Involvement of lysophosphatidic acid-LPA<sub>1</sub>-YAP signaling in healthy and pathological FAPs migration

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dc.contributor.authorBock-Pereda, Alexia
dc.contributor.authorCruz-Soca, Meilyn
dc.contributor.authorGallardo, Felipe S.
dc.contributor.authorCordova-Casanova, Adriana
dc.contributor.authorGutierrez-Rojas, Cristian
dc.contributor.authorFaundez-Contreras, Jennifer
dc.contributor.authorChun, Jerold
dc.contributor.authorCasar, Juan Carlos
dc.contributor.authorBrandan, Enrique
dc.date.accessioned2025-01-20T16:08:15Z
dc.date.available2025-01-20T16:08:15Z
dc.date.issued2024
dc.description.abstractSkeletal muscle fibrosis is defined as the excessive accumulation of extracellular matrix (ECM) components and is a hallmark of muscular dystrophies. Fibro-adipogenic progenitors (FAPs) are the main source of ECM, and thus have been strongly implicated in fibrogenesis. In skeletal muscle fibrotic models, including muscular dystrophies, FAPs undergo dysregulations in terms of proliferation, differentiation, and apoptosis, however few studies have explored the impact of FAPs migration. Here, we studied fibroblast and FAPs migration and identified lysophosphatidic acid (LPA), a signaling lipid central to skeletal muscle fibrogenesis, as a significant migration inductor. We identified LPA receptor 1 (LPA(1)) mediated signaling as crucial for this effect through a mechanism dependent on the Hippo pathway, another pathway implicated in fibrosis across diverse tissues. This cross-talk favors the activation of the Yes-associated protein 1 (YAP) and Transcriptional coactivator with PDZ-binding motif (TAZ), leading to increased expression of fibrosis-associated genes. This study reveals the role of YAP in LPA-mediated fibrotic responses as inhibition of YAP transcriptional coactivator activity hinders LPA-induced migration in fibroblasts and FAPs. Moreover, we found that FAPs derived from the mdx4cv mice, a murine model of Duchenne muscular dystrophy, display a heightened migratory phenotype due to enhanced LPA signaling compared to wild-type FAPs. Remarkably, we found that the inhibition of LPA(1) or YAP transcriptional coactivator activity in mdx4cv FAPs reverts this phenotype. In summary, the identified LPA-LPA(1)-YAP pathway emerges as a critical driver of skeletal muscle FAPs migration and provides insights into potential novel targets to mitigate fibrosis in muscular dystrophies.
dc.fuente.origenWOS
dc.identifier.doi10.1016/j.matbio.2024.08.005
dc.identifier.eissn1569-1802
dc.identifier.issn0945-053X
dc.identifier.urihttps://doi.org/10.1016/j.matbio.2024.08.005
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/90062
dc.identifier.wosidWOS:001317284600001
dc.language.isoen
dc.pagina.final115
dc.pagina.inicio103
dc.revistaMatrix biology
dc.rightsacceso restringido
dc.subjectLPA
dc.subjectFAPs
dc.subjectCell migration
dc.subjectYAP
dc.subjectTAZ
dc.subjectDuchenne muscular dystrophy
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleInvolvement of lysophosphatidic acid-LPA<sub>1</sub>-YAP signaling in healthy and pathological FAPs migration
dc.typeartículo
dc.volumen133
sipa.indexWOS
sipa.trazabilidadWOS;2025-01-12
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