RSPO1, a potent inducer of pancreatic β cell neogenesis

  • Cell Rep Med. 2025 May 20;6(5):102126. doi: 10.1016/j.xcrm.2025.102126.
Serena Silvano  1 ,  Tiziana Napolitano  1 ,  Magali Plaisant  1 ,  Anette Sousa-De-Veiga  2 ,  Hugo Fofo  2 ,  Chaïma Ayachi  2 ,  Benoit Allegrini  2 ,  Samah Rekima  2 ,  Estelle Pichery  3 ,  Jérôme Becam  4 ,  Valentin Lepage  2 ,  Caroline Treins  1 ,  Laura Etasse  1 ,  Loan Tran  1 ,  Julien Thévenet  5 ,  Gianni Pasquetti  5 ,  Julie Kerr-Conte  5 ,  François Pattou  5 ,  Paolo Botti  1 ,  Arduino Arduini  1 ,  Jacques Mizrahi  1 ,  Benjamin Charles  1 ,  Patrick Collombat  6
Affiliations
  • 1. DiogenX, 180 Avenue du Prado, 13008 Marseille, France.
  • 2. University Nice Cote D'Azur, Inserm, CNRS, iBV, 06100 Nice, France; iBV, Institut de Biologie Valrose, University Nice Sophia Antipolis, Centre de Biochimie, Parc Valrose, 28, Avenue Valrose, 06108 Nice Cedex 2, France.
  • 3. Université Côte d'Azur, Inserm, C3M, Nice, France.
  • 4. Aix-Marseille Université, CNRS, Laboratoire de Chimie Bactérienne, UMR 7283, Institut de Microbiologie de la Méditerranée, 31 Chemin Joseph Aiguier, 13009 Marseille, France.
  • 5. University Lille, Inserm, CHU Lille, U1190 Translational Research for Diabetes, European Genomic Institute for Diabetes, EGID, 59000 Lille, France.
  • 6. DiogenX, 180 Avenue du Prado, 13008 Marseille, France; University Nice Cote D'Azur, Inserm, CNRS, iBV, 06100 Nice, France; iBV, Institut de Biologie Valrose, University Nice Sophia Antipolis, Centre de Biochimie, Parc Valrose, 28, Avenue Valrose, 06108 Nice Cedex 2, France. Electronic address: [email protected].
PMID: 40339569 DOI: 10.1016/j.xcrm.2025.102126
Abstract

Inducing the neogenesis of pancreatic insulin-producing β cells holds great promise for diabetes research. However, non-toxic compounds with such activities remain to be discovered. Herein, we report the identification of RSPO1, a key agonist of the Wnt/β-catenin pathway, as an inducer of β cell replication. Specifically, we provide evidence that RSPO1 promotes a significant increase in β cell neogenesis in vitro, ex vivo, and in vivo. Importantly, RSPO1 administration is sufficient to activate Wnt/β-catenin signaling in β cells and counter chemically induced or autoimmune-mediated diabetes. Similarly, an optimized analog of RSPO1, allowing for weekly administration, also prevents diabetes in vivo. Lastly, the treatment of transplanted human islets with RSPO1 induces a significant 2.78-fold increase in human β cell numbers in only 60 days, these cells being functional. Such activities of RSPO1 to promote β cell neogenesis could therefore represent an unprecedented hope in the continued search for diabetes alternative therapies.

Keywords
Rspo1; Wnt/β-catenin signaling; diabetes; endocrine pancreas; islets of Langerhans; β cell replication.
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