Stem Cell Reviews and Reports ( IF 4.5 ) Pub Date : 2021-06-22 , DOI: 10.1007/s12015-021-10202-1 Pratibha Singh 1, 2 , Louis M Pelus 1, 2
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The factors/mechanisms regulating multipotent or bipotent hematopoietic progenitor cells lineage-commitment are not well understood. In this study, we found that prostaglandin E2 (PGE2) is a crucial physiological regulator of lineage choice for the bipotential monocyte-dendritic progenitor cell (MDP). Inhibition of endogenous PGE2 biosynthesis in mice by the dual cyclooxygenase inhibitor, indomethacin, enhances bone marrow and spleen monocyte (MO) differentiation and reduces dendritic cell (DC) differentiation. Ex vivo treatment of purified MDP with indomethacin preferentially increases MO development at the expense of DC generation, whereas addition of exogenous PGE2 reverses the indomethacin-mediated alteration in MDP differentiation potential. Treatment of MDP with selective EP receptor agonists demonstrated that EP1 signaling promotes MDP differentiation into DC at the expense of MO generation. Conversely, EP1 receptor knockout mice showed reduced DC and increased MO differentiation. Mechanistic studies revealed that PGE2 increases expression of the tyrosine kinase receptor Flt3 on MDP and increases the DC-lineage-related transcription factor PU.1, while reducing expression of M-CSFR and the MO-lineage-related transcription factor MafB. These data indicate that PGE2-EP1 signaling plays a critical role in MDP lineage commitment and DC and MO differentiation.
Graphical abstract
中文翻译：
前列腺素 E2 调节双能单核细胞-树突状祖细胞谱系-定型
调节多能或双能造血祖细胞谱系承诺的因素/机制尚不清楚。在这项研究中，我们发现前列腺素 E 2 (PGE 2 ) 是双能单核细胞-树突状祖细胞 (MDP) 谱系选择的关键生理调节剂。双重环加氧酶抑制剂吲哚美辛抑制小鼠内源性 PGE 2生物合成，增强骨髓和脾脏单核细胞 (MO) 分化并减少树突状细胞 (DC) 分化。用消炎痛离体处理纯化的 MDP 会优先增加 MO 发育，但会牺牲 DC 的产生，而添加外源性 PGE 2逆转吲哚美辛介导的 MDP 分化潜能改变。用选择性 EP 受体激动剂处理 MDP 表明 EP1 信号传导以 MO 生成为代价促进 MDP 分化为 DC。相反，EP1 受体敲除小鼠表现出 DC 减少和 MO 分化增加。机理研究表明，PGE 2增加了 MDP 上酪氨酸激酶受体 Flt3 的表达，增加了 DC 谱系相关转录因子 PU.1，同时降低了 M-CSFR 和 MO 谱系相关转录因子 MafB 的表达。这些数据表明 PGE 2 -EP1 信号传导在 MDP 谱系定型和 DC 和 MO 分化中起关键作用。
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