title: Induced pluripotency and oncogenic transformation are related processes.
abstract: Induced pluripotent stem cells (iPSCs) have the potential for creating patient-specific regenerative medicine therapies, but the links between pluripotency and tumorigenicity raise important safety concerns. More specifically, the methods employed for the production of iPSCs and oncogenic foci (OF), a form of in vitro produced tumor cells, are surprisingly similar, raising potential concerns about iPSCs. To test the hypotheses that iPSCs and OF are related cell types and, more broadly, that the induction of pluripotency and tumorigenicity are related processes, we produced iPSCs and OF in parallel from common parental fibroblasts. When we compared the transcriptomes of these iPSCs and OF to their parental fibroblasts, similar transcriptional changes were observed in both iPSCs and OF. A significant number of genes repressed during the iPSC formation were also repressed in OF, including a large cohort of differentiation-associated genes. iPSCs and OF shared a limited number of genes that were upregulated relative to parental fibroblasts, but gene ontology analysis pointed toward monosaccharide metabolism as upregulated in both iPSCs and OF. iPSCs and OF were distinct in that only iPSCs activated a host of pluripotency-related genes, while OF activated cellular damage and specific metabolic pathways. We reprogrammed oncogenic foci (ROF) to produce iPSC-like cells, a process dependent on Nanog. However, the ROF had reduced differentiation potential compared to iPSC, suggesting that oncogenic transformation leads to cellular changes that impair complete reprogramming. Taken together, these findings support a model in which OF and iPSCs are related, yet distinct cell types, and in which induced pluripotency and induced tumorigenesis are similar processes.
authors.affiliation: Department of Cell Biology and Human Anatomy, University of California Davis School of Medicine, Sacramento, California 95616, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Riggs
authors.forename: Bonnie L
authors.initials: BL
authors.lastname: Barrilleaux
authors.forename: Natasha
authors.initials: N
authors.lastname: Varlakhanova
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Bush
authors.forename: Vanessa
authors.initials: V
authors.lastname: Chan
authors.forename: Paul S
authors.initials: PS
authors.lastname: Knoepfler
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D018920:Coculture Techniques; D053595:Embryonic Stem Cells / Q000473:pathology / Q000502:physiology / Q000637:transplantation; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism* / Q000473:pathology / Q000502:physiology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology; D059467:Transcriptome
chemical_list: D000943:Antigens, Differentiation; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc