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Identification of Small Molecules Which Induce Skeletal Muscle Differentiation in Embryonic Stem Cells via Activation of the Wnt and Inhibition of Smad2/3 and Sonic Hedgehog Pathways

Lee, Hyunwoo and Haller, Corinne and Doll, Thierry and Fruh, Isabelle and Gubser Keller, Caroline and Richards, Shola and Ibig-Rehm, Yvonne and Patoor, Maude and Goette, Marjo and Bouchez, Laure and Mueller, Matthias (2015) Identification of Small Molecules Which Induce Skeletal Muscle Differentiation in Embryonic Stem Cells via Activation of the Wnt and Inhibition of Smad2/3 and Sonic Hedgehog Pathways. Stem Cells, 34 (2). pp. 299-310. ISSN 10665099

Abstract

The multi-lineage differentiation capacity of mouse and human embryonic stem (ES) cells offers a testing platform for small molecules that mediate mammalian lineage determination and cellular specialization. Here we report the identification of a small molecule which drives mouse ES cell differentiation to skeletal muscle with high efficiency without any genetic modification. Mouse embryoid bodies (EBs) were used to screen a library of 1,000 small molecules to identify compounds capable of inducing high levels of Pax3 mRNA. Stimulation of EBs with SMIs (Skeletal Muscle Inducer, SMI1 and SMI2) from the screen resulted in a high percentage of intensively twitching skeletal muscle fibers three weeks after induction. Gene expression profiling studies that were carried out for Mode of Actions (MoA) analysis showed that SMIs activated genes regulated by the Wnt pathway, and inhibited expression of Smad2/3 and Sonic Hedgehog target genes. A combination of three small molecules known to modulate these three pathways acted similarly to the SMIs found here, driving ES cells to skeletal muscle. Taken together, these data demonstrate that the SMI drives ES cells to skeletal muscle via concerted activation of the Wnt pathway, and inhibition of Smad2/3 signaling and Sonic Hedgehog (Shh) pathways. This provides important developmental biological information about skeletal muscle differentiation from embryonic stem cells and may lead to the development of new therapeutics for muscle disease.

Item Type: Article
Date Deposited: 18 May 2016 23:45
Last Modified: 04 Jul 2016 23:45
URI: https://oak.novartis.com/id/eprint/23560

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