Muscle-resident mesenchymal progenitors sense and repair peripheral nerve injury via the GDNF-BDNF axis

• Published in: eLife Vol. 13
• Main Authors: Yoo, Kyusang, Jo, Young-Woo, Yoo, Takwon, Hann, Sang-Hyeon, Park, Inkuk, Kim, Yea-Eun, Kim, Ye Lynne, Rhee, Joonwoo, Song, In-Wook, Kim, Ji-Hoon, Baek, Daehyun, Kong, Young-Yun
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 26.09.2024; eLife Sciences Publications, Ltd
• Subjects: Age; Animal models; Animals; BDNF; Brain-derived neurotrophic factor; Brain-Derived Neurotrophic Factor - metabolism; Cell culture; Denervation; fibro-adipogenic progenitor; GDNF; Glial cell line-derived neurotrophic factor; Glial Cell Line-Derived Neurotrophic Factor - genetics; Glial Cell Line-Derived Neurotrophic Factor - metabolism; Glial Cell Line-Derived Neurotrophic Factor Receptors - genetics; Glial Cell Line-Derived Neurotrophic Factor Receptors - metabolism; Homeostasis; Male; Mesenchymal Stem Cells - metabolism; Mice; Molecular modelling; Musculoskeletal system; Myelination; Myogenesis; Nerve Regeneration; Neuromuscular system; Neuroscience; Peripheral Nerve Injuries - metabolism; peripheral nerve injury; Peripheral nerves; Phosphorylation; Postpartum period; Proto-Oncogene Proteins c-ret - genetics; Proto-Oncogene Proteins c-ret - metabolism; Regeneration; schwann cell myelination; Schwann cells; Schwann Cells - metabolism; single-cell RNA-sequencing; Stem Cells and Regenerative Medicine; Transcriptomics; single-cell RNA-sequencing; mouse; stem cells; fibro-adipogenic progenitor; schwann cell myelination; GDNF; BDNF; neuroscience; regenerative medicine; peripheral nerve injury
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.97662

Fibro-adipogenic progenitors (FAPs) are muscle-resident mesenchymal progenitors that can contribute to muscle tissue homeostasis and regeneration, as well as postnatal maturation and lifelong maintenance of the neuromuscular system. Recently, traumatic injury to the peripheral nerve was shown to activate FAPs, suggesting that FAPs can respond to nerve injury. However, questions of how FAPs can sense the anatomically distant peripheral nerve injury and whether FAPs can directly contribute to nerve regeneration remained unanswered. Here, utilizing single-cell transcriptomics and mouse models, we discovered that a subset of FAPs expressing GDNF receptors and can respond to peripheral nerve injury by sensing GDNF secreted by Schwann cells. Upon GDNF sensing, this subset becomes activated and expresses . FAP-specific inactivation of ( ) resulted in delayed nerve regeneration owing to defective remyelination, indicating that GDNF-sensing FAPs play an important role in the remyelination process during peripheral nerve regeneration. In aged mice, significantly reduced expression in FAPs was observed upon nerve injury, suggesting the clinical relevance of FAP-derived BDNF in the age-related delays in nerve regeneration. Collectively, our study revealed the previously unidentified role of FAPs in peripheral nerve regeneration, and the molecular mechanism behind FAPs' response to peripheral nerve injury.