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

Stem Cells Translational Medicine

Sinead Knight¹  Ian Barrett¹  Samantha Peel¹  Björn Magnusson²  Jane McPheat²  José Sánchez²  Ulla Karlsson²  Anita Dellsén²  Boris Greber³  Anneli Nordqvist⁴  Erik Müllers⁴  Sofia Martinsson⁴  Alleyn T. Plowright⁴  Lauren Drowley⁴  Qing‐Dong Wang⁴ 

[1] Discovery Sciences R&D, AstraZeneca Cambridge UK;Discovery Sciences R&D, AstraZeneca Gothenburg Sweden;Human Stem Cell Pluripotency Laboratory Max Planck Institute for Molecular Biomedicine Münster Germany;Research and Early Development, Cardiovascular, Renal and Metabolism BioPharmaceuticals R&D Gothenburg Sweden;

关键词: cell proliferation;    gene expression;    high throughput screening assays;    induced pluripotent stem cells;    nuclear receptors;    small molecule libraries;   

DOI  :  10.1002/sctm.19-0069

来源: DOAJ

【 摘 要 】

Abstract 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.

【 授权许可】

Unknown