Molecular Mechanisms Controlling Human Hematopoietic Stem Cell Aging
Adult stem cells function throughout our life to replenish dying cells and regenerate damaged tissues. This unique ability of adult stem cells originates from their capacity to divide indefinitely and to give rise to specialized cells, processes known as stem cell self-renewal and differentiation. Understanding how stem cells self-renew and differentiate will have broad implications in regenerative medicine and cancer treatment. For example, decreased self-renewal or derailed differentiation of normal stem cells leads to tissue degeneration, while increased self-renewal of cancer stem cells results in tumorigenesis. We aim to identify the molecular regulators that control the self-renewal and differentiation of adult stem cells. As mammals age, the capacity of adult stem cells to self-renew declines and stem cell differentiation is dysregulated. Thus, we propose to use aging as a platform to understand the molecular network regulating stem cell self-renewal and differentiation. Identification of these molecular regulators holds promise for new avenues of regenerative medicine and cancer therapy.
Most studies on adult stem cells take advantage of the power of mouse genetics. However, one limitation of these studies is that it is not clear whether human adult stem cells act the same way as mouse stem cells. We will take advantage of a culture condition of human adult stem cells that mimics their living condition within the tissue and a system that permits functional evaluation of human stem cells under physiological conditions. These studies directly dissect the molecular basis underlying the self-renewal and differentiation of human adult stem cells, bringing us one step closer to therapeutic treatments in humans.
This proposal addresses the major gaps in our knowledge of adult stem cells, which form several research focuses of this RFA: human stem cell aging, molecular basis of human pluripotent stem cell (hPSC) self-renewal, and molecular determinants of stem cell fate decisions during hPSC differentiation. These knowledge are critical to our understanding of many devastating human diseases associated with aging. With CIRM's mission in mind, the proposed studies will be conducted in human adult stem cells. Therefore, the output of these studies can be directly translated into practice in human. This project will provide mechanistic insight into adult stem cell biology and significantly enhance the development of stem cell-based therapeutics for human diseases in California, such as cancer and tissue degenerative diseases.
The aged community in California will benefit most from the proposed research. The size of this community is increasing, as the baby boomers begin to enter their 60’s. The younger community will also benefit from these studies through prevention of the
diseases of aging. Developing treatments or preventions of diseases of aging will greatly improve the quality of life of aged people, allow younger people to age gracefully, and significantly lessen the healthcare burden in California. In addition, many students will be trained in this cutting-edge research and drive the progress of proposed studies. This research activity will provide an excellent training ground for the next generation of scientists in California.