Strategic Center of Cell and Bio Therapy for Heart, Diabetes & Cancer, Biomedical Research Institute, Seoul National University Hospital, Seoul 03080, Korea.
Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 03080, Korea.
BMB Rep. 2023 Sep;56(9):482-487. doi: 10.5483/BMBRep.2023-0092.
Hematopoiesis is regulated by crosstalk between long-term repopulating hematopoietic stem cells (LT-HSCs) and supporting niche cells in the bone marrow (BM). Here, we describe the role of KAI1, which is mainly expressed on LT-HSCs and rarely on other hematopoietic stem-progenitor cells (HSPCs), in nichemediated LT-HSC maintenance. KAI1 activates TGF-β1/Smad3 signal in LT-HSCs, leading to the induction of CDK inhibitors and inhibition of the cell cycle. The KAI1-binding partner DARC is expressed on macrophages and stabilizes KAI1 on LT-HSCs, promoting their quiescence. Conversely, when DARC+ BM macrophages were absent, the level of surface KAI1 on LT-HSCs decreases, leading to cell-cycle entry, proliferation, and differentiation. Thus, KAI1 acts as a functional surface marker of LTHSCs that regulates dormancy through interaction with DARCexpressing macrophages in the BM stem cell niche. Recently, we showed very special and rare macrophages expressing α-SMA+ COX2+ & DARC+ induce not only dormancy of LTHSC through interaction of KAI1-DARC but also protect HSCs by down-regulating ROS through COX2 signaling. In the near future, the strategy to combine KAI1-positive LT-HSCs and α-SMA/Cox2/DARC triple-positive macrophages will improve the efficacy of stem cell transplantation after the ablative chemo-therapy for hematological disorders including leukemia. [BMB Reports 2023; 56(9): 482-487].
造血是由长期重建造血干细胞 (LT-HSCs) 与骨髓 (BM) 中支持龛细胞之间的串扰调节的。在这里，我们描述了主要在 LT-HSCs 上表达而在其他造血干/祖细胞 (HSPCs) 上很少表达的 KAI1 在龛介导的 LT-HSC 维持中的作用。KAI1 在 LT-HSCs 中激活 TGF-β1/Smad3 信号，导致 CDK 抑制剂的诱导和细胞周期的抑制。KAI1 的结合伴侣 DARC 在巨噬细胞上表达，并稳定 LT-HSCs 上的 KAI1，促进其静止。相反，当 DARC+BM 巨噬细胞不存在时，LT-HSCs 表面 KAI1 的水平下降，导致细胞周期进入、增殖和分化。因此，KAI1 作为 LT-HSCs 的功能性表面标志物，通过与 BM 干细胞龛中表达 DARC 的巨噬细胞相互作用来调节休眠。最近，我们发现非常特殊和罕见的表达 α-SMA+COX2+&DARC+的巨噬细胞不仅通过 KAI1-DARC 的相互作用诱导 LT-HSC 休眠，而且通过 COX2 信号下调 ROS 来保护 HSCs。在不久的将来，结合 KAI1 阳性 LT-HSCs 和 α-SMA/Cox2/DARC 三阳性巨噬细胞的策略将提高血液系统疾病（包括白血病）的清髓性化疗后干细胞移植的疗效。[BMB 报告 2023;56(9):482-487]。
