Expand human umbilical cord blood hematopoietic stem cells with PPAR-a agonists

Expand human umbilical cord blood hematopoietic stem cells with PPAR-a agonists Abstract Hematopoietic stem cells (HSCs) are defined by their self-renewal potential and ability to differentiate into multiple blood lineages. Hematopoietic stem cell transplant (HSCT) is a mainstay of life-saving therapy for hematopoietic malignancies and hypoproliferative disorders. The use of umbilical cord blood (UCB)-derived HSCs provides many advantages over adult HSCs, including enhanced long-term immune recovery, decreased graft versus host disease, and availability of donors from a broad population, expanding the availability of HSCT for groups currently underrepresented in bone marrow registries. The use of haploidentical transplants addresses many of these issues, but UCB would still be a highly useful resource if UCB units contained sufficient numbers of HSCs. However, the low cell dose in most UCB units limits their use, as insufficient HSCs leads to delayed engraftment, graft failure, and severe infectious complications. Even a modest expansion of HSCs from UCB can solve many of these problems, and thus HSC expansion from UCB has remained an important goal for the field. Our goal is to use cryopreserved UCB from the NHLBI Biologic Biospecimen Repository to develop new methods to expand functional HSCs for therapeutic applications. Recent studies have achieved ex vivo expansion of HSCs using cytokine cocktails combined with small molecules, but these approaches require exposure to high concentrations of cytokines. Cytokines induce differentiation and impair the self-renewal function of primitive HSCs. HSC expansion with minimal cytokine exposure would therefore be ideal for clinical applications. Our previous studies demonstrated a combination of two inhibitors (CHIR99021 and rapamycin) maintains human and mouse long-term HSCs ex vivo in the absence of cytokines or serum. Based on this finding, we performed a high throughput screen and identified several PPAR-a agonists, which are used clinically to treat hypertriglyceridemia, that significantly expand long-term functional UCB HSC ex vivo while minimizing exposure to cytokines. In this project, we will carry out studies to optimize and implement our PPAR-a agonists-based expansion method using cryopreserved UCB stored in the NHLBI Biologic Biospecimen Repository.