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

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

Abstract

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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Sprache: Englisch