TY - JOUR
T1 - Tenogenic Induction From Induced Pluripotent Stem Cells Unveils the Trajectory Towards Tenocyte Differentiation
AU - Yoshimoto, Yuki
AU - Uezumi, Akiyoshi
AU - Ikemoto-Uezumi, Madoka
AU - Tanaka, Kaori
AU - Yu, Xinyi
AU - Kurosawa, Tamaki
AU - Yambe, Shinsei
AU - Maehara, Kazumitsu
AU - Ohkawa, Yasuyuki
AU - Sotomaru, Yusuke
AU - Shukunami, Chisa
N1 - Funding Information:
This work was supported by JSPS KAKENHI (Grant Numbers JP26893164, JP15K20373, JP17K17092, JP18J40203, JP19H04063, JP18H02966, JP21H03107), JST PRESTO JPMJPR2026 to KM; JST CREST JPMJCR16G1 to YO, the JSBMR Rising Stars Grant, AMED Practical Research Project for Rare/Intractable Diseases (number 19ek0109223h0003), Phoenix Leader Education Program for Renaissance from Radiation Disaster funded by the Program for Leading Graduate Schools, and the Frontier Development Program for Genome Editing funded by the Doctoral Program for World Leading Innovative and Smart Education.
Funding Information:
We thank Dr. Gen Kondoh of Kyoto University for providing the KY1.1 mouse ESC line. We thank Editage ( www.editage.com ) for English language editing. This work was partly performed in the Cooperative Research Project Program of the Medical Institute of Bioregulation, Kyushu University. Computations were carried out using the computer resources offered under the category of Intensively Promoted Projects by the Research Institute for Information Technology at Kyushu University.
Publisher Copyright:
Copyright © 2022 Yoshimoto, Uezumi, Ikemoto-Uezumi, Tanaka, Yu, Kurosawa, Yambe, Maehara, Ohkawa, Sotomaru and Shukunami.
PY - 2022/3/9
Y1 - 2022/3/9
N2 - 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-β2) 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-β2-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.
AB - 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-β2) 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-β2-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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U2 - 10.3389/fcell.2022.780038
DO - 10.3389/fcell.2022.780038
M3 - Article
AN - SCOPUS:85127438291
SN - 2296-634X
VL - 10
JO - Frontiers in Cell and Developmental Biology
JF - Frontiers in Cell and Developmental Biology
M1 - 780038
ER -