Identifying precursors to hematopoietic stem cells and where they arise in the mouse embryo

Inlay, Matthew

Abstract

Hematopoietic stem cell (HSC) transplantation, or HSCT, can replace a patient's diseased or damaged blood system. While it is an effective treatment option for many blood disorders, HSCT is a dangerous procedure and is thus underutilized. One possible solution is to use induced pluripotent stem cells (iPSCs), which can potentially generate an unlimited supply of patient HSCs. However, transplantable HSCs have yet to be created from iPSCs. This failure underscores a need to better understand how HSCs are created from their precursors during embryonic development. However, many questions remain regarding the origins of HSCs in embryonic development, including what cell gives rise to HSCs, where this occurs in the embryo, and what molecular pathways are involved. We have previously identified a population in the mouse embryo called eKLS that may contain precursors to HSCs. We have compared gene expression patterns between eKLS cells and adult HSCs to identify genes that could distinguish HSCs from their precursors. These findings afford us the unique opportunity to a) to define the precursors to HSCs and genes that promote engraftment through transplantation assays, and b) genetically trace where HSCs arise in the embryo using lineage-tracing models.

Public Health Relevance

Hematopoietic stem cells (HSCs) are arguably the most well-characterized of all stem cell types, yet many questions remain unresolved regarding how they arise in embryonic development. This includes the identity of the cell that gives rise to HSCs, where this occurs in the embryo, and what molecular pathways are involved. The goal of this proposal is to use transplantation assays and lineage tracing to answer these questions in mouse models in vivo.