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
Affiliations
Jason Ross
Stem Cell Program, Sanford Consortium for Regenerative Medicine, Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093, USA
Julia Busch
Stem Cell Program, Sanford Consortium for Regenerative Medicine, Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093, USA
Ellen Mintz
Department of Biological Sciences, California Polytechnic State University, San Luis Obispo, CA 93407, USA
Damian Ng
Stem Cell Program, Sanford Consortium for Regenerative Medicine, Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093, USA
Alexandra Stanley
Stem Cell Program, Sanford Consortium for Regenerative Medicine, Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093, USA
David Brafman
Stem Cell Program, Sanford Consortium for Regenerative Medicine, Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093, USA
V. Reid Sutton
Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX 77030, USA
Ignatia Van den Veyver
Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX 77030, USA; Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX 77030, USA
Karl Willert
Stem Cell Program, Sanford Consortium for Regenerative Medicine, Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093, USA; Corresponding author
Summary: 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 yields karyotypically 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 et al. 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.
