Abstract

Organ fibroblasts are essential components of homeostatic and diseased tissues. They participate in sculpting the extracellular matrix, sensing the microenvironment and communicating with other resident cells. Recent studies have revealed transcriptomic heterogeneity among fibroblasts within and between organs. To dissect the basis of inter-organ heterogeneity, we compare the gene expression of murine fibroblasts from different tissues (tail, skin, lung, liver, heart, kidney, gonads) and show that they display distinct positional and organ-specific transcriptome signatures that reflect their embryonic origins. We demonstrate that expression of genes typically attributed to the surrounding parenchyma by fibroblasts is established in embryonic development and largely maintained in culture, bioengineered tissues and ectopic transplants. Targeted knockdown of key organ-specific transcription factors affects fibroblast functions, in particular genes involved in the modulation of fibrosis and inflammation. In conclusion, our data reveal that adult fibroblasts maintain an embryonic gene expression signature inherited from their organ of origin, thereby increasing our understanding of adult fibroblast heterogeneity. The knowledge of this tissue-specific gene signature may assist in targeting fibrotic diseases in a more precise, organ-specific manner.

Data availability

All data has been made available through public databases, as per statement in main manuscript

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Elvira Forte

    Jackson Laboratory, Bar Harbor, United States
    For correspondence
    elviraforte83@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5555-9122
  2. Mirana Ramialison

    Australian Regenerative Medicine Institute, Monash University, Clayton, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6315-4777
  3. Hieu T Nim

    Faculty of Information Technology, Monash University, Clayton, Australia
    Competing interests
    The authors declare that no competing interests exist.
  4. Madison Mara

    Jackson Laboratory, Bar Harbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Jacky Y Li

    Murdoch Children's Research Institute, Parkville, Australia
    Competing interests
    The authors declare that no competing interests exist.
  6. Rachel Cohn

    Jackson Laboratory, Farmington, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Sandra L Daigle

    Jackson Laboratory, Bar Harbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Sarah Boyd

    Centre for Inflammatory Diseases, Monash University, Clayton, Australia
    Competing interests
    The authors declare that no competing interests exist.
  9. Edouard G Stanley

    Murdoch Children's Research Institute, Parkville, Australia
    Competing interests
    The authors declare that no competing interests exist.
  10. Andrew G Elefanty

    Murdoch Children's Research Institute, Parkville, Australia
    Competing interests
    The authors declare that no competing interests exist.
  11. John Travis Hinson

    Jackson Laboratory, Farmington, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Mauro W Costa

    Jackson Laboratory, Bar Harbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Nadia A Rosenthal

    Jackson Laboratory, Bar Harbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Milena B Furtado

    Jackson Laboratory, Bar Harbor, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1387-325X

Funding

Australian Research Council

  • Nadia A Rosenthal

National Health and Medical Research Council

  • Mirana Ramialison
  • Mauro W Costa
  • Nadia A Rosenthal

Heart Foundation

  • Mirana Ramialison

Jackson Laboratory

  • Nadia A Rosenthal

National Institutes of Health

  • Nadia A Rosenthal

Leducq Foundation for Cardiovascular Research

  • Nadia A Rosenthal

Australian Government

  • Nadia A Rosenthal

State Government of Victoria

  • Nadia A Rosenthal

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocol (#16010) of the Jackson Laboratory. All surgery was performed under tribromoethanol anesthesia, and every effort was made to minimize pain and suffering.

Human subjects: Human samples were obtained through the Sydney Heart Bank (SHB) in Australia. Investigators have not collected patient samples or been privy to patient records.

Reviewing Editor

  1. Paul W Noble, Cedars-Sinai Medical Centre, United States

Version history

  1. Preprint posted: June 4, 2021 (view preprint)
  2. Received: June 4, 2021
  3. Accepted: March 15, 2022
  4. Accepted Manuscript published: March 16, 2022 (version 1)
  5. Version of Record published: March 28, 2022 (version 2)

Copyright

© 2022, Forte et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Elvira Forte
  2. Mirana Ramialison
  3. Hieu T Nim
  4. Madison Mara
  5. Jacky Y Li
  6. Rachel Cohn
  7. Sandra L Daigle
  8. Sarah Boyd
  9. Edouard G Stanley
  10. Andrew G Elefanty
  11. John Travis Hinson
  12. Mauro W Costa
  13. Nadia A Rosenthal
  14. Milena B Furtado
(2022)
Adult mouse fibroblasts retain organ-specific transcriptomic identity
eLife 11:e71008.
https://doi.org/10.7554/eLife.71008

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