Jeongmin Ha1,2†‡, Bum Suk Kim3†, Byungkuk Min1, Juhyeon Nam1,2, Jae-Geun Lee2,4, Minhyung Lee1,2, Byoung-Ha Yoon5, Yoon Ha Choi3,6, Ilkyun Im7, Jung Sun Park8, Hyosun Choi9, Areum Baek1, Sang Mi Cho10, Mi-Ok Lee1,2, Ki-Hoan Nam10, Ji Young Mun11, Mirang Kim2,12, Seon-Young Kim2,5,12, Mi Young Son1,2, Yong-Kook Kang2,8, Jeong-Soo Lee2,4,13*,  Jong Kyoung Kim3,6*, Janghwan Kim1,2,14*

1Stem Cell Convergence Research Center, Korea Research Institute Bioscience and Biotechnology  (KRIBB),  Daejeon  34141,  Republic  of  Korea.  
2Department  of  Func-tional Genomics, KRIBB School of Bioscience, Korea University of Science and Tech-nology, Daejeon 34113, Republic of Korea. 3Department of New Biology, Daegu Gyeongbuk Institute of Science and Technology, Daegu 42988, Republic of Korea. 
4Microbiome Convergence Research Center, KRIBB, Daejeon 34141, Republic of Korea. 
5Korea Bioinformation Center, KRIBB, Daejeon 34141, Republic of Korea. 
6Department of Life Sciences, Pohang University of Science and Technology, Pohang 37673, Republic of Korea. 
7Bio-IT lab, NetTargets Inc., Daejeon 34141, Republic of Korea. 
8Development and Differentiation Research Center, KRIBB, Daejeon 34141, Republic  of  Korea.  
9Nanobioimaging  Center,  National  Instrumentation  Center  for  Environmental Management (NICEM), Seoul National University, Seoul, Republic of Korea. 10Laboratory Animal Resource Center, KRIBB, Cheongju 28116, Republic of Korea. 
11Neural Circuit Research Group, Korea Brain Research Institute, Daegu 41062, Republic of Korea. 
12Personalized Genomic Medicine Research Center, KRIBB, Daejeon 34141, Republic of Korea. 
13Dementia DTC R&D Convergence Pro-gram, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea. 
14R&D Center, Regeners Inc., Daejeon 34141, Republic of Korea.

*Corresponding  authors:  Jeong-Soo Lee,  Jong Kyoung Kim, Janghwan Kim
†These authors contributed equally to this work.
‡Present address: Center for Genome Engineering, Institute for Basic Science, 55, Expo-ro, Yuseong-gu, Daejeon 34126, Republic of Korea.

Amphibians and fish show considerable regeneration potential via dedifferentiation of somatic cells into blastemal cells. In terms of dedifferentiation, in vitro cellular reprogramming has been proposed to share common processes with in vivo tissue regeneration, although the details are elusive. Here, we identified the cytoskeletal linker protein desmoplakin (Dsp) as a common factor mediating both reprogramming and regeneration. Our analysis revealed that Dsp expression is elevated in distinct intermediate cells during in vitro reprogramming. Knockdown of <i>Dsp</i> impedes in vitro reprogramming into induced pluripotent stem cells and induced neural stem/progenitor cells as well as in vivo regeneration of zebrafish fins. Notably, reduced <i>Dsp</i> expression impairs formation of the intermediate cells during cellular reprogramming and tissue regeneration. These findings suggest that there is a Dsp-mediated evolutionary link between cellular reprogramming in mammals and tissue regeneration in lower vertebrates and that the intermediate cells may provide alternative approaches for mammalian regenerative therapy.