Cardiovascular disease is the leading cause of death worldwide with myocardial infarction being the frontrunner for morbidity and mortality. Although medical and surgical treatments currently can significantly improve patient outcomes there exists no treatment that can generate new cardiac tissue or reverse the damage caused by cardiovascular disease. With new research being available that challenges the idea that myocytes are incapable of regeneration, a new avenue of treatment presents itself this being cell therapy. Increasing evidence is showing that stem/progenitor cell transplantation can replenish damaged tissues, improve cardiac and vascular function, and repair injured tissues. Despite the potential of cell therapy treatment the variation in results and lack of studies concluding the best stem cell type for treatment limit its ability to become a mainline treatment.
Cardiovascular disease (CVD) is one of the leading causes of death globally, in the UK alone heart and circulatory disease caused 27% of all deaths in 2019 (Heart & Circulatory Disease Statistics 2019, 2020). CVD is defined as a group of disorders of the heart and blood vessels, which can include coronary heart disease, cerebrovascular disease and peripheral arterial disease. Coronary heart disease including myocardial infarction accounts for most CVD cases (Mozaffarian et al.,2016). Currently treatment for CVD mainly includes prevention and management of the symptoms. Despite medical intervention the prognosis for patients after suffering from CVD is bleak. In myocardial infarction 50% of patients die within 5 years of the diagnosis (Shah and Shalia, 2011). Due to this high lethality it is imperative that a solution be found to reduce the chances of death. Current research is looking at the usage of stem/progenitor cell treatment in order to reverse the damage caused to the myocardium.
Stem cells are undifferentiated cells that can turn into specific cells that the body requires; these cells are sourced from two main sources which are adult body tissues such as bone marrow and embryos (Shah and Shalia, 2011). Progenitor cells are the descendants of stem cells that have differentiated into a more specialised type. Each progenitor cell is only capable of differentiating into cells that belong to the same tissue with some progenitor cells having a final target cell that they differentiate to and others potentially terminating into more than one cell. Cell therapy aims to use the ability of stem/progenitor cells to differentiate to replace and repair the cells damaged through injury. Studies are currently looking into the efficacy of numerous stem/progenitor cells which include induced pluripotent stem cells (iPCs), endothelial progenitor cells (EPCs), Embryonic Stem Cells (ESCs), cardiac stem cells (CSCs) and bone-marrow derived mononuclear cells (BMNCs).
Bone Marrow Derived Mononuclear Cells
Cell therapy treatment being used for CVD starts with unselected bone marrow cells. These cells can be isolated from bone marrow or peripheral blood and have no need for ex vivo expansion. BMNCs are heterogenic which contain several types of stem/progenitor cells such as mesenchymal stem cells and EPCs (Hou and Li, 2018). Due to being heterogenic BMNCs can differentiate into vascular or myocyte cells and secrete growth factors that improve the regeneration of injured tissues (Hou and Li, 2018). This makes BMNCs attractive for use in treatment as it allows for easy harvesting of the cells that can be quickly applied.
Clinical trials looking into the efficacy of BMNCs have shown mixed results. The randomised BOOST trial showed an improvement of left ventricle ejection fraction (LVEF) without any significant changes to left ventricle end-diastolic volumes 4-6 months after cell transfer (Wollert et al., 2004). Another trial the REGENT trial found no significant difference in the change in LVEF between the treatment groups or controls at 6 months (Tendera et al., 2009). The difference in results is thought to be due to discrepancies in the trials. A meta-analysis looked for discrepancies in design, methods and baseline characteristics, and results. It was reported that there was a significant association between the number of discrepancies and the reported increment in ejection fraction. The studies with the most discrepancies showed a mean ejection fraction effect size of 7.7% and studies with the least showing a mean ejection fraction effect size of 0.4% (Nowbar et al., 2014).
Cardiac Stem Cells
CSCs are a group of heterogeneous cells residing in the atrium and ventricular apex of the heart in very low densities (Madigan and Atoui, 2018). CSCs can self-renew and differentiate into three different cardiac cell types. Which includes cardiomyocytes, smooth muscle cells and endothelial cells (Hou and Li, 2018). After being identified CSCs have been shown to present a variety of stem cell markers, including c-Kit+, stem cell antigen-1+, Islet 1+, stage specific embryonic antigen-1+, cardiospheres, cardiospheres-derived, and side population (Hou and Li, 2018). The current phenotype that each of these stem cell markers produce is undetermined although studies have suggested what they lead to. Such as c-Kit+ stem cells indicating a commitment to the myogenic lineage (Goichberg et al., 2014). In comparison to other stem cell groups CSCs have been shown to express cardiac markers more efficiently and effectively differentiate into cardiomyocytes in vitro and in vivo in animal models (Madigan and Atoui, 2018). When applied to post-infarction rats CSCs formed new myocytes, vasculature and protected the existing cardiomyocytes through the secretion of IGF-1 (Leong et al., 2017).
Clinical trials are showing promising results for the use of CSCs to treat CVDs. C-Kit+ is currently being tested in the phase 1 SCIPIO trial. The results of this study showed that intracoronary injection of c-Kit+ increased the LVEF by 7.6 and 13.7%. The size of the infarction also decreased by 6.9 and 7.8g after 4 and 12 months (Bolli et al.,2011).
Currently the process of harvesting CSCs is proving difficult as it involves an invasive isolation technique. CSCs also require a costly ex vivo expansion to obtain the cell numbers needed for injection as they are found in very low densities (Madigan and Atoui, 2018 and Leong et al., 2017). To overcome this issue there is the possibility of activating the endogenous CSCs using drugs, growth factors and microRNAs (Madigan and Atoui, 2018).
Endothelial Progenitor Cells
The exact characterization of EPCs is not known although they appear to be a heterogenous group of cells originating from multiple precursors within the bone marrow and are present in different stages of endothelial differentiation in peripheral blood (Lee and Poh, 2014). To identify as an EPC the cells must be positive for a hematopoietic stem cell marker such as CD34 and an endothelial marker protein such as VEGFR2 (Lee and Poh, 2014).
Since isolation EPCs have been found to migrate to peripheral blood from the bone marrow and participate in the repairing of dysfunctional endothelia by directly infusing into and forming new vessels or by secreting pro-angiogenic growth factors (Hou and Li, 2018). Pre-clinical studies are showing promising results for the usage of EPCs to treat CVD. Rats 28 days after EPC injection had a greater capillary density and had significantly less left ventricular scarring (Kawamoto et al., 2001). The same beneficial effects are being seen in clinical trials, 167 patients with refractory angina were given doses of CD34+ cells. The trial reported that at 6 months and 12 months the weekly angina frequency was significantly lower than the placebo group (Losordo et al., 2011).
Although EPC based therapy shows promise these benefits are only modest and as no large-scale clinical trial has been performed on the efficacy the exact benefit of EPC based therapy is not fully known (Hou and Li, 2018).
Embryonic Stem Cells
ESCs are a population of pluripotent cells derived from the inner cell mass of the blastocyst during embryonic development. They can give rise to all adult cell types, therefore having the potential to regenerate lost myocardium (Madigan and Atoui, 2018). The main advantage of utilising ESCs is the ability to differentiate into cardiac myocytes and electromechanically couple to the host cells (Shah and Shalia, 2011). This can be seen in vitro such as during a study using a swine model with AV block. Following transplantation of human ESCs derived cardiomyocytes, the AV block was reversed (Madigan and Atoui, 2018). ESC derived cardiomyocytes closely resemble embryonic cardiac myocytes and express the cardiac-restricted transcription factors GATA4, Nkx2.5, MEF2C, and Irx4 (Shah and Shalia, 2011). Due to the pluripotency of ESCs a risk of teratoma formation is present although this can be solved by differentiating the ESCs into cardiac myocytes prior to transplantation (Shah and Shalia, 2011).
The use of ESCs in clinical trials occurred in the ESCORT trial in which ESC derived cardiac progenitor cells were delivered to patients with advanced ischaemic heart disease (Madigan and Atoui, 2018). The study reported an increase of LVEF from 26%-36% after 3 months (Menasché et al., 2015). Although the results are promising for the usage of ESCs the source of ESCs presents ethical and political issues preventing widespread usage.
Induced Pluripotent Stem Cells
IPCs are cells that have been derived from adult somatic cells and induced to express a gene profile characteristic of ESCs (Oct 3/4, Sox2, KLF4, cMyc) (Faiella and Atoui, 2016). In order to be useful clinically IPCs need to be able differentiate into cardiomyocytes or signal angiogenesis. Methods for doing this include the use of transcription factors and the use of growth factors. Oct ¾ is a transcription organiser that is currently being looked at due to its ability to interact with the Sox2 promoter that will signal cardio genesis (Faiella and Atoui, 2016). Growth factors being used are BMP and GSK3 which can direct differentiation into cardiac progenitor cells (Faiella and Atoui, 2016).
A preclinical study using mice has control mice showing an infarct size of 32.7% compared to the IPC injected group that showed an infarct size of 25.2% (Gu et al., 2012). The issue with using IPCs is the formation of teratomas. In immunocompetent mice the cardiac environment is suitable for differentiation whereas in immunodeficient mice tumour development is observed (Tongers, Losordo and Landmesser, 2011). For future studies this would mean that immune surveillance would be of high importance in order to prevent tumour growth.
Through clinical trials and preclinical studies cell therapy for use as a treatment in CVD has shown itself to be a very promising method to improve cardiac function and blood perfusion. Despite this there are still issues regarding making cell therapy a mainline treatment. This includes treating the diversity of CVD. An example of this is that treating early post-myocardial infarction would be very different to treating end-stage cardiac dysfunction. To discover the answer to this more study is needed to compare the effectiveness of each stem cell type (Taylor and Robertson, 2009). Another issue is that there is no definitive method for the application of cell therapy, as studies vary in the delivery of cells (surgical vs endovascular) and the concentration cells used (Taylor and Robertson, 2009). Stem cell usage also raises the concern of teratoma formation which is seen in the studies using ESCs and IPCs. This would have to be eliminated in future studies which could be done through guided cardiopoietic programming to guide stem cells down the cardiac lineage (Rao et al., 2011). In conclusion cell therapy offers a new way to treat CVD and provides a treatment option that reverses damage instead of just management. Although more studies are required to determine the effectiveness of each cell type, and a more definitive method needs to be found for the application of stem cells.
- Bhf.org.uk. 2020. Heart & Circulatory Disease Statistics 2019. [online]
- Bolli, R., Chugh, A.R., D’Amario, D., Loughran, J.H., Stoddard, M.F., Ikram, S., Beache, G.M., Wagner, S.G., Leri, A., Hosoda, T. and Sanada, F., 2011. Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial. The Lancet, 378(9806), pp.1847-1857.
- Faiella, W. and Atoui, R., 2016. Therapeutic use of stem cells for cardiovascular disease. Clinical and Translational Medicine, 5(1).
- Goichberg, P., Chang, J., Liao, R. and Leri, A., 2014. Cardiac stem cells: biology and clinical applications. Antioxidants & redox signaling, 21(14), pp.2002-2017.
- Gu, M., Nguyen, P.K., Lee, A.S., Xu, D., Hu, S., Plews, J.R., Han, L., Huber, B.C., Lee, W.H., Gong, Y. and De Almeida, P.E., 2012. Microfluidic single-cell analysis shows that porcine induced pluripotent stem cell–derived endothelial cells improve myocardial function by paracrine activation. Circulation research, 111(7), pp.882-893.
- Hou, Y. and Li, C., 2018. Stem/Progenitor Cells and Their Therapeutic Application in Cardiovascular Disease. Frontiers in Cell and Developmental Biology, 6.
- Kawamoto, A., Gwon, H.C., Iwaguro, H., Yamaguchi, J.I., Uchida, S., Masuda, H., Silver, M., Ma, H., Kearney, M., Isner, J.M. and Asahara, T., 2001. Therapeutic potential of ex vivo expanded endothelial progenitor cells for myocardial ischemia. Circulation, 103(5), pp.634-637.
- Lee, P.S.S. and Poh, K.K., 2014. Endothelial progenitor cells in cardiovascular diseases. World journal of stem cells, 6(3), p.355
- Leong, Y.Y., Ng, W.H., Ellison-Hughes, G.M. and Tan, J.J., 2017. Cardiac stem cells for myocardial regeneration: they are not alone. Frontiers in cardiovascular medicine, 4, p.47.
- Losordo, D.W., Henry, T.D., Davidson, C., Sup Lee, J., Costa, M.A., Bass, T., Mendelsohn, F., Fortuin, F.D., Pepine, C.J., Traverse, J.H. and Amrani, D., 2011. Intramyocardial, autologous CD34+ cell therapy for refractory angina. Circulation research, 109(4), pp.428-436.
- Madigan, M. and Atoui, R., 2018. Therapeutic Use of Stem Cells for Myocardial Infarction. Bioengineering, 5(2), p.28.
- Menasché, P., Vanneaux, V., Hagège, A., Bel, A., Cholley, B., Cacciapuoti, I., Parouchev, A., Benhamouda, N., Tachdjian, G., Tosca, L. and Trouvin, J.H., 2015. Human embryonic stem cell-derived cardiac progenitors for severe heart failure treatment: first clinical case report. European heart journal, 36(30), pp.2011-2017.
- Mozaffarian, D., Benjamin, E.J., Go, A.S., Arnett, D.K., Blaha, M.J., Cushman, M., Das, S.R., de Ferranti, S. and Després, J.P., 2016. a report from the American Heart Association. circulation, 133, pp.e38-e360.
- Nowbar, A.N., Mielewczik, M., Karavassilis, M., Dehbi, H.M., Shun-Shin, M.J., Jones, S., Howard, J.P., Cole, G.D. and Francis, D.P., 2014. Discrepancies in autologous bone marrow stem cell trials and enhancement of ejection fraction (DAMASCENE): weighted regression and meta-analysis. Bmj, 348.
- Rao, K., Krishna, K., Krishna, K., Berrocal, R. and Rao, K., 2011. Myocardial infarction and stem cells. Journal of Pharmacy and Bioallied Sciences, 3(2), p.182.
- Shah, V. and Shalia, K., 2011. Stem Cell Therapy in Acute Myocardial Infarction: A Pot of Gold or Pandora’s Box. Stem Cells International, 2011, pp.1-20.
- Taylor, D.A. and Robertson, M.J., 2009. Cardiovascular translational medicine (IX) the basics of cell therapy to treat cardiovascular disease: one cell does not fit all. Revista Española de Cardiología (English Edition), 62(9), pp.1032-1044.
- Tendera, M., Wojakowski, W., Rużyłło, W., Chojnowska, L., Kępka, C., Tracz, W., Musiałek, P., Piwowarska, W., Nessler, J., Buszman, P. and Grajek, S., 2009. Intracoronary infusion of bone marrow-derived selected CD34+ CXCR4+ cells and non-selected mononuclear cells in patients with acute STEMI and reduced left ventricular ejection fraction: results of randomized, multicentre Myocardial Regeneration by Intracoronary Infusion of Selected Population of Stem Cells in Acute Myocardial Infarction (REGENT) Trial. European heart journal, 30(11), pp.1313-1321.
- Tongers, J., Losordo, D. and Landmesser, U., 2011. Stem and progenitor cell-based therapy in ischaemic heart disease: promise, uncertainties, and challenges. European Heart Journal, 32(10), pp.1197-1206.
- Wollert, K.C., Meyer, G.P., Lotz, J., Lichtenberg, S.R., Lippolt, P., Breidenbach, C., Fichtner, S., Korte, T., Hornig, B., Messinger, D. and Arseniev, L., 2004. Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. The Lancet, 364(9429), pp.141-148.