Mutations in fibronectin dysregulate chondrogenesis in skeletal dysplasia.
Humans
Chondrogenesis
/ genetics
Fibronectins
/ metabolism
Mesenchymal Stem Cells
/ metabolism
Cell Differentiation
/ genetics
Mutation
Chondrocytes
/ metabolism
Osteochondrodysplasias
/ genetics
Induced Pluripotent Stem Cells
/ metabolism
Cells, Cultured
Endoplasmic Reticulum
/ metabolism
Cell Proliferation
/ genetics
Female
Chondrogenesis
Differentiation
Fibronectin
Induced pluripotent stem cells
Skeletal dysplasia
Journal
Cellular and molecular life sciences : CMLS
ISSN: 1420-9071
Titre abrégé: Cell Mol Life Sci
Pays: Switzerland
ID NLM: 9705402
Informations de publication
Date de publication:
05 Oct 2024
05 Oct 2024
Historique:
received:
10
06
2024
accepted:
06
09
2024
revised:
22
08
2024
medline:
6
10
2024
pubmed:
6
10
2024
entrez:
5
10
2024
Statut:
epublish
Résumé
Fibronectin (FN) is an extracellular matrix glycoprotein essential for the development and function of major vertebrate organ systems. Mutations in FN result in an autosomal dominant skeletal dysplasia termed corner fracture-type spondylometaphyseal dysplasia (SMDCF). The precise pathomechanisms through which mutant FN induces impaired skeletal development remain elusive. Here, we have generated patient-derived induced pluripotent stem cells as a cell culture model for SMDCF to investigate the consequences of FN mutations on mesenchymal stem cells (MSCs) and their differentiation into cartilage-producing chondrocytes. In line with our previous data, FN mutations disrupted protein secretion from MSCs, causing a notable increase in intracellular FN and a significant decrease in extracellular FN levels. Analyses of plasma samples from SMDCF patients also showed reduced FN in circulation. FN and endoplasmic reticulum (ER) protein folding chaperones (BIP, HSP47) accumulated in MSCs within ribosome-covered cytosolic vesicles that emerged from the ER. Massive amounts of these vesicles were not cleared from the cytosol, and a smaller subset showed the presence of lysosomal markers. The accumulation of intracellular FN and ER proteins elevated cellular stress markers and altered mitochondrial structure. Bulk RNA sequencing revealed a specific transcriptomic dysregulation of the patient-derived cells relative to controls. Analysis of MSC differentiation into chondrocytes showed impaired mesenchymal condensation, reduced chondrogenic markers, and compromised cell proliferation in mutant cells. Moreover, FN mutant cells exhibited significantly lower transforming growth factor beta-1 (TGFβ1) expression, crucial for mesenchymal condensation. Exogenous FN or TGFβ1 supplementation effectively improved the MSC condensation and promoted chondrogenesis in FN mutant cells. These findings demonstrate the cellular consequences of FN mutations in SMDCF and explain the molecular pathways involved in the associated altered chondrogenesis.
Identifiants
pubmed: 39367925
doi: 10.1007/s00018-024-05444-4
pii: 10.1007/s00018-024-05444-4
doi:
Substances chimiques
Fibronectins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
419Subventions
Organisme : CIHR
ID : PJT-156140
Pays : Canada
Organisme : CIHR
ID : PJT-156140
Pays : Canada
Organisme : Réseau de Recherche en Santé Buccodentaire et Osseuse
ID : Réseau de Recherche en Santé Buccodentaire et Osseuse
Organisme : Réseau de Recherche en Santé Buccodentaire et Osseuse
ID : Réseau de Recherche en Santé Buccodentaire et Osseuse
Organisme : Fonds de Recherche du Québec - Santé
ID : 291220
Informations de copyright
© 2024. The Author(s).
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