8/ Very proud of this work, represented here by the amazing @prenderghost, and excited to see where this field goes next!

7/ Overall, our work highlights the importance of brain fibroblasts after injury, raising the possibility of new therapeutic opportunities for stroke and TBI involving finetuning fibroblast states/transitions to achieve optimal wound healing and immune responses.

6/ Moreover, subsets of late-timepoint fibroblasts create lesional immune niches that direct T cell positioning and suppress cytokine expression - i.e., without fibroblast-derived signals, inflammation is unleashed (with interesting implications for neuronal signaling).

5/ We found that early myofibroblasts prevent cardiovascular collapse and subsequent organ damage after severe stroke, helping explain their protective effect.

4/ Since our preprint, we’ve added some exciting new data regarding the functional roles of fibroblasts after brain injury at early and late timepoints (in addition to an expanded analysis of fibroblast ontogeny and state differentiation, new injury models, and more).

3/ An early myofibroblast state is critical for wound-healing, with fibroblast-deficient mice showing larger lesions and persistent neuroinflammation (and elevated mortality with severe stroke). Myofibroblasts subsequently transition into several late states with distinct roles.

2/ We originally found that fibroblasts, long thought to be largely excluded from the brain, are critical players after injuries including stroke and TBI. Pre-existing fibroblasts expand in a TGFβ- and myeloid cell-dependent manner, passing through several transcriptional states.

1/ Thrilled to share that my PhD thesis work is now out in its final form @Nature! A huge thanks to the entire team (which has only grown since we first put this out), our peer reviewers, the Nature editorial team, and the incredible @Molofsky_lab. https://t.co/rqrvY2QBWJ

11/ Immensely grateful for colleagues in the @Molofsky_lab, Arnold lab, and @AnnaMolofskyLab, and collaborators in @ManishKAghi, @drjamesbourne, @HelenaPaidassi, @JeanneTPaz, @COCOshaveice, and Dean Sheppard labs. Special thanks to @nick_mroz, Anthony Chang, and @SofiaCaryotakis!

10/ Collectively, our data highlight the unexpected role of brain fibroblasts and their immune interactions after injury. As stromal cells have been recently implicated in human brain pathology, fibroblasts may represent important future therapeutic targets.

9/ Fibroblast-deficient mice also showed relative deficits in pro-fibrotic macrophages, highlighting bidirectional crosstalk. Finally, in a severe model of stroke (tMCAO), fibroblast deficiency increased mortality.

8/ Attenuating the fibroblast response caused larger wounds and a failure to resolve neuroinflammation, with persistent neutrophilia in fibroblast-deficient mice (Col1a2creER; Tgfbr2flox).

7/ Fibroblasts were coordinated by TGFβ signaling, Tgfb1-expressing macrophages, and glial cells expressing integrin αvβ8 (which activates TGFβ); disrupting any of these cells or signals reduced fibroblast expansion.

6/ Subsequently, myofibroblasts transitioned into a variety of late functional states: lymphocyte-interactive fibroblasts may support brain T cell persistence, while meningeal-like fibroblasts rebuild the damaged meningeal barrier.

5/ These myofibroblasts coincided with early innate inflammation, involving infiltrating monocytes/resident microglia that converge towards a profibrotic transcriptional state and may interact with fibroblasts.

4/ Spatial/single nuclear transcriptomics revealed a spatiotemporally dynamic fibroblast response, with an early perilesional myofibroblast state reminiscent of skin wound-healing and fibrotic disease.

3/ We found that fibroblasts (which inhabit brain borders at rest) infiltrate the brain, expand, and deposit ECM in several injury models (photothrombotic damage, stroke, and TBI) in mice and non-human primates.

2/ Brain injury is a leading cause of death with few effective treatments, largely due to our poor understanding of brain wound-healing. Here we show that brain fibroblasts – rare and often overlooked – play key roles after injury.

1/ Excited to share my thesis work, now out as a pre-print: “Dynamic fibroblast-immune interactions shape wound healing after brain injury”