Transcriptional profiling of pediatric cholestatic livers identifies three distinct macrophage populations.
<h4>Background & aims</h4>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 obst...
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2021
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oai:doaj.org-article:c015eb78f3cb4aa88de1330263a1b31d2021-12-02T20:11:27ZTranscriptional profiling of pediatric cholestatic livers identifies three distinct macrophage populations.1932-620310.1371/journal.pone.0244743https://doaj.org/article/c015eb78f3cb4aa88de1330263a1b31d2021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0244743https://doaj.org/toc/1932-6203<h4>Background & aims</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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.Sarah A TaylorShang-Yang ChenGaurav GadhviLiang FengKyle D GromerHiam Abdala-ValenciaKiwon NamSalina T DominguezAnna B MontgomeryPaul A ReyfmanLorena OstillaJoshua B WechslerCarla M CudaRichard M GreenHarris PerlmanDeborah R WinterPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 1, p e0244743 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Medicine R Science Q |
| spellingShingle |
Medicine R Science Q Sarah A Taylor Shang-Yang Chen Gaurav Gadhvi Liang Feng Kyle D Gromer Hiam Abdala-Valencia Kiwon Nam Salina T Dominguez Anna B Montgomery Paul A Reyfman Lorena Ostilla Joshua B Wechsler Carla M Cuda Richard M Green Harris Perlman Deborah R Winter Transcriptional profiling of pediatric cholestatic livers identifies three distinct macrophage populations. |
| description |
<h4>Background & aims</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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. |
| format |
article |
| author |
Sarah A Taylor Shang-Yang Chen Gaurav Gadhvi Liang Feng Kyle D Gromer Hiam Abdala-Valencia Kiwon Nam Salina T Dominguez Anna B Montgomery Paul A Reyfman Lorena Ostilla Joshua B Wechsler Carla M Cuda Richard M Green Harris Perlman Deborah R Winter |
| author_facet |
Sarah A Taylor Shang-Yang Chen Gaurav Gadhvi Liang Feng Kyle D Gromer Hiam Abdala-Valencia Kiwon Nam Salina T Dominguez Anna B Montgomery Paul A Reyfman Lorena Ostilla Joshua B Wechsler Carla M Cuda Richard M Green Harris Perlman Deborah R Winter |
| author_sort |
Sarah A Taylor |
| title |
Transcriptional profiling of pediatric cholestatic livers identifies three distinct macrophage populations. |
| title_short |
Transcriptional profiling of pediatric cholestatic livers identifies three distinct macrophage populations. |
| title_full |
Transcriptional profiling of pediatric cholestatic livers identifies three distinct macrophage populations. |
| title_fullStr |
Transcriptional profiling of pediatric cholestatic livers identifies three distinct macrophage populations. |
| title_full_unstemmed |
Transcriptional profiling of pediatric cholestatic livers identifies three distinct macrophage populations. |
| title_sort |
transcriptional profiling of pediatric cholestatic livers identifies three distinct macrophage populations. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2021 |
| url |
https://doaj.org/article/c015eb78f3cb4aa88de1330263a1b31d |
| work_keys_str_mv |
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| _version_ |
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