YAP-dependent transcriptional responses in tenocytes under cyclic tensile loading: a conditional knockout RNA-sequencing study
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Published on: March 1, 2024
Xuewu Xing1,2, Alexander Piacentini2, Yuki Suzuki2
1Department of Orthopaedics, Tianjin First Central Hospital, Tianjin, China.
Background:
Tendon injuries are prevalent across various populations and significantly impair quality of life, presenting substantial healthcare challenges.
Purpose:
This study aimed to characterize Yes-associated protein (YAP) -dependent transcriptional responses in tenocytes under cyclic tensile loading, using a conditional YAP knockout approach combined with RNA sequencing. Given that tenocytes in vivo are continuously exposed to mechanical loading, this design was intended to identify genes whose regulation by YAP becomes critical under mechanical challenge.
Methods:
Employing conditional gene knockout techniques with RosaCreERT2 YAP-floxed mice and mechanical loading protocols, alongside RNA sequencing and advanced bioinformatics analyses.
Results:
We identified 54 differentially expressed genes (DEGs) in tenocytes after YAP knockout, including six upregulated and 48 downregulated genes. Notably, upregulated genes included Gzmc and Gm28151, while downregulated genes included Car3 and Rgs2. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses highlighted significant pathways, such as the PPAR signaling pathway, emphasizing their relevance in tendon pathophysiology. Furthermore, CIBERSORTx analysis revealed significant differences in immune cell infiltration, particularly in Treg and CD4 naive T cells, suggesting a link between YAP-dependent pathways and immune responses in tendon healing. Drug prediction analyses identified several small molecules interacting with hub genes, including LTC4S and CXCL13, indicating potential pharmacological targets for therapeutic intervention.
Conclusion:
Despite limitations such as a lack of in vivo validation and small sample size, this research underscores the pivotal role of YAP in tenocyte mechanotransduction and identifies key DEGs and pathways that may inform future therapeutic strategies for tendon injuries. Future studies should focus on the in-vivo implications of these findings and explore the potential for immune modulation and pharmacological interventions in tendon repair.
