Yang Jennifer, Tanaka Yoshiaki, Seay Montrell, Li Zhen, Jin Jiaqi, Garmire Lana Xia, Zhu Xun, Taylor Ashley, Li Weidong, Euskirchen Ghia, Halene Stephanie, Kluger Yuval, Snyder Michael P, Park In-Hyun, Pan Xinghua, Weissman Sherman Morton
Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
Yale Stem Cell Center, Yale School of Medicine, New Haven, CT, USA.
Nucleic Acids Res. 2017 Feb 17;45(3):1281-1296. doi: 10.1093/nar/gkw1214.
Molecular changes underlying stem cell differentiation are of fundamental interest. scRNA-seq on murine hematopoietic stem cells (HSC) and their progeny MPP1 separated the cells into 3 main clusters with distinct features: active, quiescent, and an un-characterized cluster. Induction of anemia resulted in mobilization of the quiescent to the active cluster and of the early to later stage of cell cycle, with marked increase in expression of certain transcription factors (TFs) while maintaining expression of interferon response genes. Cells with surface markers of long term HSC increased the expression of a group of TFs expressed highly in normal cycling MPP1 cells. However, at least Id1 and Hes1 were significantly activated in both HSC and MPP1 cells in anemic mice. Lineage-specific genes were differently expressed between cells, and correlated with the cell cycle stages with a specific augmentation of erythroid related genes in the G2/M phase. Most lineage specific TFs were stochastically expressed in the early precursor cells, but a few, such as Klf1, were detected only at very low levels in few precursor cells. The activation of these factors may correlate with stages of differentiation. This study reveals effects of cell cycle progression on the expression of lineage specific genes in precursor cells, and suggests that hematopoietic stress changes the balance of renewal and differentiation in these homeostatic cells.
干细胞分化背后的分子变化是人们极为感兴趣的。对小鼠造血干细胞（HSC）及其子代多能祖细胞1（MPP1）进行的单细胞RNA测序（scRNA-seq）将细胞分为3个具有不同特征的主要簇：活跃簇、静止簇和一个未表征的簇。贫血的诱导导致静止簇细胞向活跃簇的动员以及细胞周期从早期到后期的转变，某些转录因子（TFs）的表达显著增加，同时干扰素反应基因的表达保持不变。具有长期造血干细胞表面标志物的细胞增加了一组在正常循环的MPP1细胞中高表达的转录因子的表达。然而，在贫血小鼠的造血干细胞和MPP1细胞中，至少Id1和Hes1被显著激活。细胞之间谱系特异性基因的表达存在差异，并且与细胞周期阶段相关，在G2/M期红系相关基因有特定增加。大多数谱系特异性转录因子在前体细胞中随机表达，但少数转录因子，如Klf1，仅在少数前体细胞中以极低水平被检测到。这些因子的激活可能与分化阶段相关。这项研究揭示了细胞周期进程对前体细胞中谱系特异性基因表达的影响，并表明造血应激改变了这些稳态细胞中自我更新和分化的平衡。
