Cellular and molecular components of a functional niche for human and mouse hematopoietic stem cells.

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The aim of this research proposal is the definition and characterization of niche cells and their molecular factors controlling the function of blood-forming human and murine stem cells in the bone marrow. To this end, based on gene expression data, we established an interactome between niche cells and hematopoietic stem cells (HSCs). In the next funding period we will determine the role of candidate genes on HSC function in vitro and in vivo using CRISPR-Cas9 technology. We could show that the transplantation of hematopoietic cells accelerates the recovery of niche cells from ionizing irradiation and we will analyze the cellular and molecular mechanism of that support in vivo. Finally, we generated a mouse strain that supports the maintenance and function of human HSCs in vivo and we could show in the last funding period that murine niche cells respond to donor human HSCs by expansion and alterations in their gene expression profile. Taking advantage of this unique mouse strain, we will determine molecular regulators that are the basis for cross-species compatibility of the HSC niche in vivo. Together, the results of our project will contribute to an improved understanding of regulatory circuits important for the function and potentially the modulation of HSC biology in vivo. Such knowledge will be pivotal to solve acute problems in transplantation biology such as paucity of histocompatible donor cells and graft rejection.