Wnt dose escalation during the exit from pluripotency identifies tranilast as a regulator of cardiac mesoderm.

Autor:	Wu Z; Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia., Shen S; Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia., Mizikovsky D; Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia., Cao Y; Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia., Naval-Sanchez M; Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia., Tan SZ; Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia., Alvarez YD; Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia., Sun Y; Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia., Chen X; Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia., Zhao Q; Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia., Kim D; Children's Medical Research Institute, The University of Sydney, Westmead, NSW 2145, Australia., Yang P; Children's Medical Research Institute, The University of Sydney, Westmead, NSW 2145, Australia., Hill TA; Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia; Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, QLD 4072, Australia., Jones A; Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia., Fairlie DP; Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia; Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, QLD 4072, Australia., Pébay A; Department of Anatomy and Physiology, The University of Melbourne, Parkville, VIC 3010, Australia; Department of Surgery, Royal Melbourne Hospital, The University of Melbourne, Parkville, VIC 3010, Australia., Hewitt AW; Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS 7000, Australia., Tam PPL; Children's Medical Research Institute, The University of Sydney, Westmead, NSW 2145, Australia; School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia., White MD; Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia., Nefzger CM; Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia; School of Chemistry & Molecular Biosciences, The University of Queensland, Brisbane, QLD 4067, Australia., Palpant NJ; Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia. Electronic address: n.palpant@uq.edu.au.
Jazyk:	angličtina
Zdroj:	Developmental cell [Dev Cell] 2024 Mar 25; Vol. 59 (6), pp. 705-722.e8. Date of Electronic Publication: 2024 Feb 13.
DOI:	10.1016/j.devcel.2024.01.019
Abstrakt:	Wnt signaling is a critical determinant of cell lineage development. This study used Wnt dose-dependent induction programs to gain insights into molecular regulation of stem cell differentiation. We performed single-cell RNA sequencing of hiPSCs responding to a dose escalation protocol with Wnt agonist CHIR-99021 during the exit from pluripotency to identify cell types and genetic activity driven by Wnt stimulation. Results of activated gene sets and cell types were used to build a multiple regression model that predicts the efficiency of cardiomyocyte differentiation. Cross-referencing Wnt-associated gene expression profiles to the Connectivity Map database, we identified the small-molecule drug, tranilast. We found that tranilast synergistically activates Wnt signaling to promote cardiac lineage differentiation, which we validate by in vitro analysis of hiPSC differentiation and in vivo analysis of developing quail embryos. Our study provides an integrated workflow that links experimental datasets, prediction models, and small-molecule databases to identify drug-like compounds that control cell differentiation. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu