Dynamic fibroblast-immune interactions shape recovery after brain injury

Nathan A Ewing-Crystal; Nicholas M Mroz; Amara Larpthaveesarp; Carlos O Lizama; Remy Pennington; Pailin Chiaranunt; Jason I Dennis; Anthony A Chang; Eric Dean Merrill; Sofia E Caryotakis; Nikhita Kirthivasan; Leon Teo; Tatsuya Tsukui; Aditya Katewa; Gabriel L McKinsey; Sophia C K Nelson; Agnieszka Ciesielska; Nicole C Lummis; Lucija Pintarić; Madelene W Dahlgren; Amha Atakilit; Helena Paidassi; Saket Jain; Xiaodan Liu; Duan Xu; Manish K Aghi; James A Bourne; Jeanne T Paz; Richard Daneman; Fernando F Gonzalez; Dean Sheppard; Anna V Molofsky; Thomas D Arnold; Ari B Molofsky

doi:10.1038/s41586-025-09449-2

Dynamic fibroblast-immune interactions shape recovery after brain injury

Nature. 2025 Oct;646(8086):934-944. doi: 10.1038/s41586-025-09449-2. Epub 2025 Sep 3.

Authors

Nathan A Ewing-Crystal^{1

2

3}, Nicholas M Mroz^{1

2}, Amara Larpthaveesarp⁴, Carlos O Lizama^{4

5}, Remy Pennington^{4

5}, Pailin Chiaranunt^{2

6}, Jason I Dennis⁶, Anthony A Chang^{1

2}, Eric Dean Merrill², Sofia E Caryotakis^{1

2}, Nikhita Kirthivasan¹, Leon Teo⁷, Tatsuya Tsukui⁸, Aditya Katewa^{4

5}, Gabriel L McKinsey^{4

5}, Sophia C K Nelson¹, Agnieszka Ciesielska⁹, Nicole C Lummis¹⁰, Lucija Pintarić¹⁰, Madelene W Dahlgren², Amha Atakilit⁸, Helena Paidassi¹¹, Saket Jain¹², Xiaodan Liu¹³, Duan Xu¹³, Manish K Aghi¹², James A Bourne⁷, Jeanne T Paz^{9

14

15

16}, Richard Daneman¹⁰, Fernando F Gonzalez⁴, Dean Sheppard⁸, Anna V Molofsky^{6

14

15}, Thomas D Arnold^{17

18}, Ari B Molofsky^{19

20

21}

Affiliations

¹ Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA, USA.
² Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, USA.
³ Medical Scientist Training Program, University of California, San Francisco, San Francisco, CA, USA.
⁴ Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.
⁵ Newborn Brain Research Institute, University of California, San Francisco, San Francisco, CA, USA.
⁶ Department of Psychiatry, University of California, San Francisco, San Francisco, CA, USA.
⁷ Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia.
⁸ Lung Biology Center, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
⁹ Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA.
¹⁰ Departments of Pharmacology and Neurosciences, University of California, San Diego, La Jolla, CA, USA.
¹¹ Centre International de Recherche en Infectiologie (CIRI), Univ Lyon, Inserm, U1111 Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, Lyon, France.
¹² Department of Neurosurgery, University of California, San Francisco, San Francisco, CA, USA.
¹³ Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, USA.
¹⁴ Neurosciences Graduate Program, University of California, San Francisco, San Francisco, CA, USA.
¹⁵ Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
¹⁶ The Kavli Institute for Fundamental Neuroscience and The Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
¹⁷ Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA. thomas.arnold@ucsf.edu.
¹⁸ Newborn Brain Research Institute, University of California, San Francisco, San Francisco, CA, USA. thomas.arnold@ucsf.edu.
¹⁹ Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA, USA. ari.molofsky@ucsf.edu.
²⁰ Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, USA. ari.molofsky@ucsf.edu.
²¹ Diabetes Center, University of California, San Francisco, San Francisco, CA, USA. ari.molofsky@ucsf.edu.

Abstract

Fibroblasts and immune cells coordinate tissue regeneration and necessary scarring after injury. In the brain, fibroblasts are border-enriched cells whose dynamic molecular states and immune interactions after injury remain unclear¹. Here we define the shared fibroblast-immune response to brain injury. Early profibrotic myofibroblasts develop from pre-existing brain fibroblasts and infiltrate brain lesions, orchestrated by fibroblast TGFβ signalling, profibrotic macrophages and microglia, and perilesional glia. Myofibroblasts transition into several late fibroblast states, including lymphocyte-interactive fibroblasts. Interruption of the early myofibroblast state exacerbated sub-acute brain injury, tissue loss and secondary neuroinflammation, with increased mortality in the transient middle cerebral artery occlusion stroke model. Disruption of late lymphocyte-fibroblast niches via selective loss of fibroblast chemokine CXCL12 led to late brain-specific innate inflammation and lymphocyte dispersal with increased IFNγ production. These data indicate the response to brain injury is coordinated by evolving temporal and spatial fibroblast states that limit functional tissue loss and chronic neuroinflammation.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Brain / cytology
Brain / immunology
Brain / pathology
Brain Injuries* / immunology
Brain Injuries* / pathology
Brain Injuries* / physiopathology
Cell Communication*
Chemokine CXCL12 / deficiency
Chemokine CXCL12 / metabolism
Disease Models, Animal
Female
Fibroblasts* / cytology
Fibroblasts* / immunology
Fibroblasts* / metabolism
Fibroblasts* / pathology
Infarction, Middle Cerebral Artery / immunology
Infarction, Middle Cerebral Artery / pathology
Interferon-gamma / biosynthesis
Interferon-gamma / immunology
Interferon-gamma / metabolism
Lymphocytes / cytology
Lymphocytes / immunology
Lymphocytes / pathology
Macrophages / immunology
Macrophages / pathology
Male
Mice
Mice, Inbred C57BL
Microglia / immunology
Microglia / pathology
Myofibroblasts / cytology
Myofibroblasts / immunology
Myofibroblasts / metabolism
Myofibroblasts / pathology
Neuroinflammatory Diseases / immunology
Neuroinflammatory Diseases / pathology
Signal Transduction
Transforming Growth Factor beta / metabolism

Dynamic fibroblast-immune interactions shape recovery after brain injury

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