The porcupine inhibitor WNT974 provokes ectodermal lineage differentiation of human embryonic stem cells

• DOI: 10.1002/cbf.3700
• Publication Date: 2022-04-21T08:45:31Z
• Authors: Ashkan Kalantary‐...; Vahid Hosseini; Amir Mehdizadeh; Saeed Nazari Solt...; Reza Rahbarghazi; Hojjatollah Nozad...; Mohammad Nouri; Masoud Darabi
• Keywords: 0301 basic medicine; 03 medical and health sciences; Pyridines; Pyrazines; Human Embryonic Stem Cells; Humans; Membrane Proteins; Wnt Signaling Pathway; Acyltransferases; Stearoyl-CoA Desaturase

Abstract Porcupine (Porcn) enzyme plays an essential role in Wnt signaling activation. Stearoyl‐CoA desaturase‐1 (SCD1) is required to provide Porcn substrates. The aim of this study was determine the effect a novel inhibitor on fate human embryonic stem cells (hESCs) and reliance SCD1 activity. hESCs were cultured feeder layer or Matrigel‐coated plates. Small molecules WNT974 (LGK‐974) CAY10566 used inhibit activity, respectively. We assessed inhibition viability, expression targets, pluripotency markers, proliferation, differentiation, protein fatty acylation. hESCs' conditioned medium (CM) containing secreted proteins applied rescue experiments. To examine catalytic dependency SCD1, results combined treatment compared with alone. LGK‐974 at selected concentrations showed mild effects but significantly reduced messenger RNA targets (Axin‐2 c‐Myc) markers (OCT‐4 SOX‐2) ( p < .05). Adding 1 μM proliferation = .03) enhanced differentiation capacity into ectodermal progenitors .02), which reverted by CM. Click chemistry reaction did not show significant alteration acylation upon treatment. Moreover, caused no further substantial reduction relative CAY10566‐treated cultures. substrate availability for activity regulated targeting prompts transition from self‐renewal state lineage.