TY - JOUR
T1 - Screening identifies small molecules that enhance the maturation of human pluripotent stem cell-derived myotubes
AU - Selvaraj, Sridhar
AU - Mondragon-Gonzalez, Ricardo
AU - Xu, Bin
AU - Magli, Alessandro
AU - Kim, Hyunkee
AU - Lainé, Jeanne
AU - Kiley, James
AU - McKee, Holly
AU - Rinaldi, Fabrizio
AU - Aho, Joy
AU - Tabti, Nacira
AU - Shen, Wei
AU - Perlingeiro, Rita Cr
N1 - Publisher Copyright:
© 2019, eLife Sciences Publications Ltd. All rights reserved.
PY - 2019/11
Y1 - 2019/11
N2 - Targeted differentiation of pluripotent stem (PS) cells into myotubes enables in vitro disease modeling of skeletal muscle diseases. Although various protocols achieve myogenic differentiation in vitro, resulting myotubes typically display an embryonic identity. This is a major hurdle for accurately recapitulating disease phenotypes in vitro, as disease commonly manifests at later stages of development. To address this problem, we identified four factors from a small molecule screen whose combinatorial treatment resulted in myotubes with enhanced maturation, as shown by the expression profile of myosin heavy chain isoforms, as well as the upregulation of genes related with muscle contractile function. These molecular changes were confirmed by global chromatin accessibility and transcriptome studies. Importantly, we also observed this maturation in three-dimensional muscle constructs, which displayed improved in vitro contractile force generation in response to electrical stimulus. Thus, we established a model for in vitro muscle maturation from PS cells.
AB - Targeted differentiation of pluripotent stem (PS) cells into myotubes enables in vitro disease modeling of skeletal muscle diseases. Although various protocols achieve myogenic differentiation in vitro, resulting myotubes typically display an embryonic identity. This is a major hurdle for accurately recapitulating disease phenotypes in vitro, as disease commonly manifests at later stages of development. To address this problem, we identified four factors from a small molecule screen whose combinatorial treatment resulted in myotubes with enhanced maturation, as shown by the expression profile of myosin heavy chain isoforms, as well as the upregulation of genes related with muscle contractile function. These molecular changes were confirmed by global chromatin accessibility and transcriptome studies. Importantly, we also observed this maturation in three-dimensional muscle constructs, which displayed improved in vitro contractile force generation in response to electrical stimulus. Thus, we established a model for in vitro muscle maturation from PS cells.
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U2 - 10.7554/eLife.47970
DO - 10.7554/eLife.47970
M3 - Article
C2 - 31710288
AN - SCOPUS:85074742340
SN - 2050-084X
VL - 8
JO - eLife
JF - eLife
M1 - e47970
ER -