RESUMO
Understanding cell recruitment in damaged tendons is critical for improvements in regenerative therapy. We recently reported that targeted disruption of transforming growth factor beta (TGFß) type II receptor in the tendon cell lineage (Tgfbr2ScxCre) resulted in resident tenocyte dedifferentiation and tendon deterioration in postnatal stages. Here we extend the analysis and identify direct recruitment of stem/progenitor cells into the degenerative mutant tendons. Cre-mediated lineage tracing indicates that these cells are not derived from tendon-ensheathing tissues or from a Scleraxis-expressing lineage, and they turned on tendon markers only upon entering the mutant tendons. Through immunohistochemistry and inducible gene deletion, we further find that the recruited cells originated from a Sox9-expressing lineage and their recruitment was dependent on cell autonomous TGFß signaling. The cells identified in this study thus differ from previous reports of cell recruitment into injured tendons and suggest a critical role for TGFß signaling in cell recruitment, providing insights that may support improvements in tendon repair.
Assuntos
Transdução de Sinais , Células-Tronco/metabolismo , Tendões/patologia , Fator de Crescimento Transformador beta/metabolismo , Animais , Biomarcadores/metabolismo , Células Cultivadas , Células Clonais , Proteínas de Fluorescência Verde/metabolismo , Integrases/metabolismo , Camundongos , Modelos Biológicos , Mutação/genética , Receptor do Fator de Crescimento Transformador beta Tipo II/metabolismo , Tendões/ultraestrutura , Fatores de TempoRESUMO
Studies of cell fate focus on specification, but little is known about maintenance of the differentiated state. In this study, we find that the mouse tendon cell fate requires continuous maintenance in vivo and identify an essential role for TGFß signaling in maintenance of the tendon cell fate. To examine the role of TGFß signaling in tenocyte function the TGFß type II receptor (Tgfbr2) was targeted in the Scleraxis-expressing cell lineage using the ScxCre deletor. Tendon development was not disrupted in mutant embryos, but shortly after birth tenocytes lost differentiation markers and reverted to a more stem/progenitor state. Viral reintroduction of Tgfbr2 to mutants prevented and even rescued tenocyte dedifferentiation suggesting a continuous and cell autonomous role for TGFß signaling in cell fate maintenance. These results uncover the critical importance of molecular pathways that maintain the differentiated cell fate and a key role for TGFß signaling in these processes.