Discovery of retinoic acid receptor agonists as proliferators of cardiac progenitor cells through a phenotypic screening approach

Identification of small molecules with the potential to selectively proliferate cardiac progenitor cells (CPCs) will aid our understanding of the signaling pathways and mechanisms involved and could ultimately provide tools for regenerative therapies for the treatment of post‐MI cardiac dysfunction....

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Autores principales: Drowley, Lauren, McPheat, Jane, Nordqvist, Anneli, Peel, Samantha, Karlsson, Ulla, Martinsson, Sofia, Müllers, Erik, Dellsén, Anita, Knight, Sinead, Barrett, Ian, Sánchez, José, Magnusson, Björn, Greber, Boris, Wang, Qing‐Dong, Plowright, Alleyn T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons, Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954720/
https://www.ncbi.nlm.nih.gov/pubmed/31508905
http://dx.doi.org/10.1002/sctm.19-0069
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author Drowley, Lauren
McPheat, Jane
Nordqvist, Anneli
Peel, Samantha
Karlsson, Ulla
Martinsson, Sofia
Müllers, Erik
Dellsén, Anita
Knight, Sinead
Barrett, Ian
Sánchez, José
Magnusson, Björn
Greber, Boris
Wang, Qing‐Dong
Plowright, Alleyn T.
author_facet Drowley, Lauren
McPheat, Jane
Nordqvist, Anneli
Peel, Samantha
Karlsson, Ulla
Martinsson, Sofia
Müllers, Erik
Dellsén, Anita
Knight, Sinead
Barrett, Ian
Sánchez, José
Magnusson, Björn
Greber, Boris
Wang, Qing‐Dong
Plowright, Alleyn T.
author_sort Drowley, Lauren
collection PubMed
description Identification of small molecules with the potential to selectively proliferate cardiac progenitor cells (CPCs) will aid our understanding of the signaling pathways and mechanisms involved and could ultimately provide tools for regenerative therapies for the treatment of post‐MI cardiac dysfunction. We have used an in vitro human induced pluripotent stem cell‐derived CPC model to screen a 10,000‐compound library containing molecules representing different target classes and compounds reported to modulate the phenotype of stem or primary cells. The primary readout of this phenotypic screen was proliferation as measured by nuclear count. We identified retinoic acid receptor (RAR) agonists as potent proliferators of CPCs. The CPCs retained their progenitor phenotype following proliferation and the identified RAR agonists did not proliferate human cardiac fibroblasts, the major cell type in the heart. In addition, the RAR agonists were able to proliferate an independent source of CPCs, HuES6. The RAR agonists had a time‐of‐differentiation‐dependent effect on the HuES6‐derived CPCs. At 4 days of differentiation, treatment with retinoic acid induced differentiation of the CPCs to atrial cells. However, after 5 days of differentiation treatment with RAR agonists led to an inhibition of terminal differentiation to cardiomyocytes and enhanced the proliferation of the cells. RAR agonists, at least transiently, enhance the proliferation of human CPCs, at the expense of terminal cardiac differentiation. How this mechanism translates in vivo to activate endogenous CPCs and whether enhancing proliferation of these rare progenitor cells is sufficient to enhance cardiac repair remains to be investigated.
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spelling pubmed-69547202020-01-17 Discovery of retinoic acid receptor agonists as proliferators of cardiac progenitor cells through a phenotypic screening approach Drowley, Lauren McPheat, Jane Nordqvist, Anneli Peel, Samantha Karlsson, Ulla Martinsson, Sofia Müllers, Erik Dellsén, Anita Knight, Sinead Barrett, Ian Sánchez, José Magnusson, Björn Greber, Boris Wang, Qing‐Dong Plowright, Alleyn T. Stem Cells Transl Med Cell‐based Drug Development, Screening, and Toxicology Identification of small molecules with the potential to selectively proliferate cardiac progenitor cells (CPCs) will aid our understanding of the signaling pathways and mechanisms involved and could ultimately provide tools for regenerative therapies for the treatment of post‐MI cardiac dysfunction. We have used an in vitro human induced pluripotent stem cell‐derived CPC model to screen a 10,000‐compound library containing molecules representing different target classes and compounds reported to modulate the phenotype of stem or primary cells. The primary readout of this phenotypic screen was proliferation as measured by nuclear count. We identified retinoic acid receptor (RAR) agonists as potent proliferators of CPCs. The CPCs retained their progenitor phenotype following proliferation and the identified RAR agonists did not proliferate human cardiac fibroblasts, the major cell type in the heart. In addition, the RAR agonists were able to proliferate an independent source of CPCs, HuES6. The RAR agonists had a time‐of‐differentiation‐dependent effect on the HuES6‐derived CPCs. At 4 days of differentiation, treatment with retinoic acid induced differentiation of the CPCs to atrial cells. However, after 5 days of differentiation treatment with RAR agonists led to an inhibition of terminal differentiation to cardiomyocytes and enhanced the proliferation of the cells. RAR agonists, at least transiently, enhance the proliferation of human CPCs, at the expense of terminal cardiac differentiation. How this mechanism translates in vivo to activate endogenous CPCs and whether enhancing proliferation of these rare progenitor cells is sufficient to enhance cardiac repair remains to be investigated. John Wiley & Sons, Inc. 2019-09-11 /pmc/articles/PMC6954720/ /pubmed/31508905 http://dx.doi.org/10.1002/sctm.19-0069 Text en © 2019 The Authors. stem cells translational medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Cell‐based Drug Development, Screening, and Toxicology
Drowley, Lauren
McPheat, Jane
Nordqvist, Anneli
Peel, Samantha
Karlsson, Ulla
Martinsson, Sofia
Müllers, Erik
Dellsén, Anita
Knight, Sinead
Barrett, Ian
Sánchez, José
Magnusson, Björn
Greber, Boris
Wang, Qing‐Dong
Plowright, Alleyn T.
Discovery of retinoic acid receptor agonists as proliferators of cardiac progenitor cells through a phenotypic screening approach
title Discovery of retinoic acid receptor agonists as proliferators of cardiac progenitor cells through a phenotypic screening approach
title_full Discovery of retinoic acid receptor agonists as proliferators of cardiac progenitor cells through a phenotypic screening approach
title_fullStr Discovery of retinoic acid receptor agonists as proliferators of cardiac progenitor cells through a phenotypic screening approach
title_full_unstemmed Discovery of retinoic acid receptor agonists as proliferators of cardiac progenitor cells through a phenotypic screening approach
title_short Discovery of retinoic acid receptor agonists as proliferators of cardiac progenitor cells through a phenotypic screening approach
title_sort discovery of retinoic acid receptor agonists as proliferators of cardiac progenitor cells through a phenotypic screening approach
topic Cell‐based Drug Development, Screening, and Toxicology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954720/
https://www.ncbi.nlm.nih.gov/pubmed/31508905
http://dx.doi.org/10.1002/sctm.19-0069
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