Heart disease is the leading cause of death in the United States and in California. Normal heart functions require a high-degree of coordination of at least two major properties of heart cells, namely electrical and contractile functions. Since heart cells have limited ability to regenerate, their malfunction or significant loss due to aging or disease processes can lead to lethal consequences including heart failure and life-threatening rhythm disturbances.
Human embryonic stem cells (hESCs) are pluripotent and have the ability to self-renew, hence, offer an enormous potential for providing an unlimited source of cells for heart therapies. On the other hand, despite the promise, we have identified one MAJOR GAP in the field of regenerative therapy for cardiovascular diseases. The assessment and prevention of heart rhythms disturbances after transplantation of stem-cell grafts remain poorly understood.
We have obtained data showing that the electrical, contractile and structural properties of hESC-derived heart cells are immature. Moreover, in vivo transplantation of the immature cells can result in life-threatening rhythm disturbances. Taken together, the central hypothesis for the proposal is that directed cardiac differentiation and maturation of hESCs will result in mature heart cells which are more suitable for therapeutic cell transplantation by facilitating optimal integration of transplanted cells into recipient hearts.
To directly test the central hypothesis, we will utilize a multidisciplinary disease team approach with collaborators from diverse disciplines. We will use multidisciplinary state-of-the-art approaches to direct differentiation and facilitate stem cells maturation into human heart cells to a therapeutic scale to facilitate optimal integration of transplanted cells into recipient hearts. In vivo safety and long-term functional efficacy will be tested in a pre-clinical large animal models. Based on our existing platform and ongoing strong on-campus collaborative efforts, we anticipate to successfully translate our findings into novel approaches for treating heart diseases using cell-based therapies, at the pre-clinical or clinical level, in 5 years.
Heart disease is the leading cause of death in the United States and in California. Every 34 seconds, a person in the United States dies from heart disease and more than 2,500 Americans die from heart disease each day. Heart failure, in particular, is associated with a very high mortality rate and once heart failure develops, the condition is irreversible. However, recent studies have provided exciting evidence to support the notion that stem cells may offer an enormous potential for regenerative therapy for heart failure by replacing heart cells, which are lost during heart attack or other types of heart disease processes.
On the other hand, despite the promise, we have identified one MAJOR GAP in the field of regenerative therapy for heart diseases. The assessment and prevention of heart rhythm abnormalities after transplantation of stem-cell grafts remain poorly understood. Motivated by the magnitude and severity of the problems, we propose to use state-of-the-art multidisciplinary approaches to engineer human embryonic stem cells (hESCs) and to test the new customized stem cells in different clinically relevant experimental models with heart failure or rhythm abnormalities.
Indeed, we and others have obtained compelling data that strongly suggest that specific hESCs may be a potential source to derive new heart cells for “biological implantation” in humans in future. Specifically, the proposed research will aim to identify innovative techniques to drive the maturation of hESCs which are suitable for transplantation. We will directly assess the proper integration of the engineered hESC-derived heart cells in the experimental models. Based on our existing platform and ongoing on-campus collaborative efforts, we anticipate to successfully translate our findings into novel approaches for the development of mature human heart cells capable of proper integration and replacement of abnormal heart cells for patients with heart failure or rhythm abnormalities in California.