Restoration and reversible expansion of the osteoblastic hematopoietic stem cell niche after marrow radioablation
Restoration and reversible expansion of the osteoblastic hematopoietic stem cell niche after marrow radioablation
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DOI：
10.1182/blood-2008-10-183459
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发表时间：
2009-09-10
期刊：
影响因子：
20.3
通讯作者：
Horwitz, Edwin M.
中科院分区：
文献类型：
--
作者：
Dominici, Massimo;Rasini, Valeria;Horwitz, Edwin M.
细胞毒性预处理方案后造血干细胞（HSC）龛的充分恢复对于成功的骨髓移植至关重要。然而，对于骨髓损伤后驱动这些壁龛恢复的机制知之甚少。在这里，我们描述了一个深刻的破坏骨髓微环境后，致命的全身照射的小鼠，导致成骨细胞恢复HSC的生态位的产生，其次是一个短暂的，可逆的扩大这个生态位。照射后48小时内，观察到存活的宿主巨核细胞靠近骨小梁的骨内膜表面，而不是在其正常的窦旁部位，伴随着基质衍生因子-1水平的增加。随后增加2巨核细胞衍生的生长因子，血小板衍生的生长因子-β和碱性成纤维细胞生长因子，诱导N-钙粘蛋白-/骨桥蛋白阳性成骨细胞的群体的2倍扩增，相对于稳态成骨细胞群体，因此，增加了HSC植入的潜在小生境的数量。供体细胞植入后，这种扩大的微环境恢复到其稳态。我们的研究结果表明骨髓放射消融后成骨干细胞龛的快速恢复，提供了相关机制的重要见解，并提出了操纵骨髓微环境以促进HSC植入的新方法。（血。2009; 114：2333-2343）
Adequate recovery of hematopoietic stem cell (HSC) niches after cytotoxic conditioning regimens is essential to successful bone marrow transplantation. Yet, very little is known about the mechanisms that drive the restoration of these niches after bone marrow injury. Here we describe a profound disruption of the marrow microenvironment after lethal total body irradiation of mice that leads to the generation of osteoblasts restoring the HSC niche, followed by a transient, reversible expansion of this niche. Within 48 hours after irradiation, surviving host megakaryocytes were observed close to the endosteal surface of trabecular bone rather than in their normal parasinusoidal site concomitant with an increased stromal-derived factor-1 level. A subsequent increase in 2 megakaryocyte-derived growth factors, platelet-derived growth factor-beta and basic fibroblast growth factor, induces a 2-fold expansion of the population of N-cadherin-/osteopontin-positive osteoblasts, relative to the homeostatic osteoblast population, and hence, increases the number of potential niches for HSC engraftment. After donor cell engraftment, this expanded microenvironment reverts to its homeostatic state. Our results demonstrate the rapid recovery of osteoblastic stem cell niches after marrow radioablation, provide critical insights into the associated mechanisms, and suggest novel means to manipulate the bone marrow microenvironment to promote HSC engraftment. (Blood. 2009; 114: 2333-2343)