Functional Genomic Screening During Somatic Cell Reprogramming Identifies DKK3 as a Roadblock of Organ Regeneration.

Somatic cell reprogramming and tissue repair share relevant factors and molecular programs. Here, Dickkopf-3 (DKK3) is identified as novel factor for organ regeneration using combined transcription-factor-induced reprogramming and RNA-interference techniques. Loss of Dkk3 enhances the generation of induced pluripotent stem cells but does not affect de novo derivation of embryonic stem cells, three-germ-layer differentiation or colony formation capacity of liver and pancreatic organoids. However, DKK3 expression levels in wildtype animals and serum levels in human patients are elevated upon injury. Accordingly, Dkk3-null mice display less liver damage upon acute and chronic failure mediated by increased proliferation in hepatocytes and LGR5+ liver progenitor cell population, respectively. Similarly, recovery from experimental pancreatitis is accelerated. Regeneration onset occurs in the acinar compartment accompanied by virtually abolished canonical-Wnt-signaling in Dkk3-null animals. This results in reduced expression of the Hedgehog repressor Gli3 and increased Hedgehog-signaling activity upon Dkk3 loss. Collectively, these data reveal Dkk3 as a key regulator of organ regeneration via a direct, previously unacknowledged link between DKK3, canonical-Wnt-, and Hedgehog-signaling. © 2021 The Authors. Advanced Science published by Wiley‐VCH GmbH.

Citation

Frank Arnold, Pallavi U Mahaddalkar, Johann M Kraus, Xiaowei Zhong, Wendy Bergmann, Dharini Srinivasan, Johann Gout, Elodie Roger, Alica K Beutel, Eugen Zizer, Umesh Tharehalli, Nora Daiss, Ronan Russell, Lukas Perkhofer, Rupert Oellinger, Qiong Lin, Ninel Azoitei, Frank-Ulrich Weiss, Markus M Lerch, Stefan Liebau, Sarah-Fee Katz, André Lechel, Roland Rad, Thomas Seufferlein, Hans A Kestler, Michael Ott, Amar Deep Sharma, Patrick C Hermann, Alexander Kleger. Functional Genomic Screening During Somatic Cell Reprogramming Identifies DKK3 as a Roadblock of Organ Regeneration. Advanced science (Weinheim, Baden-Wurttemberg, Germany). 2021 Jul;8(14):2100626

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PMID: 34306986

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