Female reproductive life span is extended by targeted removal of fibrotic collagen from the mouse ovary

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Abstract

The female ovary contains a finite number of oocytes, and their release at ovulation becomes sporadic and disordered with aging and with obesity, leading to loss of fertility. Understanding the molecular defects underpinning this pathology is essential as age of childbearing and obesity rates increase globally. We identify that fibrosis within the ovarian stromal compartment is an underlying mechanism responsible for impaired oocyte release, which is initiated by mitochondrial dysfunction leading to diminished bioenergetics, oxidative damage, inflammation, and collagen deposition. Furthermore, antifibrosis drugs (pirfenidone and BGP-15) eliminate fibrotic collagen and restore ovulation in reproductively old and obese mice, in association with dampened M2 macrophage polarization and up-regulated MMP13 protease. This is the first evidence that ovarian fibrosis is reversible and indicates that drugs targeting mitochondrial metabolism may be a viable therapeutic strategy for women with metabolic disorders or advancing age to maintain ovarian function and extend fertility.

Abstract

Treatments that remove excess collagen from the ovary facilitate the release of eggs and extend female fertility.

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Macrophages in Tissue Repair, Regeneration, and Fibrosis.

Thomas Wynn, Kevin Vannella (2016)

Inflammatory monocytes and tissue-resident macrophages are key regulators of tissue repair, regeneration, and fibrosis. After tissue injury, monocytes and macrophages undergo marked phenotypic and functional changes to play critical roles during the initiation, maintenance, and resolution phases of tissue repair. Disturbances in macrophage function can lead to aberrant repair, such that uncontrolled production of inflammatory mediators and growth factors, deficient generation of anti-inflammatory macrophages, or failed communication between macrophages and epithelial cells, endothelial cells, fibroblasts, and stem or tissue progenitor cells all contribute to a state of persistent injury, and this could lead to the development of pathological fibrosis. In this review, we discuss the mechanisms that instruct macrophages to adopt pro-inflammatory, pro-wound-healing, pro-fibrotic, anti-inflammatory, anti-fibrotic, pro-resolving, and tissue-regenerating phenotypes after injury, and we highlight how some of these mechanisms and macrophage activation states could be exploited therapeutically.

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Fibrosis: from mechanisms to medicines

Neil C. Henderson, Florian Rieder, Thomas Wynn (2020)

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Metabolic reprogramming in macrophages and dendritic cells in innate immunity

Beth Kelly, Luke O'Neill (2015)

Activation of macrophages and dendritic cells (DCs) by pro-inflammatory stimuli causes them to undergo a metabolic switch towards glycolysis and away from oxidative phosphorylation (OXPHOS), similar to the Warburg effect in tumors. However, it is only recently that the mechanisms responsible for this metabolic reprogramming have been elucidated in more detail. The transcription factor hypoxia-inducible factor-1α (HIF-1α) plays an important role under conditions of both hypoxia and normoxia. The withdrawal of citrate from the tricarboxylic acid (TCA) cycle has been shown to be critical for lipid biosynthesis in both macrophages and DCs. Interference with this process actually abolishes the ability of DCs to activate T cells. Another TCA cycle intermediate, succinate, activates HIF-1α and promotes inflammatory gene expression. These new insights are providing us with a deeper understanding of the role of metabolic reprogramming in innate immunity.

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Author and article information

Contributors

Takashi Umehara:

ORCID: https://orcid.org/0000-0003-3897-9739

Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draft

Yasmyn E. Winstanley:

ORCID: https://orcid.org/0000-0002-0196-0965

Role: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: VisualizationRole: Writing - review & editing

Eryk Andreas:

ORCID: https://orcid.org/0000-0001-8971-2343

Role: Data curationRole: InvestigationRole: Resources

Atsushi Morimoto: Role: InvestigationRole: Methodology

Elisha J. Williams: Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Validation

Kirsten M. Smith:

ORCID: https://orcid.org/0000-0001-7505-778X

Role: InvestigationRole: MethodologyRole: Writing - review & editing

John Carroll:

ORCID: https://orcid.org/0000-0001-9644-5861

Role: ConceptualizationRole: ResourcesRole: Writing - review & editing

Mark A. Febbraio: Role: ConceptualizationRole: ResourcesRole: Writing - review & editing

Masayuki Shimada:

ORCID: https://orcid.org/0000-0002-6500-2088

Role: ConceptualizationRole: Writing - original draftRole: Writing - review & editing

Darryl L. Russell:

ORCID: https://orcid.org/0000-0002-4930-7658

Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: Visualization

Rebecca L. Robker:

ORCID: https://orcid.org/0000-0002-1538-4604

Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: SupervisionRole: VisualizationRole: Writing - review & editing

Journal

Journal ID (nlm-ta): Sci Adv

Journal ID (iso-abbrev): Sci Adv

Journal ID (publisher-id): sciadv

Journal ID (hwp): advances

Title: Science Advances

Publisher: American Association for the Advancement of Science

ISSN (Electronic): 2375-2548

Publication date Collection: June 2022

Publication date (Electronic, pub): 17 June 2022

Volume: 8

Issue: 24

Electronic Location Identifier: eabn4564

Affiliations

[1 ]Robinson Research Institute, School of Biomedicine, The University of Adelaide, Adelaide, SA, Australia.

[2 ]Graduate School of Integrated Sciences for Life, Hiroshima University, Higashi-Hiroshima, Japan.

[3 ]Development and Stem Cells Program and Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.

[4 ]Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia.

Author notes

[* ]Corresponding author. Email: rebecca.robker@ 123456adelaide.edu.au

Author information

Takashi Umehara https://orcid.org/0000-0003-3897-9739

Yasmyn E. Winstanley https://orcid.org/0000-0002-0196-0965

Eryk Andreas https://orcid.org/0000-0001-8971-2343

Kirsten M. Smith https://orcid.org/0000-0001-7505-778X

John Carroll https://orcid.org/0000-0001-9644-5861

Masayuki Shimada https://orcid.org/0000-0002-6500-2088

Darryl L. Russell https://orcid.org/0000-0002-4930-7658

Rebecca L. Robker https://orcid.org/0000-0002-1538-4604

Article

Publisher ID: abn4564

DOI: 10.1126/sciadv.abn4564

PMC ID: 9205599

PubMed ID: 35714185

SO-VID: 3ddbf156-914f-4e5b-825c-a6e48673fe3c

Copyright © Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.