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Defining Tissue Macrophage Heterogen...

Wong, Anthony M. H.,

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Defining Tissue Macrophage Heterogeneity and Identity in the Heart and Beyond /

Record Type:	Electronic resources : Monograph/item
Title/Author:	Defining Tissue Macrophage Heterogeneity and Identity in the Heart and Beyond // Anthony M. H Wong.
Author:	Wong, Anthony M. H.,
Description:	1 electronic resource (194 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 86-05, Section: B.
Contained By:	Dissertations Abstracts International86-05B.
Subject:	Immunology. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=31561488
ISBN:	9798342756211

Defining Tissue Macrophage Heterogeneity and Identity in the Heart and Beyond /
Wong, Anthony M. H.,

Defining Tissue Macrophage Heterogeneity and Identity in the Heart and Beyond /Anthony M. H Wong. - 1 electronic resource (194 pages)

Source: Dissertations Abstracts International, Volume: 86-05, Section: B.

Tissue-resident macrophages (MFs) present in all organs orchestrate essential and tissue-specific homeostatic and inflammatory functions. Initial observations of MF heterogeneity revealed major transcriptional and epigenetic differences between resident populations from different organs that were environment dependent. In recent years, a growing number of studies have used increasingly granular techniques such as single-cell RNA sequencing (scRNA-seq) to characterize MF heterogeneity within individual tissues, which had previously been overlooked. However, variable strategies to define heterogeneity has led to redundant and inconsistent subsets being analyzed in the literature. Here, we identify an underlying MF substructure across organs by investigating transcriptional and biological similarities. Flow cytometry and scRNA-seq of MFs in the heart, liver, lung, kidney, and brain revealed the presence of 3 transcriptionally distinct subsets that co-exist in each organ and could be resolved with combinatorial expression of 5 key genes: TLF+, MHC-IIhi, and CCR2+ MFs. Parabiosis and genetic fate mapping demonstrated that MFs stratified by these core markers predicted 3 lifecycles and origins in up to 17 murine tissues. Additionally, the underlying epigenetic structure of cardiac MF subsets was not known, nor in any other tissue these subsets reside in. Assay for transposase-accessible chromatin with sequencing (ATAC-seq) revealed 2 signatures of chromatin accessibility of cardiac MF - a CCR2- chromatin state that gave rise to both TLF+ and MHC-IIhi MF subsets, and a CCR2+ chromatin state that gave rise exclusively to CCR2+ MFs. Footprint analysis of transcription factor (TF) binding revealed subset-specific variations to a core TF repertoire - most notably, enrichment of AP-1 motifs in CCR2+ MFs and MAF motifs in TLF+ MFs. Loss of MAFB disrupted MHC-II expression in TLF+ MFs. Furthermore, we identify a IRF8-dependency of MHC-II expression in resident CCR2- subsets. Finally, a protocol for nuclear extraction from frozen human tissue was optimized, which will enable sequencing of large clinical cohorts. Taken together, the goal of this work beyond these individual insights is to initiate deeper examination of tissue-resident MFs across organs and species to guide development of targeted therapeutic strategies for diseases in which MFs play a role.

English

ISBN: 9798342756211Subjects--Topical Terms:

611031
Immunology.
Subjects--Index Terms:

Epigenetics

Defining Tissue Macrophage Heterogeneity and Identity in the Heart and Beyond /
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520 $a Tissue-resident macrophages (MFs) present in all organs orchestrate essential and tissue-specific homeostatic and inflammatory functions. Initial observations of MF heterogeneity revealed major transcriptional and epigenetic differences between resident populations from different organs that were environment dependent. In recent years, a growing number of studies have used increasingly granular techniques such as single-cell RNA sequencing (scRNA-seq) to characterize MF heterogeneity within individual tissues, which had previously been overlooked. However, variable strategies to define heterogeneity has led to redundant and inconsistent subsets being analyzed in the literature. Here, we identify an underlying MF substructure across organs by investigating transcriptional and biological similarities. Flow cytometry and scRNA-seq of MFs in the heart, liver, lung, kidney, and brain revealed the presence of 3 transcriptionally distinct subsets that co-exist in each organ and could be resolved with combinatorial expression of 5 key genes: TLF+, MHC-IIhi, and CCR2+ MFs. Parabiosis and genetic fate mapping demonstrated that MFs stratified by these core markers predicted 3 lifecycles and origins in up to 17 murine tissues. Additionally, the underlying epigenetic structure of cardiac MF subsets was not known, nor in any other tissue these subsets reside in. Assay for transposase-accessible chromatin with sequencing (ATAC-seq) revealed 2 signatures of chromatin accessibility of cardiac MF - a CCR2- chromatin state that gave rise to both TLF+ and MHC-IIhi MF subsets, and a CCR2+ chromatin state that gave rise exclusively to CCR2+ MFs. Footprint analysis of transcription factor (TF) binding revealed subset-specific variations to a core TF repertoire - most notably, enrichment of AP-1 motifs in CCR2+ MFs and MAF motifs in TLF+ MFs. Loss of MAFB disrupted MHC-II expression in TLF+ MFs. Furthermore, we identify a IRF8-dependency of MHC-II expression in resident CCR2- subsets. Finally, a protocol for nuclear extraction from frozen human tissue was optimized, which will enable sequencing of large clinical cohorts. Taken together, the goal of this work beyond these individual insights is to initiate deeper examination of tissue-resident MFs across organs and species to guide development of targeted therapeutic strategies for diseases in which MFs play a role.
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650 4 $a Cellular biology. $3 3172791
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653 $a Epigenetics
653 $a Genetic fate mapping
653 $a Heterogeneity
653 $a Macrophage
653 $a Ontogeny
653 $a Single cell RNA-seq
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