4.7 Article

Tenogenic Induction From Induced Pluripotent Stem Cells Unveils the Trajectory Towards Tenocyte Differentiation

Journal

Publisher

FRONTIERS MEDIA SA
DOI: 10.3389/fcell.2022.780038

Keywords

tendon; iPSCs; tenogenic differentiation; single cell analysis; Scx; retinoic acid; ligament

Funding

  1. JSPS KAKENHI [JP26893164, JP15K20373, JP17K17092, JP18J40203, JP19H04063, JP18H02966, JP21H03107]
  2. JST PRESTO [JPMJPR2026]
  3. JST CREST [JPMJCR16G1]
  4. JSBMR Rising Stars Grant
  5. AMED Practical Research Project for Rare/Intractable Diseases [19ek0109223h0003]
  6. Phoenix Leader Education Program for Renaissance from Radiation Disaster - Program for Leading Graduate Schools
  7. Frontier Development Program for Genome Editing - Doctoral Program for World Leading Innovative and Smart Education

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This study developed a method using induced pluripotent stem cells (iPSCs) to induce mature tenocytes expressing tenomodulin by monitoring green fluorescent protein (GFP) expression. Single-cell RNA sequencing revealed distinct clusters of tenocytes and a differentiation trajectory, and highlighted the importance of retinoic acid (RA) as a regulatory pathway for tenogenic differentiation.
The musculoskeletal system is integrated by tendons that are characterized by the expression of scleraxis (Scx), a functionally important transcription factor. Here, we newly developed a tenocyte induction method using induced pluripotent stem cells established from ScxGFP transgenic mice by monitoring fluorescence, which reflects a dynamic differentiation process. Among several developmentally relevant factors, transforming growth factor-beta 2 (TGF-beta 2) was the most potent inducer for differentiation of tenomodulin-expressing mature tenocytes. Single-cell RNA sequencing (scRNA-seq) revealed 11 distinct clusters, including mature tenocyte population and tenogenic differentiation trajectory, which recapitulated the in vivo developmental process. Analysis of the scRNA-seq dataset highlighted the importance of retinoic acid (RA) as a regulatory pathway of tenogenic differentiation. RA signaling was shown to have inhibitory effects on entheseal chondrogenic differentiation as well as TGF-beta 2-dependent tenogenic/fibrochondrogenic differentiation. The collective findings provide a new opportunity for tendon research and further insight into the mechanistic understanding of the differentiation pathway to a tenogenic fate.

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