Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
Nat Cell Biol. 2018 Jun;20(6):710-720. doi: 10.1038/s41556-018-0104-5. Epub 2018 May 25.
Elucidation of the identity and diversity of mechanisms that sustain long-term human blood cell production remains an important challenge. Previous studies indicate that, in adult mice, this property is vested in cells identified uniquely by their ability to clonally regenerate detectable, albeit highly variable levels and types, of mature blood cells in serially transplanted recipients. From a multi-parameter analysis of the molecular features of very primitive human cord blood cells that display long-term cell outputs in vitro and in immunodeficient mice, we identified a prospectively separable CD33CD34CD38CD45RACD90CD49f phenotype with serially transplantable, but diverse, cell output profiles. Single-cell measurements of the mitogenic response, and the transcriptional, DNA methylation and 40-protein content of this and closely related phenotypes revealed subtle but consistent differences both within and between each subset. These results suggest that multiple regulatory mechanisms combine to maintain different cell output activities of human blood cell precursors with high regenerative potential.
阐明维持长期人类血细胞生成的机制的特性和多样性仍然是一个重要的挑战。先前的研究表明，在成年小鼠中，这种特性存在于能够通过克隆再生可检测到的、但高度可变水平和类型的成熟血细胞的能力来唯一识别的细胞中，这些细胞在连续移植的受体内进行。从对具有体外和免疫缺陷小鼠中长期细胞输出的非常原始的人类脐带血细胞的分子特征进行的多参数分析中，我们鉴定出一种具有可连续移植但多样化细胞输出特征的可预测分离的 CD33CD34CD38CD45RACD90CD49f 表型。对有丝分裂反应、转录、DNA 甲基化和这一表型及其密切相关表型的 40 种蛋白质含量的单细胞测量显示，每个亚群内和亚群之间都存在细微但一致的差异。这些结果表明，多种调节机制共同维持具有高再生潜能的人类血细胞前体的不同细胞输出活性。
