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UBC Theses and Dissertations

Hic1 is a quiescence regulator of mesenchymal stromal cells in bone marrow and responsible for controlling the size of hematopoietic stem cell niche Nguyen, Phuong Ha


Hematopoietic stem cells (HSCs) are believed to reside and are protected in a special-perivascular microenvironment, which is called the hematopoietic stem cell niche. Within the niche, the fate of HSCs such as homing, self-renewal, quiescence, and differentiation is determined based on an array of intra and extracellular signals. For many decades, the identity and function of major cellular components of niches for HSCs has been a long-standing debate. One key candidate is a population of mesenchymal stromal cells (MSCs). Due to the complexity of the bone marrow matrix, it has been very challenging to identify a signature marker that specifically labels these MSCs. Recently, CXC chemokine ligand (CXCL)12-abundant reticular (CAR) cells or leptin receptor-expressing (LepR⁺) cells have been found to play an important role in hematopoiesis. They are not only a major cellular component of HSC niches but also can give rise to osteoblasts and adipocytes in bone marrow. However, it remains unclear how osteogenesis and adipogenesis are prevented in most CAR/LepR⁺ cells to maintain HSC niches and marrow cavities. Moreover, how the number of niche is controlled is not yet fully understood, as only about 0.01% of whole bone marrow cells are found to be HSCs being present at any time under homeostasis. Our preliminary data indicated that the transcription factor Hic1 is preferentially expressed in MSCs across all tissues in the body, including bone marrow. Hic1-expressing cells have been described as quiescent mesenchymal stromal cells that have the full capacity to become adipocytes and/or osteoblasts. Single cell RNA sequencing analysis revealed that Hic1⁺ MSCs isolated from bone marrow are heterogeneous but with the majority of such cells expressing high levels of CXCL12 and LepR. When Hic1 is deleted, MSCs numbers expand dramatically, and in mice there is an associated increase in HSC activity and HSC frequency in bone marrow compared to wild type individuals. Thus, we propose that Hic1 acts as a quiescence regulator of MSCs in bone marrow and is responsible for controlling the size of the hematopoietic stem cell niche.

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