Pancreatic β-cell regeneration in situ by the ALK3 agonist THR-123

Silvia Álvarez-Cubela, Isabella D. Altilio, Mayur Doke, Dagmar Klein, Alejandro Tamayo, Óscar Alcázar, Carlos García Santana, Mirza Muhammad Fahd Qadir, Charles García Alver, Francis Cruz, Olivia Biggs, Jorge David Tovar Castro, Belén Navarro-Rubio, Camillo Ricordi, Alejandro Caicedo, Peter Buchwald, Ashutosh Agarwal, Elisa Oltra, Ricardo Luis Pastori () and Juan Domínguez-Bendala ()
Additional contact information
Silvia Álvarez-Cubela: University of Miami Miller School of Medicine (UM-MSoM)
Isabella D. Altilio: University of Miami Miller School of Medicine (UM-MSoM)
Mayur Doke: University of Miami Miller School of Medicine (UM-MSoM)
Dagmar Klein: University of Miami Miller School of Medicine (UM-MSoM)
Alejandro Tamayo: UM-MSoM
Óscar Alcázar: University of Miami Miller School of Medicine (UM-MSoM)
Carlos García Santana: University of Miami Miller School of Medicine (UM-MSoM)
Mirza Muhammad Fahd Qadir: University of Miami Miller School of Medicine (UM-MSoM)
Charles García Alver: UM-MSoM
Francis Cruz: University of Miami Miller School of Medicine (UM-MSoM)
Olivia Biggs: University of Miami Miller School of Medicine (UM-MSoM)
Jorge David Tovar Castro: University of Miami Miller School of Medicine (UM-MSoM)
Belén Navarro-Rubio: Universidad Francisco de Vitoria
Camillo Ricordi: University of Miami Miller School of Medicine (UM-MSoM)
Alejandro Caicedo: UM-MSoM
Peter Buchwald: University of Miami Miller School of Medicine (UM-MSoM)
Ashutosh Agarwal: UM-MSoM
Elisa Oltra: Universidad Católica de Valencia
Ricardo Luis Pastori: University of Miami Miller School of Medicine (UM-MSoM)
Juan Domínguez-Bendala: University of Miami Miller School of Medicine (UM-MSoM)

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract The demonstration that BMP signaling activates progenitor-like populations within pancreatic ducts supports the potential use of BMP receptor agonists to induce islet neogenesis in situ. In this context, we tested the ability of THR-123, a cyclic peptide with BMP-7-like activity, to regenerate β-cell mass in diabetic mice. We show here that treatment with THR-123 reduces hyperglycemia through the rapid formation of new BrdU-labeled islets, many in apposition to ducts. These islets, unlike those from non-diabetic controls, feature an extensive intrainsular network of ductal tissue. The earlier stages of THR-123-induced β-cell formation were reproduced in live pancreatic slices, an organotypic model that allowed us to visualize ductal cells transitioning to glucose-responsive insulin-expressing cells in real time. scRNAseq analyses further suggest that this transition occurs through a hybrid ducto-acinar stage similar to that previously reported in humans. Taken together, our data support the conclusion that these islets arise predominantly by neogenesis. These results pave the way for the design of pharmacological strategies to treat insulin-dependent diabetes.

Date: 2025
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DOI: 10.1038/s41467-025-61534-2

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