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Osteoblastic cells regulate the haematopoietic stem cell niche

机译：成骨细胞调节造血干细胞的生态位

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摘要

Stem cell fate is influenced by specialized microenvironments that remain poorly defined in mammals. 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). 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 Notch 1 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 γ-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.
机译：干细胞的命运受到专门的微环境的影响，在哺乳动物中，微环境的定义仍然不明确。为了探究造血干细胞从骨骼中获取调节信息的可能性，以说明造血细胞在骨髓中的定位，我们评估了经过基因改造以产生成骨细胞特异性激活PTH / PTHrP受体（PPRs）的小鼠。在这里，我们显示数量增加的PPR刺激的成骨细胞产生高水平的Notch配体锯齿状1并支持造血干细胞数量的增加，体内Notch 1活化的证据。此外，甲状旁腺激素（PTH）对PPR的依赖于配体的激活增加了基质培养物中成骨细胞的数量，并增加了被γ-分泌酶抑制Notch激活所消除的离体原始造血细胞的生长。注射PTH后，在野生型动物中观察到干细胞数量增加，并且骨髓移植后的存活率显着提高。因此，成骨细胞是体内造血干细胞生态位的调节成分，其通过Notch激活影响干细胞功能。生态位组成细胞或信号通路为基于干细胞疗法的治疗潜力提供了药理学靶标。

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