Transcriptional profiling of pediatric cholestatic livers identifies three distinct macrophage populations.
Transcriptional profiling of pediatric cholestatic livers identifies three distinct macrophage populations.
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DOI：
10.1371/journal.pone.0244743
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发表时间：
2021
期刊：
影响因子：
3.7
通讯作者：
Winter DR
中科院分区：
文献类型：
--
作者：
Taylor SA;Chen SY;Gadhvi G;Feng L;Gromer KD;Abdala-Valencia H;Nam K;Dominguez ST;Montgomery AB;Reyfman PA;Ostilla L;Wechsler JB;Cuda CM;Green RM;Perlman H;Winter DR
对特定巨噬细胞亚群在胆汁淤积性肝损伤发病机制中的作用的有限理解是推进药物治疗的障碍。巨噬细胞在阻塞性胆汁淤积症中的适应不良和保护性反应中均有牵连。最近在非患病的人类肝脏中鉴定出两个巨噬细胞亚群;然而，迄今为止没有研究完全定义胆汁淤积发病过程中的异质性巨噬细胞亚群。在这里，我们的目的是进一步描述小儿胆汁淤积性肝病中巨噬细胞的转录谱。我们通过荧光激活细胞分选法从胆道闭锁（BA）、Alagille综合征（ALGS）和非胆汁淤积的儿童肝脏中分离出活的肝脏免疫细胞。通过单细胞RNA测序分析和免疫荧光，我们对胆汁淤积性巨噬细胞进行了表征。接下来，我们将儿科胆汁淤积性和非胆汁淤积性巨噬细胞群体的转录谱与先前发表的正常成人肝巨噬细胞的数据进行了比较。我们在胆汁淤积性肝脏样本中鉴定了3种不同的巨噬细胞群体，并基于其转录谱将其注释为脂质相关巨噬细胞、单核细胞样巨噬细胞和适应性巨噬细胞。使用每个亚组的标志物对肝组织进行免疫荧光证实了它们在BA（n = 6）和ALGS（n = 6）患者中的存在。与正常肝巨噬细胞相比，胆汁淤积性巨噬细胞表现出免疫调节基因的表达减少，并且与健康成人或儿科非胆汁淤积性肝脏中定义的巨噬细胞群体不同。我们是第一个对人类小儿胆汁淤积性肝脏进行单细胞RNA测序的人，并从健康的肝脏巨噬细胞中鉴定出具有不同转录特征的三个巨噬细胞亚群。进一步的分析将确定这些巨噬细胞亚群在胆汁淤积性肝病病因中的相似性和差异。总之，这些发现可能允许未来开发靶向治疗策略，以将巨噬细胞重编程为免疫调节表型并减少胆汁淤积性肝损伤。
Limited understanding of the role for specific macrophage subsets in the pathogenesis of cholestatic liver injury is a barrier to advancing medical therapy. Macrophages have previously been implicated in both the mal-adaptive and protective responses in obstructive cholestasis. Recently two macrophage subsets were identified in non-diseased human liver; however, no studies to date fully define the heterogeneous macrophage subsets during the pathogenesis of cholestasis. Here, we aim to further characterize the transcriptional profile of macrophages in pediatric cholestatic liver disease. We isolated live hepatic immune cells from patients with biliary atresia (BA), Alagille syndrome (ALGS), and non-cholestatic pediatric liver by fluorescence activated cell sorting. Through single-cell RNA sequencing analysis and immunofluorescence, we characterized cholestatic macrophages. We next compared the transcriptional profile of pediatric cholestatic and non-cholestatic macrophage populations to previously published data on normal adult hepatic macrophages. We identified 3 distinct macrophage populations across cholestatic liver samples and annotated them as lipid-associated macrophages, monocyte-like macrophages, and adaptive macrophages based on their transcriptional profile. Immunofluorescence of liver tissue using markers for each subset confirmed their presence across BA (n = 6) and ALGS (n = 6) patients. Cholestatic macrophages demonstrated reduced expression of immune regulatory genes as compared to normal hepatic macrophages and were distinct from macrophage populations defined in either healthy adult or pediatric non-cholestatic liver. We are the first to perform single-cell RNA sequencing on human pediatric cholestatic liver and identified three macrophage subsets with distinct transcriptional signatures from healthy liver macrophages. Further analyses will identify similarities and differences in these macrophage sub-populations across etiologies of cholestatic liver disease. Taken together, these findings may allow for future development of targeted therapeutic strategies to reprogram macrophages to an immune regulatory phenotype and reduce cholestatic liver injury.
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