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Differentiation alters stem cell nuclear architecture, mechanics, and mechano-sensitivity.

ABSTRACT: Mesenchymal stem cell (MSC) differentiation is mediated by soluble and physical cues. In this study, we investigated differentiation-induced transformations in MSC cellular and nuclear biophysical properties and queried their role in mechanosensation. Our data show that nuclei in differentiated bovine and human MSCs stiffen and become resistant to deformation. This attenuated nuclear deformation was governed by restructuring of Lamin A/C and increased heterochromatin content. This change in nuclear stiffness sensitized MSCs to mechanical-loading-induced calcium signaling and differentiated marker expression. This sensitization was reversed when the 'stiff' differentiated nucleus was softened and was enhanced when the 'soft' undifferentiated nucleus was stiffened through pharmacologic treatment. Interestingly, dynamic loading of undifferentiated MSCs, in the absence of soluble differentiation factors, stiffened and condensed the nucleus, and increased mechanosensitivity more rapidly than soluble factors. These data suggest that the nucleus acts as a mechanostat to modulate cellular mechanosensation during differentiation.

SUBMITTER: Heo SJ

PROVIDER: S-EPMC5148611 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Differentiation alters stem cell nuclear architecture, mechanics, and mechano-sensitivity.

Heo Su-Jin SJ Driscoll Tristan P TP Thorpe Stephen D SD Nerurkar Nandan L NL Baker Brendon M BM Yang Michael T MT Chen Christopher S CS Lee David A DA Mauck Robert L RL

eLife 20161130

Mesenchymal stem cell (MSC) differentiation is mediated by soluble and physical cues. In this study, we investigated differentiation-induced transformations in MSC cellular and nuclear biophysical properties and queried their role in mechanosensation. Our data show that nuclei in differentiated bovine and human MSCs stiffen and become resistant to deformation. This attenuated nuclear deformation was governed by restructuring of Lamin A/C and increased heterochromatin content. This change in nucl ...[more]

PMID: 27901466

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Project description:Potential epigenetic mechanisms underlying fetal alcohol syndrome (FAS) include alcohol-induced alterations of methyl metabolism, resulting in aberrant patterns of DNA methylation and gene expression during development. Having previously demonstrated an essential role for epigenetics in neural stem cell (NSC) development and that inhibiting DNA methylation prevents NSC differentiation, here we investigated the effect of alcohol exposure on genome-wide DNA methylation patterns and NSC differentiation.Neural stem cells in culture were treated with or without a 6-hour 88 mM ("binge-like") alcohol exposure and examined at 48 hours, for migration, growth, and genome-wide DNA methylation. The DNA methylation was examined using DNA-methylation immunoprecipitation followed by microarray analysis. Further validation was performed using Independent Sequenom analysis.? Neural stem cell differentiated in 24 to 48 hours with migration, neuronal expression, and morphological transformation. Alcohol exposure retarded the migration, neuronal formation, and growth processes of NSC, similar to treatment with the methylation inhibitor 5-aza-cytidine. When NSC departed from the quiescent state, a genome-wide diversification of DNA methylation was observed-that is, many moderately methylated genes altered methylation levels and became hyper- and hypomethylated. Alcohol prevented many genes from such diversification, including genes related to neural development, neuronal receptors, and olfaction, while retarding differentiation. Validation of specific genes by Sequenom analysis demonstrated that alcohol exposure prevented methylation of specific genes associated with neural development [cut-like 2 (cutl2), insulin-like growth factor 1 (Igf1), epidermal growth factor-containing fibulin-like extracellular matrix protein 1 (Efemp1), and SRY-box-containing gene 7 (Sox 7)]; eye development, lens intrinsic membrane protein 2 (Lim 2); the epigenetic mark Smarca2 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 2); and developmental disorder [DiGeorge syndrome critical region gene 2 (Dgcr2)]. Specific sites altered by DNA methylation also correlated with transcription factor binding sites known to be critical for regulating neural development.The data indicate that alcohol prevents normal DNA methylation programming of key neural stem cell genes and retards NSC differentiation. Thus, the role of DNA methylation in FAS warrants further investigation.

Dataset Information

Differentiation alters stem cell nuclear architecture, mechanics, and mechano-sensitivity.

Publications

Differentiation alters stem cell nuclear architecture, mechanics, and mechano-sensitivity.

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