHA.116.303311
Zhu, D., Li, Z., Huang, K., Caranasos, T. G., Rossi, J. S., & Cheng, K. (2021). Minimally invasive delivery of therapeutic agents by hydrogel injection into the pericardial cavity for cardiac repair. Nature Communications, 12, 1412. https://doi.org/10.1038/s41467-021-21682-7
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