The Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, New York, NY, 10461, USA.
Department of Cell Biology, Albert Einstein College of Medicine, New York, NY, 10461, USA.
Nat Commun. 2018 Jun 22;9(1):2449. doi: 10.1038/s41467-018-04726-3.
Endothelial cells (ECs) contribute to haematopoietic stem cell (HSC) maintenance in bone marrow, but the differential contributions of EC subtypes remain unknown, owing to the lack of methods to separate with high purity arterial endothelial cells (AECs) from sinusoidal endothelial cells (SECs). Here we show that the combination of podoplanin (PDPN) and Sca-1 expression distinguishes AECs (CD45 Ter119 Sca-1 PDPN) from SECs (CD45 Ter119 Sca-1 PDPN). PDPN can be substituted for antibodies against the adhesion molecules ICAM1 or E-selectin. Unexpectedly, prospective isolation reveals that AECs secrete nearly all detectable EC-derived stem cell factors (SCF). Genetic deletion of Scf in AECs, but not SECs, significantly reduced functional HSCs. Lineage-tracing analyses suggest that AECs and SECs self-regenerate independently after severe genotoxic insults, indicating the persistence of, and recovery from, radio-resistant pre-specified EC precursors. AEC-derived SCF also promotes HSC recovery after myeloablation. These results thus uncover heterogeneity in the contribution of ECs in stem cell niches.
内皮细胞（ECs）有助于骨髓中的造血干细胞（HSC）维持，但由于缺乏分离高纯度动脉内皮细胞（AECs）和窦状内皮细胞（SECs）的方法，EC 亚型的差异贡献仍不清楚。本文展示了 podoplanin（PDPN）和 Sca-1 表达的组合可将 AECs（CD45 Ter119 Sca-1 PDPN）与 SECs（CD45 Ter119 Sca-1 PDPN）区分开来。PDPN 可替代针对粘附分子 ICAM1 或 E-选择素的抗体。出乎意料的是，前瞻性分离显示 AECs 分泌几乎所有可检测到的 EC 来源的干细胞因子（SCF）。AEC 中 Scf 的基因缺失，但不是 SEC 中，显著降低了功能性 HSCs。谱系追踪分析表明，AECs 和 SECs 在严重的遗传毒性损伤后可以独立地自我再生，表明存在耐辐射的预指定 EC 前体，并能从中恢复。AEC 衍生的 SCF 也可促进骨髓清除后 HSC 的恢复。这些结果揭示了 EC 在干细胞龛中的贡献存在异质性。
