Life science
Medical & healthcare, Drug development

Niche cells essential for hematopoietic stem cell maintenance andhematopoiesis and adipo-osteogenesis in bone marrow
Graduate School of Frontier Biosciences/Graduate School of Medicine/Immunology Frontier Research Center (WPI-IFReC)
Distinguished Professor Takashi Nagasawa

https://researchmap.jp/read0094728

Associate Professor Yoshiki Omatsu

https://researchmap.jp/yskomt

Life science

Abstract
Special microenvironments known as niches are essential forthe maintenance of hematopoietic stem cells (HSCs) and lympho-hematopoiesis within bone marrow. We found that CAR cells
are the major producer of CXCL12 and SCF and the major cellularcomponents of niches for HSCs and immune cells, that CAR cells
are mesenchymal stem cells, which give rise to adipocytes andosteoblasts, and that the transcription factors, Foxc1 and Ebf3 are
preferentially expressed in CAR cells and play a critical role in theformation and maintenance of niches for HSCs and immune cells,
inhibiting differentiation of CAR cells into adipocytes and osteoblasts, respectively. Recently, we found that CAR cells require thetranscription factors Runx1 or Runx2 to prevent their fibrotic conversion and maintain HSCs and hematopoiesis in adults.

▍ Significance of the research and Future perspective
We found that CAR cells are the bone marrow specific fibroblastic reticular cells, which express specific and critical transcription
factors, including Foxc1, Ebf 1/3, and Runx1/2, providing HSC
niches and bone. For clinical application, our results raise the possibility that activators and/or inhibitors of CAR cell functions might
be applied to novel non-cell-autonomous therapies targeting theniches for HSCs and immune cells in hematological disorders andinfection.

▍ Background & Results
Special microenvironments known as niches are essential for themaintenance of hematopoietic stem cells (HSCs), which give rise to
all blood cells, within bone marrow. We identified a population of fibroblastic reticular cells expressing CXCL12 at high levels, termed
CXCL12-abundant reticular (CAR) cells within murine bone marrowand found that CAR cells are the major producer of CXCL12 andSCF, and the major cellular components of niches for HSCs andimmune cells. In addition, we determined the nature of CAR cells,
showing that CAR cells are mesenchymal stem cells, which giverise to adipocytes and osteoblasts and that transcription factors,
Foxc1 and Ebf3 are preferentially expressed in CAR cells and playa critical role in the formation and maintenance of niches for HSCs
and immune cells, inhibiting differentiation of CAR cells into adipocytes and osteoblasts, respectively.
Runx2, which is essential for generation of osteoblasts, is highly
expressed in CAR cells. Recently, we showed that Runx1, which
is known to be essential for the establishment of HSCs during ontogeny, is predominantly expressed in CAR cells. CAR cells arenormally formed and maintained in mice lacking Runx1 or Runx2 in
CAR cells. However, mice lacking both Runx1 and Runx2 in CARcells (Ebf3-CreERT2;Runx1f/fRunx2f/f mice) displayed an increase infibrosis and bone formation with markedly reduced HSCs and hematopoietic progenitor cells in bone marrow. Consistent with this,CAR cells from the mutants displayed markedly increased expression of fibrotic genes, including Col1a1, Col3a1, and Col6a3. Thus,CAR cells require Runx1 or Runx2 to prevent their fibrotic conversion and maintain HSCs and hematopoiesis in adults.

P a t e n tOmatsu, Yoshiki; Aiba, Shota; Nagasawa, Takashi et al. Runx1 and Runx2 inhibit fibrotic conversion of cellular niches for hematopoietic stem cells. NatCommun. 2022; 13(1), p2654, doi: 10.1038/s41467-022-30266-y
Seike, Masanari; Omatsu, Yoshiki; Nagasawa, Takashi et al. Stem cell niche-specific Ebf3 maintains the bone marrow cavity. Genes Dev. 2018, 32(5-6),
p359-372, doi: 10.1101/gad.311068.117
Omatsu, Yoshiki; Seike, Masanari; Nagasawa, Takashi et al. Foxc1 is a critical regulator of haematopoietic stem/progenitor cell niche formation. Nature
Tr e a t i s e
2014, 508, p536-540, doi: 10.1038/nature13071
Omatsu, Yoshiki; Sugiyama, Tatsuki; Nagasawa, Takashi et al. The essential functions of adipo-osteogenic progenitors as the hematopoietic stem andprogenitor cell niche. Immunity 2010, 33, p387-399, doi: 10.1016/j.immuni.2010.08.017
Sugiyama, Tatsuki; Kohara, Hiroshi; Nagasawa, Takashi et al. Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling inbone marrow stromal cell niches. Immunity 2006, 25, p977-988, doi: 10.1016/j.immuni.2006.10.016
URL
K e y w o r d hematopoietic stm cell, niche, bone marrow