Singh Pratibha, Pelus Louis M
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA.
Department of Medicine, Indiana University School of Medicine, 980 West Walnut Street, Indianapolis, IN, 46202, USA.
Stem Cell Rev Rep. 2021 Dec;17(6):2338-2346. doi: 10.1007/s12015-021-10202-1. Epub 2021 Jun 22.
The factors/mechanisms regulating multipotent or bipotent hematopoietic progenitor cells lineage-commitment are not well understood. In this study, we found that prostaglandin E (PGE) is a crucial physiological regulator of lineage choice for the bipotential monocyte-dendritic progenitor cell (MDP). Inhibition of endogenous PGE 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 PGE 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 PGE 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 PGE-EP1 signaling plays a critical role in MDP lineage commitment and DC and MO differentiation.
调节多能或双能造血祖细胞谱系定向的因素/机制尚未完全明确。在本研究中，我们发现前列腺素E（PGE）是双潜能单核细胞-树突状祖细胞（MDP）谱系选择的关键生理调节因子。双环氧化酶抑制剂吲哚美辛抑制小鼠内源性PGE生物合成，可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。用吲哚美辛对纯化的MDP进行体外处理，优先增加MO发育，同时以DC生成减少为代价，而添加外源性PGE可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信号传导促进MDP分化为DC，同时以MO生成减少为代价。相反，EP1受体敲除小鼠显示DC减少，MO分化增加。机制研究表明，PGE增加MDP上酪氨酸激酶受体Flt3的表达，并增加DC谱系相关转录因子PU.1，同时降低M-CSFR和MO谱系相关转录因子MafB的表达。这些数据表明，PGE-EP1信号传导在MDP谱系定向以及DC和MO分化中起关键作用。
