Zbtb46-dependent altered developmental program in embryonic stem cell-derived blood cell progenitors,STEM CELLS

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Zbtb46-dependent altered developmental program in embryonic stem cell-derived blood cell progenitors
STEM CELLS ( IF 4.0 ) Pub Date : 2021-05-31 , DOI: 10.1002/stem.3424
Pal Boto _{1,

2} , Timea Beatrix Gerzsenyi ₁ , Adel Lengyel ₁ , Balint Szunyog ₁ , Istvan Szatmari _{1,

3}

Affiliation

Zbtb46 is a recently identified dendritic cell (DC)-specific transcription factor with poorly defined biology. Although Zbtb46 is highly expressed in conventional DCs, evidence also points to its presence in erythroid progenitors and endothelial cells suggesting that this factor might influence the early hematopoietic development. Here, we probe the effect of this transcription factor in embryonic stem cell (ESC)-derived blood cell progenitors using chemically inducible mouse cell lines. Unexpectedly, forced expression of this protein elicited a broad repressive effect at the early stage of ESC differentiation. Ectopic expression of Zbtb46 interfered with the mesoderm formation and cell proliferation was also negatively impacted. More importantly, reduced number of CD11b+ myeloid blood cells were generated from ESC-derived Flk1+ mesoderm cells in the presence of Zbtb46. Consistent with this finding, our gene expression profiling revealed that numerous myeloid and immune response related genes, including Irf8, exhibited lower expression in the Zbtb46-primed cells. Despite these repressive effects, however, Zbtb46 overexpression was associated with enhanced formation of erythroid blood cell colonies and increased adult hemoglobin (Hbb-b1) expression at the early phase of ESC differentiation. Moreover, elevated percent of CD105 (Endoglin) positive cells were detected in the Zbtb46-primed samples. In summary, our results support that Zbtb46 suppresses the ESC-derived myeloid development and diverts mesoderm cells toward erythroid developmental pathway. Moreover, our transcriptomic data provide a resource for exploration of the Zbtb46 regulatory network in ESC-derived progenitors.

中文翻译：

Zbtb46 依赖的胚胎干细胞衍生血细胞祖细胞发育程序改变

Zbtb46 是最近发现的树突状细胞 (DC) 特异性转录因子，其生物学定义不明确。尽管 Zbtb46 在常规 DCs 中高度表达，但有证据表明它存在于红系祖细胞和内皮细胞中，表明该因素可能影响早期造血发育。在这里，我们使用化学诱导的小鼠细胞系探讨这种转录因子在胚胎干细胞 (ESC) 衍生的血细胞祖细胞中的作用。出乎意料的是，这种蛋白质的强制表达在 ESC 分化的早期阶段引起了广泛的抑制作用。Zbtb46 的异位表达干扰了中胚层的形成，细胞增殖也受到了负面影响。更重要的是，在 Zbtb46 存在下，由 ESC 衍生的 Flk1+ 中胚层细胞产生的 CD11b+ 骨髓血细胞数量减少。与这一发现一致，我们的基因表达谱显示，许多骨髓和免疫反应相关基因，包括 Irf8，在 Zbtb46 引发的细胞中表现出较低的表达。然而，尽管有这些抑制作用，但 Zbtb46 过表达与 ESC 分化早期红细胞集落形成增强和成人血红蛋白 (Hbb-b1) 表达增加有关。此外，在 Zbtb46-primed 样本中检测到 CD105 (Endoglin) 阳性细胞的百分比升高。总之，我们的结果支持 Zbtb46 抑制 ESC 衍生的骨髓发育并将中胚层细胞转向红系发育途径。而且，

更新日期：2021-05-31

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