Transplant Reports : Open Access
Open Access

Heart transplantation; Stem cells; Heart failure; Graft survival; Organ regeneration; Immunosuppression; Regenerative medicine; Cell therapy; Heart repair; Clinical trials

Introduction

Heart transplantation is the gold-standard treatment for patients with end-stage heart failure, a condition that often results from coronary artery disease, dilated cardiomyopathy, or congenital heart defects. While heart transplant outcomes have improved significantly over the years, several challenges remain, including organ shortage, transplant rejection, and long-term complications such as graft vasculopathy and chronic rejection. According to recent data, over 3,000 heart transplants are performed annually in the United States, with survival rates of around 90% at one year and 75% at five years, though the number of patients on the waiting list far exceeds the available organs [1]. The scarcity of donor hearts and the demand for heart transplants have led researchers to explore alternative strategies, including the use of stem cells to improve graft function and reduce complications.

Stem cells, particularly mesenchymal stem cells (MSCs), induced pluripotent stem cells (iPSCs), and cardiac progenitor cells (CPCs), have gained significant attention in recent years for their potential to repair damaged heart tissue and promote tissue regeneration. These cells possess the ability to differentiate into various cell types, including cardiomyocytes, endothelial cells, and smooth muscle cells, which are essential for cardiac repair. Moreover, stem cells have the potential to modulate the immune response, reducing the need for immunosuppressive therapy, which often leads to significant side effects such as infections and malignancies.

Description

Stem cells used in heart transplantation can be broadly categorized into three main types: mesenchymal stem cells (MSCs), induced pluripotent stem cells (iPSCs), and cardiac progenitor cells (CPCs). Each of these cell types offers unique advantages and challenges in the context of heart transplantation.

MSCs are multipotent stem cells derived from various tissues, including bone marrow, adipose tissue, and umbilical cord. These cells have been extensively studied for their regenerative potential in various organ systems, including the heart. MSCs can differentiate into cardiomyocyte-like cells, endothelial cells, and smooth muscle cells, promoting tissue repair after myocardial infarction or heart failure. Additionally, MSCs have immunomodulatory properties, which can help reduce transplant rejection and mitigate the need for long-term immunosuppression [2].

However, the use of iPSCs in clinical applications is still in its early stages, with challenges related to tumorigenicity and the efficiency of reprogramming techniques [3]. CPCs are stem cells that are specifically committed to the cardiac lineage and are capable of differentiating into cardiomyocytes. These cells can be isolated from adult hearts, embryonic hearts, or from induced pluripotent stem cells. CPCs have shown potential in improving cardiac function after myocardial injury and are being explored as a potential therapeutic option in heart transplantation. Their use in heart transplantation aims not only at tissue repair but also at enhancing graft function by improving the viability and performance of the transplanted heart [4].

Stem cells, particularly iPSCs and CPCs, can differentiate into functional cardiomyocytes, which replace damaged heart tissue and restore contractile function. This regenerative process can be especially beneficial following a heart transplant, as it may help the new organ recover more quickly and prevent long-term complications such as graft failure or dysfunction [5].

Stem cells can also promote angiogenesis, the formation of new blood vessels, which is critical for ensuring adequate oxygen and nutrient supply to the heart. MSCs and CPCs have been shown to secrete various growth factors that stimulate the growth of new blood vessels in the damaged heart tissue, improving overall graft function [6].

In addition to their regenerative properties, stem cells have been shown to modulate the immune response, reducing inflammation and potentially decreasing the risk of transplant rejection. MSCs, in particular, have immunosuppressive effects that can help prevent graft rejection and reduce the need for conventional immunosuppressive therapy, which is associated with significant long-term side effects such as infections and malignancies [7].

Several preclinical and clinical studies have investigated the use of stem cells to improve heart transplant outcomes. One of the most promising approaches is the use of MSCs to enhance graft survival and reduce transplant rejection. Clinical trials have demonstrated that the administration of MSCs after heart transplantation can improve cardiac function and reduce the incidence of rejection. In some studies, MSCs have been used to treat patients with heart failure following transplant, improving myocardial perfusion and function.

For example, a phase II clinical trial tested the use of bone marrow-derived MSCs in patients with heart failure after heart transplant. Results showed that patients treated with MSCs had significantly improved left ventricular ejection fraction (LVEF) and reduced levels of biomarkers associated with graft rejection. Moreover, the treatment was well tolerated, with no significant adverse effects [8].

Discussion

Despite the promising results from preclinical and clinical studies, the application of stem cells in heart transplantation faces several challenges. One of the major obstacles is the risk of tumorigenicity, particularly with iPSCs, which have the potential to form teratomas if not fully differentiated before transplantation [9]. Furthermore, the efficiency of generating functional cardiomyocytes from stem cells remains a significant hurdle, as the reprogramming process for iPSCs and the differentiation of stem cells into mature heart cells are still not fully optimized.

Another challenge is the immune rejection of transplanted stem cells. While MSCs have some immunomodulatory properties, they may not be entirely immune-privileged, especially in the context of allogeneic transplantation. This means that immune rejection of transplanted stem cells remains a concern, especially if the stem cells are not autologous. Additionally, the long-term effects of stem cell-based therapies in heart transplantation remain largely unknown, and further research is needed to evaluate the safety and durability of these approaches [10].

Future research in stem cell-based therapies for heart transplantation will likely focus on improving the efficiency of stem cell reprogramming and differentiation, optimizing protocols for the generation of functional cardiomyocytes, and addressing the risks of tumorigenicity and immune rejection. Moreover, advances in gene editing technologies, such as CRISPR, may help enhance the regenerative potential of stem cells and allow for the development of safer, more effective therapies.

Conclusion

Stem cell-based therapies hold immense potential for improving outcomes in heart transplantation. By promoting cardiac regeneration, angiogenesis, and immune modulation, stem cells may help reduce graft rejection, improve graft survival, and enhance the overall quality of life for heart transplant recipients. While challenges remain, particularly regarding tumorigenicity and immune rejection, ongoing research is paving the way for safer and more effective stem cell-based therapies in heart transplantation. With continued advancements in stem cell biology and regenerative medicine, the future of heart transplantation may see significant improvements in both short-term and long-term outcomes.

Acknowledgement

None

Conflict of Interest

None

References

1. Delgado JF, Reyne AG, de Dios S, López-Medrano F, Jurado A, et al. (2015) Influence of cytomegalovirus infection in the development of cardiac allograft vasculopathy after heart transplantation. J Heart Lung Transplant 3:1112-1119.

Indexed at, Google Scholar, Crossref

2. Raffa GM, Di Gesaro G, Sciacca S, Tuzzolino F, Turrisi M, et al. (2016) Heart transplant program at IRCCS-ISMETT: Impact of mechanical circulatory support on pre- and post -transplant survival. Int J Cardiol 219: 358-361.

Indexed at, Google Scholar, Crossref

3. Zielińska K, Kukulski L, Wróbel M, Przybyłowski P, Rokicka D, et al. (2022) Carbohydrate Metabolism Disorders in Relation to Cardiac Allograft Vasculopathy (CAV) Intensification in Heart Transplant Patients According to the Grading Scheme Developed by the International Society for Heart and Lung Transplantation (ISHLT). Ann Transplant 27: 933420.

Indexed at, Google Scholar, Crossref

4. Conway J, Manlhiot C, Kirk R, Edwards LB, McCrindle BW, et al. Mortality and morbidity after retransplantation after primary heart transplant in childhood: an analysis from the registry of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 33: 241-251.

Indexed at, Google Scholar, Crossref

5. R D Vanderlaan, C Manlhiot, L B Edwards, J Conway, B W McCrindle, et al. (2015) Risk factors for specific causes of death following pediatric heart transplant: An analysis of the registry of the International Society of Heart and Lung Transplantation. Pediatr Transplant 19: 896-905.

Indexed at, Google Scholar, Crossref

6. Kitamura S (2012) Heart transplantation in Japan: a critical appraisal for the results and future prospects. Gen Thorac Cardiovasc Surg 60: 639-644.

Indexed at, Google Scholar, Crossref

7. Wever-Pinzon O, Edwards LB, Taylor DO, Kfoury AG, Drakos SG, et al. (2017) Association of recipient age and causes of heart transplant mortality: Implications for personalization of post-transplant management-An analysis of the International Society for Heart and Lung Transplantation Registry. J Heart Lung Transplant 36: 407-417.

Indexed at, Google Scholar, Crossref

8. Saczkowski R, Dacey C, Bernier PL (2010) Does ABO-incompatible and ABO-compatible neonatal heart transplant have equivalent survival. Interact Cardiovasc Thorac Surg 10: 1026-1033.

Indexed at, Google Scholar, Crossref

9. Jeewa A, Manlhiot C, Kantor PF, Mital S, McCrindle BW, et al. (2014) Risk factors for mortality or delisting of patients from the pediatric heart transplant waiting list. J Thorac Cardiovasc Surg 147: 462-468.

Indexed at, Google Scholar, Crossref

10. Sivathasan C, Lim CP, Kerk KL, Sim DK, Mehra MR, et al. (2017) Mechanical circulatory support and heart transplantation in the Asia Pacific region. J Heart Lung Transplant 36: 13-18.

Indexed at, Google Scholar, Crossref