CDKN2B upregulation prevents teratoma formation in multipotent fibromodulin-reprogrammed cells

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 integra...

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Bibliographic Details
Published in:The Journal of clinical investigation 2019-08, Vol.129 (8), p.3236-3251
Main Authors: Zheng, Zhong, Li, Chenshuang, Ha, Pin, Chang, Grace X, Yang, Pu, Zhang, Xinli, Kim, Jong Kil, Jiang, Wenlu, Pang, Xiaoxiao, Berthiaume, Emily A, Mills, Zane, Haveles, Christos S, Chen, Eric, Ting, Kang, Soo, Chia
Format: Article
Language:English
Subjects:
Cell Line
Cellular Reprogramming
Comparative analysis
Cyclin-Dependent Kinase Inhibitor p15 - biosynthesis
Diagnostic reagents industry
Fibromodulin - genetics
Fibromodulin - metabolism
Gene Expression Regulation, Neoplastic
Genomes
Genomics
Humans
Multipotent Stem Cells - metabolism
Multipotent Stem Cells - pathology
Novels
Skeletal muscle
Stem cells
Teratoma
Teratoma - genetics
Teratoma - metabolism
Teratoma - pathology
Up-Regulation
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Summary: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.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI125015