YoonA Kang Abstract Type B 2024

Hematopoietic stem cells (HSCs) maintain life-long hematopoiesis through the balance act between self-renewal and differentiation. Quiescent HSCs have higher self-renewal capacity and increased repopulation potential compared to activated/cycling HSCs. Therefore, a better understanding of HSC quiescence mechanisms will provide critical insights into the development of new strategies to increase self-renewal capacity of HSCs for clinical application. The overarching goal of this project is to find new strategies to increase self-renewal capacity of HSCs ex vivo so we can increase the availability of rare HSC population for transplantation as well as for gene therapy. We found that HSCs can secrete cytokines and their secretion profiles change in a context dependent manner. We also found that a proteoglycan protein is uniquely secreted by steady state HSCs among hematopoietic stem and progenitor cells and a proteoglycan protein can increase quiescent HSCs in culture conditions. Based on these findings, this proposal aims to investigate the function of a proteoglycan protein in HSC quiescence and to test whether a proteoglycan protein can be used to increase self-renewal capacity of HSCs ex vivo. In Aim 1, we will investigate whether a proteoglycan protein promotes HSC quiescence and the underlying mechanism using genetic mouse models and transplantation assays. In Aim 2, we will test whether a proteoglycan protein can increase human HSC self-renewal capacity ex vivo using a 3D bone marrow organoid model and transplantation assays. Collectively, this study will identify a novel self-regulatory mechanism of HSC quiescence whereby HSCs maintain their quiescence pool through autocrine by secreting a proteoglycan protein. This study will also help provide new strategies to expand HSCs ex vivo for therapeutic purposes.