Clonal Compensation between Hematopoietic Stem Cells upon Differentiation Deficiency

University Of Southern California, Los Angeles CA

Investigators

Linked publications, trials & patents

Abstract

Abstract Many hematopoietic disorders are characterized by an unbalanced blood system whereby certain cell types are either abnormally abundant or deficient. Currently, the primary treatment available for these diseases involves bone marrow transplantation from healthy donors. In this treatment, donor hematopoietic stem cells (HSCs) adapt their differentiation programs to the presence or absence of other HSCs. However, few studies have addressed this intercellular coordination between stem cells, which plays a critical role in maintaining a balanced blood system. The proposed research will offer a clonal perspective on the progression of hematopoietic disorders that result from an unbalanced blood system. In particular, HSCs with specific differentiation characteristics (i.e., balanced blood production) may possess a greater capacity to respond to changes to other HSCs. In my proposed research, I will investigate the dynamics of HSC coordination by precisely perturbing a specific cell type in the blood system and assaying the temporal responses of individual HSCs. These experiments will identify HSCs that respond quickly and/or persistently to perturbations to the HSC population, two characteristics that are highly desirable for therapeutic purposes. I will determine how HSCs dynamically adapt their differentiation programs in response to deficiencies in their partner HSCs. I will track individual normal HSCs in vivo using a single cell tracking technology that was previously developed in our lab. This novel approach will allow the tracing of thousands of individual HSCs simultaneously in a mouse model and help identify the interactions between normal and lineage deficient HSCs. Finally, I will determine whether compensation for lymphoid lineage deficiency can be enhanced by stimulating the normal transplanted HSCs with small molecule compounds using a novel in vivo small molecule screening assay I developed. Compounds that increase the production of certain blood cell types or enhance the engraftment of transplanted HSCs can be applied to improve efficacy transplantation efficacy.