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....
Autores principales: | , , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1783486846480678912 |
---|---|
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. |
format | Online Article Text |
id | pubmed-6954720 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | John Wiley & Sons, Inc. |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT drowleylauren discoveryofretinoicacidreceptoragonistsasproliferatorsofcardiacprogenitorcellsthroughaphenotypicscreeningapproach AT mcpheatjane discoveryofretinoicacidreceptoragonistsasproliferatorsofcardiacprogenitorcellsthroughaphenotypicscreeningapproach AT nordqvistanneli discoveryofretinoicacidreceptoragonistsasproliferatorsofcardiacprogenitorcellsthroughaphenotypicscreeningapproach AT peelsamantha discoveryofretinoicacidreceptoragonistsasproliferatorsofcardiacprogenitorcellsthroughaphenotypicscreeningapproach AT karlssonulla discoveryofretinoicacidreceptoragonistsasproliferatorsofcardiacprogenitorcellsthroughaphenotypicscreeningapproach AT martinssonsofia discoveryofretinoicacidreceptoragonistsasproliferatorsofcardiacprogenitorcellsthroughaphenotypicscreeningapproach AT mullerserik discoveryofretinoicacidreceptoragonistsasproliferatorsofcardiacprogenitorcellsthroughaphenotypicscreeningapproach AT dellsenanita discoveryofretinoicacidreceptoragonistsasproliferatorsofcardiacprogenitorcellsthroughaphenotypicscreeningapproach AT knightsinead discoveryofretinoicacidreceptoragonistsasproliferatorsofcardiacprogenitorcellsthroughaphenotypicscreeningapproach AT barrettian discoveryofretinoicacidreceptoragonistsasproliferatorsofcardiacprogenitorcellsthroughaphenotypicscreeningapproach AT sanchezjose discoveryofretinoicacidreceptoragonistsasproliferatorsofcardiacprogenitorcellsthroughaphenotypicscreeningapproach AT magnussonbjorn discoveryofretinoicacidreceptoragonistsasproliferatorsofcardiacprogenitorcellsthroughaphenotypicscreeningapproach AT greberboris discoveryofretinoicacidreceptoragonistsasproliferatorsofcardiacprogenitorcellsthroughaphenotypicscreeningapproach AT wangqingdong discoveryofretinoicacidreceptoragonistsasproliferatorsofcardiacprogenitorcellsthroughaphenotypicscreeningapproach AT plowrightalleynt discoveryofretinoicacidreceptoragonistsasproliferatorsofcardiacprogenitorcellsthroughaphenotypicscreeningapproach |