ATIP / Avenir
Hematopoietic stem cells (HSCs) differentiate and self-renew, and this activity ensures lifelong hematopoiesis. Nevertheless, several key hematopoietic defects are associated with age, including the increased incidence of myeloid neoplasms. These defects are thought to arise, at least in part, within HSCs, but exactly how this occurs is poorly understood. Experimentally, HSC function is often measured using transplantation assays. While transplantation reveals what an HSC is capable of doing, it does not show what an HSC actually does in homeostasis. New approaches are thus required to resolve the fundamental properties of endogenous HSCs, i.e. in the absence of transplantation, both at the steady state and in other in vivo contexts. We recently developed transgenic reporters that enable the study of endogenous HSCs. Our system specifically labels the fraction of HSCs with the least differentiated phenotype and the capacity for durable self-renewal (1,2). We performed lineage tracing found that labeled HSCs actively contribute to steady-state hematopoiesis (1,2). We also performed single-cell RNA-Sequencing on the labeled cells that appeared over time and established the in vivo kinetics of differentiation to different hematopoietic lineages. In addition to defining the function of HSCs in the steady state, we have begun to use our system to define the impact of age on endogenous HSC function. Furthermore, building upon this transgenic system, we have established a novel model that allows inducible oncogene expression within a fraction of HSCs, which may recapitulate the initiation of myeloid leukemia. This system enables the identification and distinction between normal and leukemic stem cells and may be useful in determining the impact of leukemia on normal hematopoiesis as well as studying the functions of leukemic stem cells. We are also investigating the impact of age on the development of myeloid leukemia, which may provide insight into the link between age and the increased incidence of leukemia.
Figure 1 Pdzk1ip1 transgenic reporter for lineage tracing of hematopoietic stem cells.
- Sawai CM, et al. Hematopoietic stem cells are the major source of multilineage hematopoiesis at the steady state. Immunity 2016 (3):597-609.
- Upadhaya S, Reizis B, and Sawai CM. New genetic tools for the in vivo study of hematopoietic stem cells. Experimental Hematology 2018 (61):26-35.
- Upadhaya S, et al. Kinetics of adult hematopoietic stem cell differentiation in vivo. Journal of Experimental Medicine 2018 (11):2815-2832.
- Nazaraliyev A, Richard E, and Sawai CM. In vivo differentiation of adult hematopoietic stem cells from a single-cell point of view. Current Opinion in Hematology 2020 in press.