Osteoblastic cells regulate the haematopoietic stem cell niche
Osteoblastic cells regulate the haematopoietic stem cell niche
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DOI：
10.1038/nature02040
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发表时间：
2003-10-23
期刊：
影响因子：
64.8
通讯作者：
Scadden, DT
中科院分区：
文献类型：
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作者：
Calvi, LM;Adams, GB;Scadden, DT
干细胞的命运是由专门的微环境，仍然不明确的哺乳动物（1-3）的影响。为了探索造血干细胞从骨中获得调控信息的可能性，解释骨髓中造血的定位，我们评估了经遗传改变以产生成骨细胞特异性活化PTH/PTHrP受体（PPR）的小鼠（4）。在这里，我们表明，PPR刺激的成骨细胞的数量增加，产生高水平的Notch配体锯齿状1和支持的数量增加的造血干细胞的证据Notch 1在体内激活。此外，PPR与甲状旁腺激素（PTH）的配体依赖性激活增加了基质培养中的成骨细胞的数量，并增强了体外原始造血细胞的生长，而这种生长被Notch激活的γ-分泌酶抑制所废除。在注射PTH后的野生型动物中观察到干细胞数量的增加，骨髓移植后的存活率显著提高。因此，成骨细胞是体内造血干细胞生态位的调节成分，通过Notch激活影响干细胞功能。小生境组成细胞或信号通路为基于干细胞的疗法提供了具有治疗潜力的药理学靶点。
Stem cell fate is influenced by specialized microenvironments that remain poorly defined in mammals(1-3). To explore the possibility that haematopoietic stem cells derive regulatory information from bone, accounting for the localization of haematopoiesis in bone marrow, we assessed mice that were genetically altered to produce osteoblast-specific, activated PTH/PTHrP receptors (PPRs)(4). Here we show that PPR-stimulated osteoblastic cells that are increased in number produce high levels of the Notch ligand jagged 1 and support an increase in the number of haematopoietic stem cells with evidence of Notch1 activation in vivo. Furthermore, ligand-dependent activation of PPR with parathyroid hormone (PTH) increased the number of osteoblasts in stromal cultures, and augmented ex vivo primitive haematopoietic cell growth that was abrogated by gamma-secretase inhibition of Notch activation. An increase in the number of stem cells was observed in wild-type animals after PTH injection, and survival after bone marrow transplantation was markedly improved. Therefore, osteoblastic cells are a regulatory component of the haematopoietic stem cell niche in vivo that influences stem cell function through Notch activation. Niche constituent cells or signalling pathways provide pharmacological targets with therapeutic potential for stem-cell-based therapies.