Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
Sci Transl Med. 2011 Oct 12;3(104):104ra101. doi: 10.1126/scitranslmed.3002191.
Success with transplantation of autologous hematopoietic stem and progenitor cells (HSPCs) in patients depends on adequate collection of these cells after mobilization from the bone marrow niche by the cytokine granulocyte colony-stimulating factor (G-CSF). However, some patients fail to achieve sufficient HSPC mobilization. Retrospective analysis of bone marrow transplant patient records revealed that diabetes correlated with poor mobilization of CD34+ HSPCs. In mouse models of type 1 and type 2 diabetes (streptozotocin-induced and db/db mice, respectively), we found impaired egress of murine HSPCs from the bone marrow after G-CSF treatment. Furthermore, HSPCs were aberrantly localized in the marrow niche of the diabetic mice, and abnormalities in the number and function of sympathetic nerve termini were associated with this mislocalization. Aberrant responses to β-adrenergic stimulation of the bone marrow included an inability of marrow mesenchymal stem cells expressing the marker nestin to down-modulate the chemokine CXCL12 in response to G-CSF treatment (mesenchymal stem cells are reported to be critical for HSPC mobilization). The HSPC mobilization defect was rescued by direct pharmacological inhibition of the interaction of CXCL12 with its receptor CXCR4 using the drug AMD3100. These data suggest that there are diabetes-induced changes in bone marrow physiology and microanatomy and point to a potential intervention to overcome poor HSPC mobilization in diabetic patients.
自体造血干细胞和祖细胞（HSPC）移植的成功取决于在细胞因子粒细胞集落刺激因子（G-CSF）从骨髓龛中动员后，能否充分采集这些细胞。然而，有些患者未能实现足够的 HSPC 动员。对骨髓移植患者记录的回顾性分析显示，糖尿病与 CD34+HSPC 动员不良相关。在 1 型和 2 型糖尿病（链脲佐菌素诱导和 db/db 小鼠）的小鼠模型中，我们发现 G-CSF 治疗后，小鼠 HSPC 从骨髓中迁出受损。此外，HSPC 异常定位于糖尿病小鼠的骨髓龛中，并且交感神经末梢数量和功能的异常与这种定位异常有关。骨髓对β-肾上腺素刺激的异常反应包括，表达巢蛋白标志物的骨髓间充质干细胞在 G-CSF 治疗下无法下调趋化因子 CXCL12（据报道，间充质干细胞对 HSPC 动员至关重要）。使用药物 AMD3100 直接抑制 CXCL12 与其受体 CXCR4 的相互作用，挽救了 HSPC 动员缺陷。这些数据表明，骨髓生理学和微解剖学存在糖尿病诱导的变化，并指出了一种潜在的干预措施，可以克服糖尿病患者 HSPC 动员不良的问题。
