The maintenance mechanism of hematopoietic stem cell dormancy: role for a subset of macrophages
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Hematopoiesis is regulated by crosstalk between long-term repopulatinghematopoietic stem cells (LT-HSCs) and supportingniche cells in the bone marrow (BM). Here, we describe therole of KAI1, which is mainly expressed on LT-HSCs and rarelyon other hematopoietic stem-progenitor cells (HSPCs), in nichemediatedLT-HSC maintenance. KAI1 activates TGF-β1/Smad3signal in LT-HSCs, leading to the induction of CDK inhibitorsand inhibition of the cell cycle. The KAI1-binding partner DARCis expressed on macrophages and stabilizes KAI1 on LT-HSCs,promoting their quiescence. Conversely, when DARC+ BMmacrophages were absent, the level of surface KAI1 on LT-HSCsdecreases, leading to cell-cycle entry, proliferation, and differentiation. Thus, KAI1 acts as a functional surface marker of LTHSCsthat regulates dormancy through interaction with DARCexpressingmacrophages in the BM stem cell niche. Recently,we showed very special and rare macrophages expressingα-SMA+ COX2+ & DARC+ induce not only dormancy of LTHSCthrough interaction of KAI1-DARC but also protect HSCsby down-regulating ROS through COX2 signaling. In the nearfuture, the strategy to combine KAI1-positive LT-HSCs andα-SMA/Cox2/DARC triple-positive macrophages will improvethe efficacy of stem cell transplantation after the ablative chemo-therapy for hematological disorders including leukemia.
Abstract
Hematopoiesis is regulated by crosstalk between long-term repopulatinghematopoietic stem cells (LT-HSCs) and supportingniche cells in the bone marrow (BM). Here, we describe therole of KAI1, which is mainly expressed on LT-HSCs and rarelyon other hematopoietic stem-progenitor cells (HSPCs), in nichemediatedLT-HSC maintenance. KAI1 activates TGF-β1/Smad3signal in LT-HSCs, leading to the induction of CDK inhibitorsand inhibition of the cell cycle. The KAI1-binding partner DARCis expressed on macrophages and stabilizes KAI1 on LT-HSCs,promoting their quiescence. Conversely, when DARC+ BMmacrophages were absent, the level of surface KAI1 on LT-HSCsdecreases, leading to cell-cycle entry, proliferation, and differentiation. Thus, KAI1 acts as a functional surface marker of LTHSCsthat regulates dormancy through interaction with DARCexpressingmacrophages in the BM stem cell niche. Recently,we showed very special and rare macrophages expressingα-SMA+ COX2+ & DARC+ induce not only dormancy of LTHSCthrough interaction of KAI1-DARC but also protect HSCsby down-regulating ROS through COX2 signaling. In the nearfuture, the strategy to combine KAI1-positive LT-HSCs andα-SMA/Cox2/DARC triple-positive macrophages will improvethe efficacy of stem cell transplantation after the ablative chemo-therapy for hematological disorders including leukemia.
참고문헌 (45)
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