Departmental Papers (Dental)
CDKN2B Upregulation Prevents Teratoma Formation in Multipotent Fibromodulin-Reprogrammed Cells
Date of this Version
Journal of Clinical Investigation
Tumorigenicity is a well-documented risk to overcome for pluripotent or multipotent cell applications in regenerative medicine. To address the emerging demand for safe cell sources in tissue regeneration, we established a novel, protein-based reprogramming method that does not require genome integration or oncogene activation to yield multipotent fibromodulin (FMOD)-reprogrammed (FReP) cells from dermal fibroblasts. When compared with induced pluripotent stem cells (iPSCs), FReP cells exhibited a superior capability for bone and skeletal muscle regeneration with markedly less tumorigenic risk. Moreover, we showed that the decreased tumorigenicity of FReP cells was directly related to an upregulation of cyclin-dependent kinase inhibitor 2B (CDKN2B) expression during the FMOD reprogramming process. Indeed, sustained suppression of CDKN2B resulted in tumorigenic, pluripotent FReP cells that formed teratomas in vivo that were indistinguishable from iPSC-derived teratomas. These results highlight the pivotal role of CDKN2B in cell fate determination and tumorigenic regulation and reveal an alternative pluripotent/multipotent cell reprogramming strategy that solely uses FMOD protein. © 2019, American Society for Clinical Investigation.
Cell Line, Cellular Reprogramming, Cyclin-Dependent Kinase Inhibitor p15, Fibromodulin, Gene Expression Regulation, Neoplastic, Humans, Multipotent Stem Cells, Teratoma, Up-Regulation, cyclin dependent kinase inhibitor 2B, fibromodulin, CDKN2B protein, human, cyclin dependent kinase inhibitor 2B, fibromodulin, FMOD protein, human, adult, Article, bone regeneration, carcinogenesis, carcinogenicity, cell fate, cell reprogramming technique, controlled study, engraftment, human, human cell, in vivo study, induced pluripotent stem cell, male, mouse, multipotent stem cell, muscle regeneration, nonhuman, priority journal, SCID beige mouse, SCID mouse, skeletal muscle, skin fibroblast, teratoma, tibialis anterior muscle, upregulation, biosynthesis, cell line, gene expression regulation, genetics, metabolism, nuclear reprogramming, pathology, teratoma, upregulation
Zheng, Z., Li, C., Ha, P., Chang, G. X., Yang, P., Zhang, X., Kim, J. K., Jiang, W., Pang, X., Berthiaume, E. A., Mills, Z., Haveles, C. S., Chen, E., Tine, K., & Soo, C. (2019). CDKN2B Upregulation Prevents Teratoma Formation in Multipotent Fibromodulin-Reprogrammed Cells. Journal of Clinical Investigation, 129 (8), 3236-3251. http://dx.doi.org/10.1172/JCI125015
Date Posted: 10 February 2023
This document has been peer reviewed.
At the time of publication, author Chenshuang Li was affiliated with the School of Dentistry, University of California. Currently, (s)he is a faculty member at the School of Medical Dentistry at the University of Pennsylvania.