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Arnold, F.* ; Mahaddalkar, P.U. ; Kraus, J.M.* ; Zhong, X.* ; Bergmann, W.* ; Srinivasan, D.* ; Gout, J.* ; Roger, E.* ; Beutel, A.K.* ; Zizer, E.* ; Tharehalli, U.* ; Daiss, N.* ; Russell, R.* ; Perkhofer, L.* ; Oellinger, R.* ; Lin, Q.S.* ; Azoitei, N.* ; Weiss, F.U.* ; Lerch, M.M.* ; Liebau, S.* ; Katz, S.F.* ; Lechel, A.* ; Rad, R.* ; Seufferlein, T.* ; Kestler, H.A.* ; Ott, M.* ; Sharma, A.D.* ; Hermann, P.C.* ; Kleger, A.*

Functional genomic screening during somatic cell reprogramming identifies DKK3 as a roadblock of organ regeneration.

Adv. Sci. 8:2100626 (2021)

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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. +

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Functional Shrna Screen ; Regeneration ; Reprogramming ; Wnt-/hedgehog-signaling; Pluripotent Stem-cells; Liver-regeneration; Acinar Morphogenesis; Self-renewal; Adult Liver; Cancer; Hedgehog; Wnt; Dickkopf-3; Expression

ISSN (print) / ISBN 2198-3844

e-ISSN 2198-3844

Journal Advanced science

Quellenangaben Volume: 8, Issue: 14, Article Number: 2100626

Publisher Wiley

Publishing Place Weinheim

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Diabetes and Regeneration Research (IDR)

Grants Collaborative Research Centre grant of the German Research Foundation
German Cancer Aid Priority Program 'Translational Oncology'
Max Eder Fellowship of the German Cancer Aid
Else-Kroner-Fresenius Excellence funding
INDIMED-Verbund PancChip
DFG
German Cancer Aid
Baden-Wurttemberg-Foundation ExPO-Chip
Deutsche Forschungsgemeinschaft (DFG)
Bausteinprogramm of Ulm University