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Suture-specific regulation of coronal and lambdoid suture patency by PTHLH and HHIP activity in mice

ABSTRACT: Craniofacial development depends on the formation of fibrous joints, or sutures, between skull bones. Premature fusion of sutures, or craniosynostosis, is a common human pathology. Ectopic Hedgehog (HH) signaling is one cause of craniosynostosis. Hhip encodes an inhibitor of HH ligands, and we previously identified coronal suture dysgenesis in embryonic Hhip-/- mice, in which suture mesenchyme was depleted between closely opposed but unfused osteogenic fronts at E18.5. Here, we report that the lambdoid suture fuses in Hhip-/- mice by E18.5. RNA-seq analysis of the Hhip-/- coronal and lambdoid sutures show that HH target gene expression, including Pthlh, is upregulated. Paradoxically, expression of Ihh is downregulated. We hypothesized that PTHLH, a negative regulator of Ihh expression, may reduce HH signaling to promote coronal suture patency and prevent fusion of the Hhip-/- coronal suture. We generated Hhip-/-;Pthlh-/- embryos and found that coronal sutures are fusing by E18.5. Our results reveal a previously undescribed role for Pthlh in suture development and demonstrate suture-specific roles for HH inhibitors in maintaining suture patency.

ORGANISM(S): Mus musculus

PROVIDER: GSE294710 | GEO | 2025/09/26

REPOSITORIES: GEO

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Project description:Many surgical tendon repairs fail despite advances in surgical materials and techniques. Tendon repair failure can be partially attributed to the tendon’s poor intrinsic healing capacity and the repurposing of sutures from use in other tissues. Electrospun materials show promise as a biological scaffold to support endogenous tendon repair, but their relatively low tensile strength has limited their clinical translation. It is hypothesized that combining electrospun fibres with a stronger material may improve the suture’s mechanical properties while retaining biophysical cues necessary to encourage cell-mediated repair. This paper describes the production of a hybrid electrospun-extruded suture with a sheath of submicron electrospun fibres and a core of melt-extruded fibres. The porosity and tensile strength of this hybrid suture is compared to an electrospun-only braided suture and clinically used sutures Vicryl and PDS. Bioactivity is assessed by measuring the adsorbed serum proteins on electrospun and melt-extruded filaments using mass spectrometry. Human hamstring tendon fibroblast attachment and proliferation was quantified and compared between the hybrid and control sutures. Combining an electrospun sheath with melt-extruded cores created a hybrid braid with increased tensile strength (70.1±0.3N) compared to an electrospun only suture (12.9±1N, p<0.0001). The hybrid suture had a similar force at break to clinical sutures, but lower stiffness and stress. The Young’s modulus was 772.6±32Mpa for the hybrid suture, 1693.0±69Mpa for PDS, and 3838.0±132MPa for Vicryl, p<0.0001. Hybrid sutures had lower overall porosity than electrospun-only sutures (40±4% and 60±7%, respectively, p=0.0018) but had a significantly larger overall porosity and average pore diameter compared to surgical sutures. There were similar clusters of adsorbed proteins on electrospun and melt-extruded filaments, which were distinct from PDS. Tendon fibroblast attachment on hybrid and electrospun sutures was significantly higher than on clinical sutures (hybrid 28±7%; electrospun 24±7%; Vicryl 10±5%; PDS 2±0.1%, p<0.0001). Cell proliferation was significantly higher on hybrid and electrospun sutures compared to on clinical sutures. Overall, this study demonstrated that a bioactive suture with increased tensile strength and lower stiffness could be produced by adding a core of 10um melt-extruded fibres to a sheath of electrospun fibres. In contrast to currently used sutures, the hybrid sutures promoted a bioactive response: serum proteins adsorbed, and fibroblasts attached, survived, grew along the sutures, and adopted appropriate morphologies.

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Suture-specific regulation of coronal and lambdoid suture patency by PTHLH and HHIP activity in mice

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