Intermittent Hypoxia Mobilizes Bone Marrow-Derived Very Small Embryonic-Like Stem Cells and Activates Developmental Transcriptional Programs in Mice
Intermittent Hypoxia Mobilizes Bone Marrow-Derived Very Small Embryonic-Like Stem Cells and Activates Developmental Transcriptional Programs in Mice
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DOI：
10.1093/sleep/33.11.1439
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发表时间：
2010-11-01
期刊：
影响因子：
5.6
通讯作者：
Gozal, David
中科院分区：
文献类型：
--
作者：
Gharib, Sina A.;Dayyat, Ehab A.;Gozal, David
背景资料：阻塞性睡眠呼吸暂停是一种与认知功能障碍、心血管和代谢疾病相关的常见疾病，其特征在于睡眠期间反复发作的缺氧。骨髓来源的非常小的胚胎样（VSEL）多能干细胞代表了一个可招募的库，可能在损伤后的器官修复中发挥重要作用。我们假设，暴露于间歇性缺氧（IH）可以动员VSELs从骨髓（BM）到外周血（PB）中的小鼠，可以激活不同的转录programmes.Methods：成年小鼠暴露于IH或常氧48小时。使用流式细胞术从BM和PB中分选VSEL。测定干细胞趋化因子、基质细胞衍生因子-1（SDF-1）、肝细胞生长因子（HGF）和白血病抑制因子（LIF）的血浆水平。VSELs的转录谱进行，差异表达的基因被映射到丰富的功能类别和遗传networks.Results：暴露于IH引起的迁移的VSELs从BM到PB和升高的血浆水平的趋化因子。超过1100个独特的基因差异表达的VSEL响应IH。基因本体论和网络分析揭示了这些genes.Conclusions器官特异性发育程序的激活：暴露于IH动员VSELs从BM到PB和激活不同的转录程序在VSELs丰富的发展途径，包括中枢神经系统的发展和血管生成。因此，VSELs可以作为多能干细胞的储备移动的库，其可以被募集到PB中，并且可以在IH期间在促进终末器官修复中发挥重要作用。
Background: Obstructive sleep apnea is a prevalent disorder associated with cognitive dysfunction and cardiovascular and metabolic morbidity and is characterized by recurrent episodes of hypoxia during sleep. Bone marrow-derived very small embryonic-like (VSEL) pluripotent stem cells represent a recruitable pool that may play an important role in organ repair after injury. We hypothesized that exposure to intermittent hypoxia (IH) can mobilize VSELs from the bone marrow (BM) to peripheral blood (PB) in mice and can activate distinct transcriptional programs.Methods: Adult mice were exposed to IH or normoxia for 48 hours. VSELs were sorted from BM and PB using flow cytometry. Plasma levels of stem cell chemokines, stromal cell derived factor-1 (SDF-1), hepatocyte growth factor (HGF), and leukemia inhibitory factor (LIF) were measured. Transcriptional profiling of VSELs was performed, and differentially expressed genes were mapped to enriched functional categories and genetic networks.Results: Exposure to IH elicited migration of VSELs from BM to PB and elevations in plasma levels of chemokines. More than 1100 unique genes were differentially expressed in VSELs in response to IH. Gene Ontology and network analysis revealed the activation of organ-specific developmental programs among these genes.Conclusions: Exposure to IH mobilizes VSELs from the BM to PB and activates distinct transcriptional programs in VSELs that are enriched in developmental pathways, including central nervous system development and angiogenesis. Thus, VSELs may serve as a reserve mobile pool of pluripotent stem cells that can be recruited into PB and may play an important role in promoting end-organ repair during IH.