Open AccessInfluencing the Fate of Cardiac and Neural Stem Cell Differentiation Using Small Molecule Inhibitors of ALK5
Author(s) -
Zhong Qixing,
Laco Filip,
Liao MeiChih,
Woo Tsung L.,
Oh Steve K.W.,
Chai Christina L.L.
Publication year - 2018
Publication title -
stem cells translational medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.781
H-Index - 71
eISSN - 2157-6580
pISSN - 2157-6564
DOI - 10.1002/sctm.17-0246
Subject(s) - wnt signaling pathway , induced pluripotent stem cell , regenerative medicine , microbiology and biotechnology , neural stem cell , small molecule , chemistry , cellular differentiation , stem cell , embryonic stem cell , smad , neural development , pharmacology , biology , signal transduction , biochemistry , gene
In this study, 50 tri‐substituted imidazoles (TIs), which are analogs of the small molecules TA‐01 and SB203580, were synthesized and screened for cardiomyogenic activities. Several TIs displayed cardiomyogenic activities when applied during the differentiation from days 3–5. The TIs did not affect the Wnt/β‐catenin pathway during cardiomyogenesis and the likely mechanism of action is through the inhibition of ALK5 of the TGFβ pathway. Interestingly, these TIs promoted the neural differentiation of human pluripotent stem cells (hPSCs) with a similar potency to that of the dual SMAD inhibitors SB431542/LDN‐193189 when dosed from days 1 to 9. The neural induction activities of the TIs correlated with their ALK5 inhibitory activities. This study reports the discovery of small molecule inhibitors of ALK5, which can promote the differentiation of hPSCs into cardiomyocytes or neural cells depending on the time of dosing, showing potential for the production of clinical‐grade cardiac/neural cells for regenerative therapy. Stem Cells Translational Medicine 2018;7:709–720