Written by: Krystal, Chongqing Medical University
Expert review: Professor Li Jing, Affiliated Hospital of Jiangsu University
In recent years, clinical trials of mesenchymal stem cells for ischemic cardiomyopathy have been widely carried out. Recently, a review published in the journal Stem cell research & therapy summarized a number of clinical trials of mesenchymal stem cells for the treatment of ischemic cardiomyopathy [1], believing that mesenchymal stem cell-based therapies have certain safety and efficacy, and that the route of administration, stem cell source and dosage are the key points of thinking for the development of future clinical applications, and the future clinical development can still be breakthroughs.
01
Mesenchymal stem cells: a promising means of myocardial repair and regeneration
The high incidence and mortality of cardiovascular disease remain the leading causes of death worldwide, with coronary heart disease being one of the most common. Prolonged myocardial ischemia caused by coronary heart disease often leads to ischemic cardiomyopathy. At present, different degrees of myocardial dysfunction and fibrosis have been detected in ischemic cardiomyopathy. Over the past few decades, treatment for ischemic cardiomyopathy has focused on relieving symptoms, preventing disease progression, and improving survival and quality of life.
Mesenchymal stem cells can secrete a variety of molecules with anti-inflammatory and immunomodulatory activities, with anti-fibrosis, anti-inflammatory, anti-apoptosis, immunomodulatory and pro-angiogenesis and other properties, can stimulate the repair and regeneration of damaged myocardium, is considered to be a promising treatment in the field of myocardial repair and regeneration.
In patients with dilated cardiomyopathy, mesenchymal stem cells improve heart function by restoring endothelial function, thereby enhancing coronary artery circulation. In patients with ischemic cardiomyopathy, mesenchymal stem cells are used by antifibrosis to reduce scarring and reverse left ventricular remodeling.
Image from literature[1]
Relationship between the mechanism of action of mesenchymal stem cells (red circle) and the key component of reduced ejection fraction heart failure (blue circle).
The regenerative capacity of mesenchymal stem cells is attributed to their paracrine. Mesenchymal stem cells not only secrete a variety of growth factors, such as insulin-like growth factor-1, vascular endothelial growth factor, and fibroblast growth factor, but also express a variety of cytokines such as angiopoietin-1, interleukin-1, interleukin-6, and plasminogen activators, which can stimulate cardiomyocyte proliferation in a variety of ways.
Mesenchymal stem cells can differentiate into endothelial cells, smooth muscle cells, and improve the function of resident cardiomyocytes, an important cellular component of the heart. Mesenchymal stem cell therapy in animal models of ischemia results in improved ventricular pump function, scar tissue reduction, and new angiogenesis after myocardial infarction [2].
Image from literature[1]
Hybrid therapies that combine cell, exosome-mediated mesenchymal stem cells and engineered heart patches with MSC+/- ESC are a future approach to improving heart repair and regeneration. (MSC mesenchymal stem cells, ESC embryonic stem cells)
02
Clinical studies have confirmed the efficacy of mesenchymal stem cells
Image from literature[1]
Clinical efficacy of mesenchymal stem cell therapy
In recent years, mesenchymal stem cells have been widely adopted in the therapeutic research field of acute and old myocardial infarction. In animal models, mesenchymal stem cells have achieved good results for acute and stale myocardial infarction [3], as well as in human clinical trials.
Studies have shown that mesenchymal stem cell therapy can reduce the area of infarction, reverse remodeling of the left ventricle, improve local myocardial wall contractility, and reduce the volume of end-diastolic and end-systolic period (LVEDV/LVESV). In a 2015 publication[4], patients with ST-segment elevation myocardial infarction (STEMI) received coronary artery mesenchymal stem cell injections for 6 months, myocardial perfusion and overall cardiac function improved, and had a good safety profile. The literature published in 2014 has also demonstrated signs of safety and efficacy of intracardial injection of mesenchymal precursor cells in patients with end-stage heart failure [5].
However, some studies have come to different conclusions, such as a 2015 study published in Cytotherapy that found that patients with ST-segment elevation myocardial infarction after intravenous injection of bone marrow-derived mesenchymal stem cells did not benefit clinically [6].
More clinical studies are needed in the future to explore the use of mesenchymal stem cells in the field of ischemic cardiomyopathy.
03
Reflections on the clinical application of mesenchymal stem cell therapy
At present, mesenchymal stem cells are still in the clinical research stage of cardiomyopathy, and many factors still need to be considered before entering large-scale clinical applications, including the use of autologous and allogeneic stem cells, the route of administration and the preparation of cells.
The use of autologous and allogeneic stem cells can be judged according to the specific disease. Due to the lack of major histocompatibility complex class II and sympletimulators, mesenchymal stem cells are considered immunely privileged. In addition, studies have shown that paracrine signaling from mesenchymal stem cells prevents them from being destroyed by lymphocytes. However, due to the clearance effects of the immune system, allogeneic mesenchymal stem cells may trigger the production of allogeneic antibodies. Older and coexisting cardiovascular risk factors may also affect the function of autologous mesenchymal stem cells [7].
In acute coronary artery disease, allogeneic mesenchymal stem cells are favored over autologous mesenchymal stem cells because they are immediately available, while in chronic coronary artery disease, autologous mesenchymal stem cells are the best choice [8].
Another important direction of thinking is the preparation of cells and the route of administration. The viability and route of administration of transplanted cells affect the clinical efficacy of mesenchymal stem cells, which also has a certain impact on clinical applications.
After acute myocardial infarction, the microenvironmental oxygen concentration and free radical concentration of damaged myocardial tissue are low and considered harmful to transplanted cells [9]. Transplanted cells require extravasation to reach the injured heart muscle, and intracorrelial infusions dilute mesenchymal stem cells, reducing efficacy [10]. In addition, only a few of the intracorrovascular injected mesenchymal stem cells remain in the myocardium and most of them enter the systemic circulation [11].
On the other hand, the preparation of mesenchymal stem cells, including isolation, culture, inoculation, storage, etc., will also affect the therapeutic properties of the cells, thus also having a certain impact on the treatment results [12].
brief summary:
Although treatment strategies for ischemic cardiomyopathy are evolving, there are still limited improvements in survival and quality of life. Mesenchymal stem cells have the ability to regenerate cardiomyocytes after myocardial injury and are a promising treatment for ischemic cardiomyopathy. Studies have demonstrated the safety and efficacy of mesenchymal stem cell therapy in ischemic cardiomyopathy. However, the differences in clinical trial results still need to be explored, and continuous exploration and research are still needed in the future to reach clinical consensus and develop standardized use methods.
bibliography:
[1] Razeghian-Jahromi, I., Matta, A. G., Canitrot, R., Zibaeenezhad, M. J., Razmkhah, M., Safari, A., Nader, V., & Roncalli, J. (2021). Surfing the clinical trials of mesenchymal stem cell therapy in ischemic cardiomyopathy. Stem cell research & therapy, 12(1), 361. https://doi.org/10.1186/s13287-021-02443-1
[2] Mathiasen, A. B., Haack-S rensen, M., & Kastrup, J. (2009). Mesenchymal stromal cells for cardiovascular repair: current status and future challenges. Future cardiology, 5(6), 605–617. https://doi.org/10.2217/fca.09.42
[3] Perin, E. C., Sanz-Ruiz, R., Sánchez, P. L., Lasso, J., Pérez-Cano, R., Alonso-Farto, J. C., Pérez-David, E., Fernández-Santos, M. E., Serruys, P. W., Duckers, H. J., Kastrup, J., Chamuleau, S., Zheng, Y., Silva, G. V., Willerson, J. T., & Fernández-Avilés, F. (2014). Adipose-derived regenerative cells in patients with ischemic cardiomyopathy: The PRECISE Trial. American heart journal, 168(1), 88–95.e2. https://doi.org/10.1016/j.ahj.2014.03.022
[4] Premer, C., Blum, A., Bellio, M. A., Schulman, I. H., Hurwitz, B. E., Parker, M., Dermarkarian, C. R., DiFede, D. L., Balkan, W., Khan, A., & Hare, J. M. (2015). Allogeneic Mesenchymal Stem Cells Restore Endothelial Function in Heart Failure by Stimulating Endothelial Progenitor Cells. EBioMedicine, 2(5), 467–475. https://doi.org/10.1016/j.ebiom.2015.03.020
[5] Ascheim, D. D., Gelijns, A. C., Goldstein, D., Moye, L. A., Smedira, N., Lee, S., Klodell, C. T., Szady, A., Parides, M. K., Jeffries, N. O., Skerrett, D., Taylor, D. A., Rame, J. E., Milano, C., Rogers, J. G., Lynch, J., Dewey, T., Eichhorn, E., Sun, B., Feldman, D., … Woo, Y. J. (2014). Mesenchymal precursor cells as adjunctive therapy in recipients of contemporary left ventricular assist devices. Circulation, 129(22), 2287–2296. https://doi.org/10.1161/CIRCULATIONAHA.113.007412
[6] Chullikana, A., Majumdar, A. S., Gottipamula, S., Krishnamurthy, S., Kumar, A. S., Prakash, V. S., & Gupta, P. K. (2015). Randomized, double-blind, phase I/II study of intravenous allogeneic mesenchymal stromal cells in acute myocardial infarction. Cytotherapy, 17(3), 250–261. https://doi.org/10.1016/j.jcyt.2014.10.009
[7] Kinkaid, H. Y., Huang, X. P., Li, R. K., & Weisel, R. D. (2010). What's new in cardiac cell therapy? Allogeneic bone marrow stromal cells as "universal donor cells". Journal of cardiac surgery, 25(3), 359–366. https://doi.org/10.1111/j.1540-8191.2009.00984.x
[8] Mathiasen, A. B., J rgensen, E., Qayyum, A. A., Haack-S rensen, M., Ekblond, A., & Kastrup, J. (2012). Rationale and design of the first randomized, double-blind, placebo-controlled trial of intramyocardial injection of autologous bone-marrow derived Mesenchymal Stromal Cells in chronic ischemic Heart Failure (MSC-HF Trial). American heart journal, 164(3), 285–291. https://doi.org/10.1016/j.ahj.2012.05.026
[9] Brodarac, A., ari , T., Oberwallner, B., Mahmoodzadeh, S., Neef, K., Albrecht, J., Burkert, K., Oliverio, M., Nguemo, F., Choi, Y. H., Neiss, W. F., Morano, I., Hescheler, J., & Stamm, C. (2015). Susceptibility of murine induced pluripotent stem cell-derived cardiomyocytes to hypoxia and nutrient deprivation. Stem cell research & therapy, 6(1), 83. https://doi.org/10.1186/s13287-015-0057-6
[10] Trachtenberg, B., Velazquez, D. L., Williams, A. R., McNiece, I., Fishman, J., Nguyen, K., Rouy, D., Altman, P., Schwarz, R., Mendizabal, A., Oskouei, B., Byrnes, J., Soto, V., Tracy, M., Zambrano, J. P., Heldman, A. W., & Hare, J. M. (2011). Rationale and design of the Transendocardial Injection of Autologous Human Cells (bone marrow or mesenchymal) in Chronic Ischemic Left Ventricular Dysfunction and Heart Failure Secondary to Myocardial Infarction (TAC-HFT) trial: A randomized, double-blind, placebo-controlled study of safety and efficacy. American heart journal, 161(3), 487–493. https://doi.org/10.1016/j.ahj.2010.11.024
[11] Penicka, M., Widimsky, P., Kobylka, P., Kozak, T., & Lang, O. (2005). Images in cardiovascular medicine. Early tissue distribution of bone marrow mononuclear cells after transcoronary transplantation in a patient with acute myocardial infarction. Circulation, 112(4), e63–e65. https://doi.org/10.1161/CIRCULATIONAHA.104.496133
[12] Pountos, I., Corscadden, D., Emery, P., & Giannoudis, P. V. (2007). Mesenchymal stem cell tissue engineering: techniques for isolation, expansion and application. Injury, 38 Suppl 4, S23–S33. https://doi.org/10.1016/s0020-1383(08)70006-8
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