Adult stem cell transplantation is an emerging therapeutic strategy with wide potential to treat numerous age-related disorders such as cardiovascular disease, diabetes, and neurodegenerative disease. However, very little research has explored the causes of decreased efficacy of stem cell transplantation in the elderly population, who may have the most to gain from these new therapeutic strategies. Our laboratory is attacking this question using a 'seed vs. soil'model, asking whether an inherent dysfunction in the transplanted cells, the 'seed', or an inhospitable aged host microenvironment, the 'soil', is responsible for decreased therapeutic potential. We are specifically interested in te role of senescent cells in this interaction between 'seed'and 'soil'in transplantation. Senescent cells are growth-arrested cells that remain metabolically active and have been shown to promote a pro-inflammatory environment through the secretion of various cytokines, growth factors, and matrix remodeling factors, collectively known as the senescence-associated secretory phenotype (SASP). With aging, senescent cell numbers increase throughout the body, and are thought to contribute to many age-related diseases. Therefore, the long term goal of this study is to determine the role of increasing senescent cell burden in transplant failure. Our hypothesis is that removal of senescent cells from either the donor cells or the recipient mouse will improve transplant outcomes. We also hypothesize that by using pharmacologic agents shown to limit the SASP, namely rapamycin and Janus-activated kinase (Jak) inhibitors, we can limit the detrimental effects of senescent cells and improve transplant outcomes. To test these hypotheses, we will pursue the following specific aims:
AIM 1. Soil: Prepare the transplant microenvironment by removing senescent cells in recipient mice.
AIM 2. Seed: Prepare the cells to be transplanted by removing senescent cells from donor ADSCs.
AIM 3. Pharmacologic Intervention: Determine the effect of SASP inhibition in the recipient on efficacy of autologous ADSC transplant. In these studies, we will use a novel mouse model in which senescent cells can be selectively cleared from the mouse by administration of a drug that does not affect normal cells. We will study the transplantation of adipose-derived stem cells on skin wounds in mice, allowing easy tracking of stem cell engraftment and incorporation into regenerating tissue, as well as wound closure. Senescent cells will be cleared either from the recipient prior to transplantation of adipose-derived stem cells, to prepare the host environment (the 'soil') for transplant, or senescent cells will be cleared from mice before isolation of stem cells, to prepare the transplanted cells (the 'seed'). Alternatively, recipient animals will be treated with SASP-limiting agents rapamycin or Jak inhibitors prior to transplantation. A timeline for these experiments can be found at the end of the Research Strategy section of this proposal. The insights we gain into the role of senescent cells in stem cell transplantation may be hugely beneficial to the development of new therapeutic strategies that allow the application of emerging stem cell technologies to the elderly population.
to public health: Although elderly patients may have the most to gain from adult stem cell transplantation, this and related interventions are rarely practiced in older individuals due to decreased success. Our laboratory seeks to determine whether senescent cells, a specific pro-inflammatory cell type that increases in the body with aging, may play a role in decreased success of transplantation. The information gained from these studies may be directly translated to a clinical setting in order to improve outcomes for elderly recipients of adult stem cell transplants.
