A Rare Human Syndrome Provides Genetic Evidence that WNT Signaling Is Required for Reprogramming of Fibroblasts to Induced Pluripotent Stem Cells

Jason Ross, Julia Busch, Ellen Mintz, Damian Ng, Alexandra Stanley, David Brafman, V. Reid Sutton, Ignatia Van den Veyver, Karl Willert

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

WNT signaling promotes the reprogramming of somatic cells to an induced pluripotent state. We provide genetic evidence that WNT signaling is a requisite step during the induction of pluripotency. Fibroblasts from individuals with focal dermal hypoplasia (FDH), a rare genetic syndrome caused by mutations in the essential WNT processing enzyme PORCN, fail to reprogram with standard methods. This blockade in reprogramming is overcome by ectopic WNT signaling and PORCN overexpression, thus demonstrating that WNT signaling is essential for reprogramming. The rescue of reprogramming is critically dependent on the level of WNT signaling: steady baseline activation of the WNT pathway yieldskaryotypically normal iPSCs, whereas daily stimulation with Wnt3a produces FDH-iPSCs with severely abnormal karyotypes. Therefore, although WNT signaling is required for cellular reprogramming, inappropriate activation of WNT signaling induces chromosomal instability, highlighting the precarious nature of ectopic WNT activation and its tight relationship with oncogenic transformation. WNT signaling is required for embryonic development, maintenance of stem cells in an undifferentiated state, and homeostasis of adult tissues. Here, Ross etal. provide genetic evidence that this signaling pathway is also essential to the process of reprogramming of somatic cells to an induced pluripotent state. These studies also reveal an unexpected link between aberrant WNT signaling and chromosomal instability.

Original languageEnglish (US)
Pages (from-to)1770-1780
Number of pages11
JournalCell Reports
Volume9
Issue number5
DOIs
StatePublished - Dec 11 2014
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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