In:
PLOS ONE, Public Library of Science (PLoS), Vol. 16, No. 1 ( 2021-1-7), p. e0244743-
Abstract:
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. Methods 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. Results 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. Conclusions 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.
Type of Medium:
Online Resource
ISSN:
1932-6203
DOI:
10.1371/journal.pone.0244743
DOI:
10.1371/journal.pone.0244743.g001
DOI:
10.1371/journal.pone.0244743.g002
DOI:
10.1371/journal.pone.0244743.g003
DOI:
10.1371/journal.pone.0244743.g004
DOI:
10.1371/journal.pone.0244743.g005
DOI:
10.1371/journal.pone.0244743.s001
DOI:
10.1371/journal.pone.0244743.s002
DOI:
10.1371/journal.pone.0244743.s003
DOI:
10.1371/journal.pone.0244743.s004
DOI:
10.1371/journal.pone.0244743.s005
DOI:
10.1371/journal.pone.0244743.s006
DOI:
10.1371/journal.pone.0244743.s007
DOI:
10.1371/journal.pone.0244743.s008
DOI:
10.1371/journal.pone.0244743.s009
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2021
detail.hit.zdb_id:
2267670-3
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