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Cited by 18Liver physiology and pathologyPluripotent Stem Cells ResearchTissue Engineering and Regenerative Medicine

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

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Arnold, Frank, Mahaddalkar, Pallavi U, Kraus, Johann M., Zhong, Xiaowei, Bergmann, Wendy, Srinivasan, Dharini, Gout, Johann, Roger, Elodie +21 more·2021·Advanced Science
DOI 10.1002/advs.202100626PMC PMC8292873
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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.

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  • Common mechanisms and similar genetic programs between stem cell induction, organ homeostasis, and regeneration from injury have been identified for the pancreas.

    “Common mechanisms and similar genetic programs between stem cell induction, organ homeostasis, and regeneration from injury have been identified for the pancreas [20, 21].”

    From TBX3 is dynamically expressed in pancreatic organogenesis and fine-tunes regeneration (2023) · cites this paper as [20]

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Cited by

Sorted by citations

Authors
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., Azoitei, N., Weiss, F., Lerch, M. M., Liebau, S., Katz, S., Lechel, A., Rad, R., Seufferlein, T., Kestler, H. A., Ott, M., Sharma, A. D., Hermann, P. C., & Kleger, A.
Affiliations
  • University Hospital Ulm (DE)
  • Helmholtz Munich (DE)
  • Universität Ulm (DE)
  • Medizinische Hochschule Hannover (DE)
  • Universitätsmedizin Rostock (DE)
  • Department of Internal Medicine I University Hospital Ulm Albert‐Einstein Allee 23 89081 Ulm Germany
  • University of California, San Francisco (US)
  • Technical University of Munich (DE)
  • Bayer (Germany) (DE)
  • Universitätsmedizin Greifswald (DE)
  • University of Tübingen (DE)
Corresponding author
Kleger, Alexander
ORCID
Venue
Advanced Science
Publisher
Wiley
Published
2021-05-13
Volume
8
Issue
14
Pages
2100626-2100626
ISSN
2198-3844 (ISSN-L)
DOI
10.1002/advs.202100626
PMC
PMC8292873
OpenAlex
W3160973552
Cited by
18
References
10
Citations by year
2026: 2 · 2025: 4 · 2024: 2 · 2023: 3 · 2022: 4 · 2021: 3
FWCI
2.09
Type
journal article
Language
en
Open access
Licence
Locations
  • Advanced Science (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
  • OPen Access Repositorium der Universität Ulm (OPARU) (Ulm University) (submittedVersion, other-oa)
  • Site cant be reached (submittedVersion, cc-by)
  • Universität Ulm, Kommunikations- und Informationszentrum (kiz) (cc-by)
Funders
  • Deutsche Krebshilfe
  • Deutsche Forschungsgemeinschaft
  • Bundesministerium für Bildung und Forschung
  • Universität Ulm
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
  • Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
Keywords
DKK3, Dickkopf-3, organ regeneration, somatic cell reprogramming, induced pluripotent stem cells, liver regeneration, pancreatic regeneration, pancreatitis, Wnt/β-catenin signaling, Hedgehog signaling, Gli3, liver progenitor cells, hepatocyte proliferation, organoids, tissue repair
MeSH terms
Animals, Disease Models, Animal, Mice, Inbred C57BL, Regeneration, Genomics, Organogenesis, Adaptor Proteins, Signal Transducing, Mice, Cellular Reprogramming

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