# Distinct early and late programs of fibroblast - immune crosstalk govern functional responses to brain injury

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $765,176

## Abstract

PROJECT SUMMARY/ABSTRACT
Fibroblasts are stromal cells that are critical to both wound repair and the support and regulation of tissue-
resident immune cells; when dysregulated, they drive pathologic scarring and maladaptive immunity. While the
Central Nervous System (CNS) is an immunoprivileged site, brain and spinal cord inflammation, injury, and
pathologic aging all disrupt this delicate balance, leading to increased immune cell activation and infiltration, and
contributing to a range of neuropsychiatric diseases. Although fibroblasts are essentially absent from CNS
parenchyma, they are abundant at CNS borders, and perturbations drive the expansion and infiltration of
fibroblasts, potentially regulating both acute brain injury and the long-term generation of de novo immune niches,
which themselves can alter CNS function. However, the regulatory mechanisms and impacts of CNS fibroblast-
immune crosstalk are poorly understood. Our preliminary data show that lesional CNS fibroblasts expand in
mouse models of brain injury, transiently adopting a myofibroblast-like state that requires fibroblast-intrinsic
TGF? signaling and is spatially correlated with macrophages. Mice with inducible myofibroblast loss have
enlarged CNS lesions and sub-acute CNS functional deficits. The myofibroblast program subsides, yet
fibroblasts persist for months, intimately associate with late lesional CNS lymphocytes, and are necessary and
sufficient to support lymphocytes. Spatial transcriptomics indicate a lesional transition from an early
myofibroblast to a late immunoregulatory state. We hypothesize that CNS damage promotes early myofibroblast
expansion, requiring macrophages and TGF? activation, to drive wound contraction and limit CNS functional
loss, followed by a transition to an immunoregulatory fibroblast state that persists and creates de novo CNS
lymphocyte niches. The specific goals of this proposal are to understand how CNS fibroblast-macrophage
interactions govern responses to brain damage and establishment of lymphoid niches. Here we will focus on
three related questions: (1) How do early injury-associated myofibroblasts regulate CNS damage and functional
impairment? (2) What are the cells and signals that regulate CNS fibroblast state transition? (3) How do late
CNS immunofibroblasts regulate T-cell accumulation and function? Successful completion of the proposed work
will illuminate how brain fibroblasts regulate early CNS damage responses and late immune cell accumulation,
laying the foundation for future work in humans and driving therapeutic approaches that target stromal cells to
modulate CNS immunity and function.

## Key facts

- **NIH application ID:** 10999718
- **Project number:** 1R01AI180438-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Ari B Molofsky
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $765,176
- **Award type:** 1
- **Project period:** 2024-07-02 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10999718

## Citation

> US National Institutes of Health, RePORTER application 10999718, Distinct early and late programs of fibroblast - immune crosstalk govern functional responses to brain injury (1R01AI180438-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10999718. Licensed CC0.

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