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단국대학교 조직재생공학연구원/치과대학

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Adv. Sci., Sep 19 2023 | https://doi.org/10.1002/advs.202303395 Cyclic Stretch Promotes Cellular Reprogramming Process through Cytoskeletal-Nuclear Mechano-Coupling and Epigenetic Modification.

Sung-Min Park ^1,2, Jung-Hwan Lee ^{1,2,3,4,5,6,7}, Kwang Sung Ahn ^1,2, Hye Won Shim ^1,2,3, Ji-Young Yoon^1,2,3,6, Jeongeun Hyun ^1,2,3,5,6,7, Jun Hee Lee^1,2,3,5,6,7, Sunyoung Jang ⁸, Kyung Hyun Yoo ⁸, Yoon-Kwan Jang ⁹, Tae-Jin Kim^9,10, Hyun Kyu Kim ¹¹, Man Ryul Lee ¹¹, Jun-Hyeog Jang ¹², Hosup Shim ^1,2, Hae-Won Kim ^{1,2,3,4,5,6,7}

¹Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan, 31116, Republic of Korea.

²Department of Nanobiomedical Science and BK21 NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan, 31116, Republic of Korea.

³Mechanobiology Dental Medicine Research Center, Dankook University, Cheonan, 31116, Republic of Korea.

⁴Department of Biomaterials Science, College of Dentistry, Dankook University, Cheonan, 31116, Republic of Korea.

⁵Department of Regenerative Dental Medicine, College of Dentistry, Dankook University, Cheonan, 31116, Republic of Korea.

⁶Cell & Matter Institute, Dankook University, Cheonan, 31116, Republic of Korea.

⁷UCL Eastman-Korea Dental Medicine Innovation Centre, Dankook University, Cheonan, 31116, Republic of Korea.

⁸Laboratory of Biomedical Genomics, Department of Biological Sciences, Sookmyung Women's University, Seoul, 04310, Republic of Korea.

⁹Department of Integrated Biological Science, Pusan National University, Pusan, 46241, Republic of Korea.

¹⁰Department of Biological Sciences, Pusan National University, Pusan, 46241, Republic of Korea.

¹¹Soonchunhyang Institute of Medi-Bio Science (SIMS), Soonchunhyang University, Cheonan, 31151, Republic of Korea.

¹²Department of Biochemistry, Inha University School of Medicine, Incheon, 22212, Republic of Korea.

S.-M.P., J.-H.L., and K.S.A. contributed equally to this work as co-first authors.

CORRESPONDING AUTHORS : Jung-Hwan Lee, Hosup Shim, Hae-Won Kim

Abstract

Advancing the technologies for cellular reprogramming with high efficiency has significant impact on regenerative therapy, disease modeling, and drug discovery. Biophysical cues can tune the cell fate, yet the precise role of external physical forces during reprogramming remains elusive. Here the authors show that temporal cyclic-stretching of fibroblasts significantly enhances the efficiency of induced pluripotent stem cell (iPSC) production. Generated iPSCs are proven to express pluripotency markers and exhibit in vivo functionality. Bulk RNA-sequencing reveales that cyclic-stretching enhances biological characteristics required for pluripotency acquisition, including increased cell division and mesenchymal-epithelial transition. Of note, cyclic-stretching activates key mechanosensitive molecules (integrins, perinuclear actins, nesprin-2, and YAP), across the cytoskeletal-to-nuclear space. Furthermore, stretch-mediated cytoskeletal-nuclear mechano-coupling leads to altered epigenetic modifications, mainly downregulation in H3K9 methylation, and its global gene occupancy change, as revealed by genome-wide ChIP-sequencing and pharmacological inhibition tests. Single cell RNA-sequencing further identifies subcluster of mechano-responsive iPSCs and key epigenetic modifier in stretched cells. Collectively, cyclic-stretching activates iPSC reprogramming through mechanotransduction process and epigenetic changes accompanied by altered occupancy of mechanosensitive genes. This study highlights the strong link between external physical forces with subsequent mechanotransduction process and the epigenetic changes with expression of related genes in cellular reprogramming, holding substantial implications in the field of cell biology, tissue engineering, and regenerative medicine.

논문정보

형식Research article
게재일2023년 09월 (BRIC 등록일 2023-09-27)
연구진국내 연구진
분야 의약학 > 재생의학

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