Type 2 Innate Signals Stimulate Fibro/Adipogenic Progenitors to Facilitate Muscle Regeneration
Open accessAbstract
In vertebrates, activation of innate immunity is an early response to injury, implicating it in the regenerative process. However, the mechanisms by which innate signals might regulate stem cell functionality are unknown. Here, we demonstrate that type 2 innate immunity is required for regeneration of skeletal muscle after injury. Muscle damage results in rapid recruitment of eosinophils, which secrete IL-4 to activate the regenerative actions of muscle resident fibro/adipocyte progenitors (FAPs). In FAPs, IL-4/IL-13 signaling serves as a key switch to control their fate and functions. Activation of IL-4/IL-13 signaling promotes proliferation of FAPs to support myogenesis while inhibiting their differentiation into adipocytes. Surprisingly, type 2 cytokine signaling is also required in FAPs, but not in myeloid cells, for rapid clearance of necrotic debris, a process that is necessary for timely and complete regeneration of tissues.
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Infiltrating eosinophils partly mediate FAP expansion by secreting IL-4, which stimulates FAP proliferation.
“In part, the expansion of resident FAPs is mediated by the infiltration of eosinophils that secrete IL-4, which activates FAP proliferation78.”
From The central role of muscle stem cells in regenerative failure with aging (2015) · cites this paper as [78]
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- Authors
- Heredia, J. E., Mukundan, L., Chen, F. M., Mueller, A. A., Deo, R. C., Locksley, R. M., Rando, T. A., & Chawla, A.
- Affiliations
- University of California, San Francisco (US)
- Stanford Medicine (US)
- QB3 (US)
- Howard Hughes Medical Institute (US)
- VA Palo Alto Health Care System (US)
- Corresponding author
- Chawla, Ajay
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2013-04
- Volume
- 153
- Issue
- 2
- Pages
- 376-388
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3663598
- OpenAlex
- W1999353686
- Cited by
- 818
- References
- 49
- Citations by year
- 2026: 63 · 2025: 39 · 2024: 54 · 2023: 63 · 2022: 77 · 2021: 90 · 2020: 79 · 2019: 68 · 2018: 58 · 2017: 59 · 2016: 55 · 2015: 49 · 2014: 42 · 2013: 21
- FWCI
- 24.91
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (DP1OD006415, DP1OD000392)
- National Institute on Aging (R37AG023806, R01AG023806, P01AG036695)
- National Heart, Lung, and Blood Institute (K08HL098361, T32HL007731)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK081405, R01DK081405)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR062185, DP1AR064158)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
- Keywords
- skeletal muscle regeneration, fibro-adipogenic progenitors, eosinophils, IL-4, IL-13 signaling, myogenesis, adipogenesis, muscle damage, stem cell fate
- MeSH terms
- Animals, Cobra Cardiotoxin Proteins, Eosinophils, Immunity, Innate, Receptors, Cell Surface, Regeneration, Signal Transduction, Interleukin-4, Muscle, Skeletal, Interleukin-13, Myeloid Cells, Muscle Development, STAT6 Transcription Factor, Mice, Interleukin-4 Receptor alpha Subunit
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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