Temporal mechanisms of myogenic specification in human induced pluripotent stem cells

Abstract

Understanding the mechanisms of myogenesis in human induced pluripotent stem cells (hiPSCs) is a prerequisite to achieving patient-specific therapy for diseases of skeletal muscle. hiPSCs of different origin show distinctive kinetics and ability to differentiate into myocytes. To address the unique cellular and temporal context of hiPSC differentiation, we perform a longitudinal comparison of the transcriptomic profiles of three hiPSC lines that display differential myogenic specification, one robust and two blunted. We detail temporal differences in mechanisms that lead to robust myogenic specification. We show gene expression signatures of putative cell subpopulations and extracellular matrix components that may support myogenesis. Furthermore, we show that targeted knockdown of ZIC3 at the outset of differentiation leads to improved myogenic specification in blunted hiPSC lines. Our study suggests that β-catenin transcriptional cofactors mediate cross-talk between multiple cellular processes and exogenous cues to facilitate specification of hiPSCs to mesoderm lineage, leading to robust myogenesis.

Molecular Characterization Reveals Subclasses of 1q Gain in Intermediate Risk Wilms Tumors

“…This association between CTNNB1/WT1 mutations and muscle differentiation has been observed previously and suggested to be induced by chemotherapy or reflect developmental arrest in the mesenchymal stem cell-like precursor lineage [48,49]. Notably, the transcription factor MYOG located on 1q can induce terminal differentiation upon overexpression [50] and is highly expressed in both the 1q+ and CTNNB1/WT1-mutated tumors of cluster EX1. Taken together, we found that a subset of 1q+ tumors cluster together in EX1 with CTNNB1/WT1-mutated tumors based on gene expression patterns, which could indicate that they also have a similar cell of origin or susceptibility to chemotherapy.…”

Molecular characterization reveals subclasses of 1q gain in intermediate-risk Wilms tumors

“…This association between CTNNB1/WT1 mutations and muscle differentiation has been observed previously and suggested to be induced by chemotherapy or reflect developmental arrest in the mesenchymal stem cell-like precursor lineage 19,20 . Notably, the transcription factor MYOG located on 1q can induce terminal differentiation upon overexpression 21 and is highly expressed in both the 1q+ and CTNNB1/WT1 -mutated tumors of cluster EX1. Our results show that the 1q+ tumors of EX1 resemble the expression profile of CTNNB1/WT1 -mutated tumors, which could indicate that they also have a similar cell of origin or susceptibility to chemotherapy.…”

“…Notably, the transcription factor MYOG located on 1q can induce terminal differentiation upon overexpression 21 and is highly expressed in both the 1q+ and CTNNB1/WT1-mutated tumors of cluster EX1. Our results show that the 1q+ tumors of EX1 resemble the expression profile of CTNNB1/WT1-mutated tumors, which could indicate that they also have a similar cell of origin or susceptibility to chemotherapy.…”

Neuromuscular Development and Disease: Learning From in vitro and in vivo Models

“…Recent transcriptomic analyses have shown that hiPSC-derived myogenic progenitors are developmentally immature and arrested between embryonic and fetal muscle stem cell stages ( Xi et al, 2020 ; Nayak et al, 2021 ). Nevertheless, they can successfully fuse into myotubes that exhibit key functional behaviors of SkM, including generation of calcium transients and contractile force and robust response to acetylcholine ( Skoglund et al, 2014 ; Rao et al, 2018 ), albeit at lower levels compared to primary human myotubes ( Rao et al, 2018 ).…”