The M3 Muscarinic Acetylcholine Receptor Promotes Epidermal Differentiation.
The M3 Muscarinic Acetylcholine Receptor Promotes Epidermal Differentiation.
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DOI：
10.1016/j.jid.2022.06.013
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发表时间：
2022-12
影响因子：
6.5
通讯作者：
Grando, Sergei A.
中科院分区：
文献类型：
--
作者：
Duan, Junyan;Grando, Charles;Liu, Shuman;Chernyavsky, Alex;Chen, Jefferson K.;Andersen, Bogi;Grando, Sergei A.
M3毒蕈碱乙酰胆碱受体主要表达于基底表皮层，介导自分泌/旁分泌细胞递质乙酰胆碱的作用。自身免疫性水疱性天疱疮患者产生M3毒蕈碱乙酰胆碱受体自身抗体，角质细胞粘附、增殖和分化发生改变，提示M3毒蕈碱乙酰胆碱受体控制着这些细胞功能。Chmr3 - / -小鼠表现出与寻常型天疱疮患者相似的表皮形态改变。在本研究中，我们研究了M3毒蕈碱乙酰胆碱受体控制表皮结构和功能的细胞和分子机制。我们使用单细胞RNA测序来评估Chmr3−/−新生小鼠表皮细胞特定亚群中的角质细胞异质性，并鉴定差异表达基因。我们发现Chmr3−/−小鼠的表皮形态异常，其特征是有核基底细胞聚集，基底角质形成细胞萎缩，细胞间隙增大。这些形态学变化与细胞增殖基因的上调和参与表皮分化、细胞外基质形成、细胞间粘附和细胞排列的基因的下调有关。据我们所知，这些发现提供了以前未报道的关于乙酰胆碱如何控制表皮分化的见解，并为未来评估胆碱能药物在皮肤病学中的治疗潜力的转化研究奠定了基础。
The M3 muscarinic acetylcholine receptor is predominantly expressed in the basal epidermal layer where it mediates the effects of the autocrine/paracrine cytotransmitter acetylcholine. Patients with the autoimmune blistering disease pemphigus develop autoantibodies to M3 muscarinic acetylcholine receptor and show alterations in keratinocyte adhesion, proliferation, and differentiation, suggesting that M3 muscarinic acetylcholine receptor controls these cellular functions. Chmr3−/− mice display altered epidermal morphology resembling that seen in patients with pemphigus vulgaris. In this study, we characterized the cellular and molecular mechanisms through which M3 muscarinic acetylcholine receptor controls epidermal structure and function. We used single-cell RNA sequencing to evaluate keratinocyte heterogeneity and identify differentially expressed genes in specific subpopulations of epidermal cells in Chmr3−/− neonatal mice. We found that Chmr3−/− mice feature abnormal epidermal morphology characterized by accumulation of nucleated basal cells, shrinkage of basal keratinocytes, and enlargement of intercellular spaces. These morphologic changes were associated with upregulation of cell proliferation genes and downregulation of genes contributing to epidermal differentiation, extracellular matrix formation, intercellular adhesion, and cell arrangement. These findings provide, to our knowledge, previously unreported insights into how acetylcholine controls epidermal differentiation and lay a groundwork for future translational studies evaluating the therapeutic potential of cholinergic drugs in dermatology.
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