Institute of Hematology, the Third Affiliated Hospital of Sun Yat-Sen University; Key Laboratory of Stem Cells and Tissue Engineering Sun Yat-Sen University, Guangzhou 510000, China; Stowers Institute for Medical Research, Kansas City, MO 66110, USA.
Stowers Institute for Medical Research, Kansas City, MO 66110, USA; Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Cell Rep. 2019 Jan 15;26(3):652-669.e6. doi: 10.1016/j.celrep.2018.12.093.
Regulation of hematopoietic stem cells (HSCs) by bone marrow (BM) niches has been extensively studied; however, whether and how HSC subpopulations are distinctively regulated by BM niches remain unclear. Here, we functionally distinguished reserve HSCs (rHSCs) from primed HSCs (pHSCs) based on their response to chemotherapy and examined how they are dichotomously regulated by BM niches. Both pHSCs and rHSCs supported long-term hematopoiesis in homeostasis; however, pHSCs were sensitive but rHSCs were resistant to chemotherapy. Surviving rHSCs restored the HSC pool and supported hematopoietic regeneration after chemotherapy. The rHSCs were preferentially maintained in the endosteal region that enriches N-cadherin (N-cad) bone-lining cells in homeostasis and post-chemotherapy. N-cad cells were functional bone and marrow stromal progenitor cells (BMSPCs), giving rise to osteoblasts, adipocytes, and chondrocytes in vitro and in vivo. Finally, ablation of N-cad niche cells or deletion of SCF from N-cad niche cells impaired rHSC maintenance during homeostasis and regeneration.
骨髓（BM）龛对造血干细胞（HSCs）的调节作用已得到广泛研究；然而，HSC 亚群是否以及如何受到 BM 龛的独特调节仍不清楚。在这里，我们根据对化疗的反应，从造血干细胞中功能上区分储备造血干细胞（rHSCs）和初始造血干细胞（pHSCs），并研究它们如何受到 BM 龛的二分调节。pHSCs 和 rHSCs 均在体内稳态中支持长期造血；然而，pHSCs 对化疗敏感，而 rHSCs 则有抗性。存活的 rHSCs 恢复了 HSC 池，并在化疗后支持造血再生。rHSCs 优先存在于富含 N-钙黏蛋白（N-cad）的骨内膜细胞的骨内膜区，在体内稳态和化疗后。N-cad 细胞是功能性的骨和骨髓基质祖细胞（BMSPCs），在体外和体内可分化为成骨细胞、脂肪细胞和成软骨细胞。最后，N-cad 龛细胞的缺失或 N-cad 龛细胞中 SCF 的缺失，损害了体内稳态和再生过程中 rHSC 的维持。
