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Tgf? signaling is required for tenocyte recruitment and functional neonatal tendon regeneration.

ABSTRACT: Tendon injuries are common with poor healing potential. The paucity of therapies for tendon injuries is due to our limited understanding of the cells and molecular pathways that drive tendon regeneration. Using a mouse model of neonatal tendon regeneration, we identified TGF? signaling as a major molecular pathway that drives neonatal tendon regeneration. Through targeted gene deletion, small molecule inhibition, and lineage tracing, we elucidated TGF?-dependent and TGF?-independent mechanisms underlying tendon regeneration. Importantly, functional recovery depended on canonical TGF? signaling and loss of function is due to impaired tenogenic cell recruitment from both Scleraxis-lineage and non-Scleraxis-lineage sources. We show that TGF? signaling is directly required in neonatal tenocytes for recruitment and that TGF? ligand is positively regulated in tendons. Collectively, these results show a functional role for canonical TGF? signaling in tendon regeneration and offer new insights toward the divergent cellular activities that distinguish regenerative vs fibrotic healing.

SUBMITTER: Kaji DA

PROVIDER: S-EPMC7324157 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Tgfβ signaling is required for tenocyte recruitment and functional neonatal tendon regeneration.

Kaji Deepak A DA Howell Kristen L KL Balic Zerina Z Hubmacher Dirk D Huang Alice H AH

eLife 20200605

Tendon injuries are common with poor healing potential. The paucity of therapies for tendon injuries is due to our limited understanding of the cells and molecular pathways that drive tendon regeneration. Using a mouse model of neonatal tendon regeneration, we identified TGFβ signaling as a major molecular pathway that drives neonatal tendon regeneration. Through targeted gene deletion, small molecule inhibition, and lineage tracing, we elucidated TGFβ-dependent and TGFβ-independent mechanisms u ...[more]

PMID: 32501213

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Project description:BackgroundTendon derived stem cells (TDSCs) have proven to be effective in tendon repair by secreting paracrine factors, which modulate the function of resident cells and inflammatory process. Exosomes, which are secreted from cells to mediate intercellular communication, may be used to treat tendon injuries. Here, we aimed to determine the effects of exosomes from TDSCs (TDSC-Exos) on tendon repair and to explore the underlying mechanism by investigating the role of microRNAs (miRNAs).MethodsTDSC-Exos were isolated from TDSC conditioned medium. In vitro studies were performed to investigate the effects of TDSC-Exos on the proliferation, migration, cytoprotection, collagen production and tendon-specific markers expression in tenocytes. In order to determine the therapeutic effects of TDSC-Exos in vivo, we used a scaffold of photopolymerizable hyaluronic acid (p-HA) loaded with TDSC-Exos (pHA-TDSC-Exos) to treat tendon defects in the rat model. Subsequently, RNA sequencing and bioinformatic analyses were used to screen for enriched miRNAs in TDSC-Exos and predict target genes. The miRNA-target transcript interaction was confirmed by a dual-luciferase reporter assay system. In order to determine the role of candidate miRNA and its target gene in TDSC-Exos-regulated tendon repair, miRNA mimic and inhibitor were transfected into tenocytes to evaluate cell proliferation and migration.ResultsTreatment with TDSC-Exos promoted proliferation, migration, type I collagen production and tendon-specific markers expression in tenocytes, and also protected tenocytes from oxidative stress and serum deprivation. The scaffold of pHA-TDSC-Exos could sever as a sustained release system to treat the rat model of tendon defects. In vivo study showed that TDSC-Exos promoted early healing of injured tendons. Rats treated with TDSC-Exos had better fiber arrangement and histological scores at the injury site. Besides, the injured tendons treated with TDSC-Exos had better performance in the biomechanical testing. Therefore, the pHA-TDSC-Exos scaffold proved to facilitate tendon repair in the rat model. miR-144-3p was enriched in TDSC-Exos and promoted tenocyte proliferation and migration via targeting AT-rich interactive domain 1A (ARID1A).ConclusionsTDSC-Exos enhanced tenon repair through miR-144-3p-regulated tenocyte proliferation and migration. These results suggest that TDSC-Exos can serve as a promising strategy to treat tendon injuries.

Dataset Information

Tgf? signaling is required for tenocyte recruitment and functional neonatal tendon regeneration.

Publications

Tgfβ signaling is required for tenocyte recruitment and functional neonatal tendon regeneration.

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