By Muhammed Din
Heart disease, linked with a sedentary lifestyle, consuming junk food and smoking, is a leading cause of death accounting for 31% of global mortality. With so many people suffering with heart disease and current therapeutics being inadequate in replacing damaged myocardium, advances in regenerative medicine may offer a means to improve clinical practice. What if we could regenerate heart cells to replace those damaged in heart disease patients?
The human heart is 70-80% cardiomyocytes (heart muscle cells). These contain myofibrils, which house the fundamental contractile units responsible for muscle contraction, called sarcomeres. Loss of cardiomyocytes contributes to disease progression in heart failure¹.
Cardiomyocyte damage correlates with socioeconomic factors which inevitably cause morbidity and mortality¹-². The role of social factors contributing to congenital heart disease (CHD) in developed countries in not well documented, but a large population-based study conducted in Sweden has shown that the incidence of CHD increases in deprived neighbourhoods³.
There may also be genetic factors. An example of an inherited cardiac disease is long QT syndrome (LQTS), an autosomal dominant disorder affecting 1:1000 live births, associated with 500 different mutations in 15 different genes. Patients show prolonged repolarisation phases (the period of time where heart muscle is regaining electrical potential after contraction) which may predispose them to potentially life-threatening Torsade’s de pointe, otherwise known as ventricular arrhythmias. Mutations commonly arise in KCNQ1 and KCNH2 gene causing LQTS1 and LQTS2, respectively⁴.
Induced pluripotent stem cells (iPSC) are generated from somatic cells harvested from a patient and converted to stem cells, allowing for autologous transplantation, thereby reducing the need for immunosuppressants.
From their induced stem cell state, iPSCs can be converted into any type of cell present in the adult human body (pluripotency). When appropriately stimulated in vitro, iPSCs undergo differentiation, becoming cardiomyocytes appropriate for tissue engineering or 3D bioprinting for transplantation purposes¹. This scientific discovery has generated a new practice of converting iPSCs to heart cells which can be placed into a damaged heart.
In recent times, widespread use of 3D culture models in scientific research has enabled the experimental modelling of beating heart cells. These cultures give a physiological environment for cells to thrive in, thus allowing the generation of cardiomyocytes from iPSCs. These generated cells are morphologically and functionally like the real thing!
A hydrogel-based cardiac patch was developed with self-morphing properties. This gave a stretchable patch with fibre-like arrangements and mechanical features of a human heart. From here, regenerative medicine and stem cell therapy could expand even further¹.
Many methods have been adopted in regenerative medicine to generate functional sheets appropriate for use in transplantation, an advancement which may eventually remove the need for organ donors. Organ transplantation carries a risk of organ rejection as the immune system discerns the new organ as not being of self-origin, triggering autoimmunity.
Studies have demonstrated the role of innate cells in transplant rejection: they have been shown to contribute to both graft rejection and acceptance. Transplant rejection takes place in a number of steps involving the rejection response: allograft rejection leading to recruitment of innate cells and cytokines stimulating immune cells. Thereafter graft destruction is initiated by T cells and non-T cells⁵.
3D bioprinting has brought forth new potential for the use of bioengineering in providing new and enhanced technologies for the regeneration of cardiomyocytes, thus allowing the addition of cells and biomaterials to a well organised structure. Using this cutting-edge approach, iPSC derived cardiomyocytes have been bio-printed into vascularized cardiac tissue and transplanted into a defective heart. As well as this, 3D bioprinting was used to embed supporting cells into a defective heart, for instance, fibroblasts and vascular cells leading to improved therapeutic outcomes in mice.
As a result of this, a fully functional patch was created with expected action potential and electrical conduction as observed in a fully functional heart¹.
The ending of the decade came-forth with a breakthrough in stem cell therapy where we witnessed two Chinese men becoming the first to receive iPSCs therapy for heart disease⁶. This laid down the foundation for innovation and breakthrough in regenerative medicine for decades to come shaping medicine for future generations.
1. Wang K-L, Xue Q, Xu X-H, Hu F, Shao H. Recent progress in induced pluripotent stem cell-derived 3D cultures for cardiac regeneration. Cell Tissue Res. Published online February 5, 2021. doi:10.1007/s00441-021-03414-x
2. Psaltopoulou T, Hatzis G, Papageorgiou N, Androulakis E, Briasoulis A, Tousoulis D. Socioeconomic status and risk factors for cardiovascular disease: Impact of dietary mediators. Hell J Cardiol. 2017;58(1):32-42. doi:10.1016/j.hjc.2017.01.022
3. Peyvandi S, Baer RJ, Chambers CD, et al. Environmental and Socioeconomic Factors Influence the Live‐Born Incidence of Congenital Heart Disease: A Population‐Based Study in California. J Am Heart Assoc. 2020;9(8). doi:10.1161/JAHA.119.015255
4. van Mil A, Balk GM, Neef K, et al. Modelling inherited cardiac disease using human induced pluripotent stem cell-derived cardiomyocytes: progress, pitfalls, and potential. Cardiovasc Res. 2018;114(14):1828-1842. doi:10.1093/cvr/cvy208
5. Liu W, Li XC. An overview on non-T cell pathways in transplant rejection and tolerance. Curr Opin Organ Transplant. 2010;15(4):422-426. doi:10.1097/MOT.0b013e32833b7903
6. Mallapaty S. Revealed: two men in China were first to receive pioneering stem-cell treatment for heart disease. Nature. 2020;581(7808):249-250. doi:10.1038/d41586-020-01285-w