Diabetes impairs hematopoietic stem cell mobilization by altering niche function.
Diabetes impairs hematopoietic stem cell mobilization by altering niche function.
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DOI：
10.1126/scitranslmed.3002191
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发表时间：
2011-10-12
影响因子：
17.1
通讯作者：
Scadden DT
中科院分区：
文献类型：
--
作者：
Ferraro F;Lymperi S;Méndez-Ferrer S;Saez B;Spencer JA;Yeap BY;Masselli E;Graiani G;Prezioso L;Rizzini EL;Mangoni M;Rizzoli V;Sykes SM;Lin CP;Frenette PS;Quaini F;Scadden DT
自体造血干细胞/祖细胞（HSPC）移植的成功取决于给予g - csf后足够的细胞收集，而很大一部分患者未能实现。对患者记录的回顾性分析表明，糖尿病与CD34+细胞动员降低相关。通过小鼠模型，我们发现链脲佐菌素诱导或db/db糖尿病动物骨髓中HSPC的表达受损。HSPC在糖尿病动物骨髓微环境中的异常定位与交感神经元数量和功能异常有关。在与HSPC动员相关的巢蛋白表达间充质细胞中，交感神经元密度显著增加，伴有对β-肾上腺素能刺激的异常反应，以及不能产生g - csf诱导的CXCL12梯度。通过直接药理抑制CXCL12-CXCR4相互作用的替代动员挽救了缺陷。这些数据揭示了糖尿病诱导的骨髓生理学和显微解剖学的变化，并指出了一种基于病理生理学的方法来克服糖尿病患者的HSPC动员缺陷。
Autologous hematopoietic stem/progenitor cells (HSPC) transplantation success depends upon adequate cell collection after G-CSF-administration that a substantial fraction of patients fails to achieve. Retrospective analysis of patient records demonstrated that diabetes correlated with lower CD34+ cell mobilization. Using mouse models, we found impaired HSPC egress from the bone marrow in either streptozotocin-induced or db/db diabetic animals. HSPC aberrantly localized within the marrow microenvironment of diabetic animals in association with abnormalities in sympathetic neuron number and function. Markedly increased sympathetic neuron density was accompanied by abnormal response to β-adrenergic stimulation and a failure to generate the G-CSF-induced CXCL12 gradient in nestin-expressing mesenchymal cells associated with HSPC mobilization. Alternative mobilization by direct pharmacologic inhibition of CXCL12-CXCR4 interaction rescued the defect. These data reveal diabetes-induced changes in bone marrow physiology and microanatomy and point to a pathophysiologically based approach to overcome HSPC mobilization defects in diabetic patients.
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