Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.
Department of Hematology, Erasmus Medical Center, Rotterdam, the Netherlands.
Sci Rep. 2016 Sep 2;6:32034. doi: 10.1038/srep32034.
Osteolineage cells represent one of the critical bone marrow niche components that support maintenance of hematopoietic stem and progenitor cells (HSPCs). Recent studies demonstrate that extracellular vesicles (EVs) regulate stem cell development via horizontal transfer of bioactive cargo, including microRNAs (miRNAs). Using next-generation sequencing we show that human osteoblast-derived EVs contain highly abundant miRNAs specifically enriched in EVs, including critical regulators of hematopoietic proliferation (e.g., miR-29a). EV treatment of human umbilical cord blood-derived CD34(+) HSPCs alters the expression of candidate miRNA targets, such as HBP1, BCL2 and PTEN. Furthermore, EVs enhance proliferation of CD34(+) cells and their immature subsets in growth factor-driven ex vivo expansion cultures. Importantly, EV-expanded cells retain their differentiation capacity in vitro and successfully engraft in vivo. These discoveries reveal a novel osteoblast-derived EV-mediated mechanism for regulation of HSPC proliferation and warrant consideration of EV-miRNAs for the development of expansion strategies to treat hematological disorders.
成骨细胞系是骨髓龛的关键组成部分之一，它支持造血干细胞和祖细胞（HSPCs）的维持。最近的研究表明，细胞外囊泡（EVs）通过生物活性物质的水平转移来调节干细胞的发育，包括 microRNAs（miRNAs）。我们使用下一代测序技术表明，人成骨细胞衍生的 EV 含有高度丰富的 miRNAs，这些 miRNAs 特异性地富集在 EV 中，包括造血增殖的关键调节因子（例如 miR-29a）。人脐带血来源的 CD34+ HSPCs 的 EV 处理改变了候选 miRNA 靶标的表达，例如 HBP1、BCL2 和 PTEN。此外，EV 增强了生长因子驱动的体外扩增培养中 CD34+细胞及其未成熟亚群的增殖。重要的是，EV 扩增的细胞在体外保留其分化能力，并在体内成功植入。这些发现揭示了一种新型的成骨细胞衍生的 EV 介导的 HSPC 增殖调节机制，并证明了 EV-miRNAs 在开发治疗血液疾病的扩增策略中的应用价值。
