Nuclear envelope wrinkling predicts mesenchymal progenitor cell mechano-response in 2D and 3D microenvironments

Cosgrove, Brian D.; Loebel, Claudia; Driscoll, Tristan P.; Tsinman, Tonia; Dai, Eric; Heo, Su‐Jin; Dyment, Nathaniel A.; Burdick, Jason A.; Mauck, Robert L.

doi:10.1016/j.biomaterials.2021.120662

Cited by 41 publications

(49 citation statements)

References 90 publications

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“…A proteomics study revealed that the expression of YAP is ∼two fold higher in slow-twitch muscle fibers than in fast-twitch muscle fibers from young subjects; in aged subjects, the YAP expression was ∼50% lower in both muscle fiber types compared to younger controls ( Murgia et al, 2017 ). However, YAP/TAZ signaling may be elevated in aged skeletal muscle and associated with changes in the nuclear lamina ( Iyer et al, 2021 ).Together, these results suggest that altered YAP expression and localization via changes in nuclear architecture ( Cosgrove et al, 2021 ) or nuclear mechanotransduction ( Driscoll et al, 2015 ) could play a role in muscle adaptation and age-dependent loss of skeletal muscle mass. Wnt/β-catenin signaling has been suggested to be involved in augmenting myofiber hypertrophy in response to increased mechanical load ( Armstrong and Esser, 2005 ; Armstrong et al, 2006 ) and may be modulated by nuclear access to β-catenin via the LINC complex ( Uzer et al, 2018 ).…”

Section: Potential Mechanisms For Nuclear Mechanotransduction In Regulating Muscle Mass and Functionmentioning

confidence: 94%

“…Collectively, NE stretch-dependent Ca 2+ release is emerging as a powerful intermediary between mechanical inputs and cellular responses. In addition to the effect on calcium release, the amount of NE folding or “wrinkling” is associated with the translocation of mechanosensitive transcription factors, including YAP/TAZ ( Cosgrove et al, 2021 ). One explanation for this altered transcription factor localization could be the accumulation of NPCs in NE invaginations, as has been shown in progeroid cells ( Goldman et al, 2004 ; Röhrl et al, 2021 ), leading to a physical barrier affecting NPC transport.…”

Section: Evidence For Nuclear Mechanotransduction In Non-skeletal Muscle Cellsmentioning

confidence: 99%

“…This can be accomplished by either performing assays on isolated nuclei ( Guilluy and Burridge, 2015 ; Stephens et al, 2019 ), or via the more biologically relevant technique of restricting mechanical signals from reaching the nucleus. In practice, this can be done by expressing dominant-negative nesprin or SUN constructs ( Lombardi et al, 2011 ; Uzer et al, 2018 ), which globally disrupt all LINC complexes, or via targeting of specific LINC complex or LINC-complex associated proteins ( Staszewska et al, 2015 ; Tajik et al, 2016 ; Cosgrove et al, 2021 ).…”

Section: Important Considerations and Future Directionsmentioning

confidence: 99%

“…Traditionally the cell nucleus has been viewed as a passive organelle, simply serving as a reservoir for DNA and requiring cytosolic events to dictate nuclear responses. However, recent evidence has emerged showing that the nucleus itself can act as a mechanosensitive element, directly translating mechanical forces into a cellular response ( Kirby and Lammerding, 2018 ; Aureille et al, 2019 ; Stephens et al, 2019 ) in a process termed “nuclear mechanotransduction.” The mechanisms by which nuclear mechanotransduction impacts cellular processes include nuclear envelope stretching ( Enyedi et al, 2016 ; Lomakin et al, 2020 ; Venturini et al, 2020 ), modification of nuclear envelope proteins ( Guilluy et al, 2014 ), histone modifications and chromatin architecture ( Le et al, 2016 ; Nava et al, 2020 ), transcription factor localization ( Elosegui-Artola et al, 2017 ; Cosgrove et al, 2021 ), and gene expression ( Tajik et al, 2016 ). Limited evidence exists for a putative role of nuclear mechanotransduction in regulating muscle homeostasis and adaptation ( Piccus and Brayson, 2020 ; Jabre et al, 2021 ), despite the clear link between mechanical loading and skeletal muscle mass.…”

Section: Introductionmentioning

confidence: 99%

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LINCing Nuclear Mechanobiology With Skeletal Muscle Mass and Function

Ingen

Kirby

2021

Front. Cell Dev. Biol.

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Skeletal muscle demonstrates a high degree of adaptability in response to changes in mechanical input. The phenotypic transformation in response to mechanical cues includes changes in muscle mass and force generating capabilities, yet the molecular pathways that govern skeletal muscle adaptation are still incompletely understood. While there is strong evidence that mechanotransduction pathways that stimulate protein synthesis play a key role in regulation of muscle mass, there are likely additional mechano-sensitive mechanisms important for controlling functional muscle adaptation. There is emerging evidence that the cell nucleus can directly respond to mechanical signals (i.e., nuclear mechanotransduction), providing a potential additional level of cellular regulation for controlling skeletal muscle mass. The importance of nuclear mechanotransduction in cellular function is evident by the various genetic diseases that arise from mutations in proteins crucial to the transmission of force between the cytoskeleton and the nucleus. Intriguingly, these diseases preferentially affect cardiac and skeletal muscle, suggesting that nuclear mechanotransduction is critically important for striated muscle homeostasis. Here we discuss our current understanding for how the nucleus acts as a mechanosensor, describe the main cytoskeletal and nuclear proteins involved in the process, and propose how similar mechanoresponsive mechanisms could occur in the unique cellular environment of a myofiber. In addition, we examine how nuclear mechanotransduction fits into our current framework for how mechanical stimuli regulates skeletal muscle mass.

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Section: Potential Mechanisms For Nuclear Mechanotransduction In Regulating Muscle Mass and Functionmentioning

confidence: 94%

Section: Evidence For Nuclear Mechanotransduction In Non-skeletal Muscle Cellsmentioning

confidence: 99%

Section: Important Considerations and Future Directionsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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LINCing Nuclear Mechanobiology With Skeletal Muscle Mass and Function

Ingen

Kirby

2021

Front. Cell Dev. Biol.

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“…Modulation of extracellular matrix (ECM) stiffness causes mechanical force effects on lamin A/C protein levels, lamin A/C structure, and nuclear lamina organization. Decreasing ECM stiffness decreases lamin A/C levels and causes relocalization of lamin A/C and lamin B into the interior of the nucleus [70] and causes the deformation and folding of lamin A/C [124,125]. In MSCs, ECM stiffness alters LBR:lamin A/C ratios.…”

Section: Nuclear Laminsmentioning

confidence: 99%

Nuclear envelope mechanobiology: linking the nuclear structure and function

Goelzer

Ferguson

et al. 2021

Nucleus

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The nucleus, central to cellular activity, relies on both direct mechanical input as well as its molecular transducers to sense external stimuli and respond by regulating intra-nuclear chromatin organization that determines cell function and fate. In mesenchymal stem cells of musculoskeletal tissues, changes in nuclear structures are emerging as a key modulator of their differentiation and proliferation programs. In this review we will first introduce the structural elements of the nucleoskeleton and discuss the current literature on how nuclear structure and signaling are altered in relation to environmental and tissue level mechanical cues. We will focus on state-ofthe-art techniques to apply mechanical force and methods to measure nuclear mechanics in conjunction with DNA, RNA, and protein visualization in living cells. Ultimately, combining realtime nuclear deformations and chromatin dynamics can be a powerful tool to study mechanisms of how forces affect the dynamics of genome function.

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Microtissue Geometry and Cell‐Generated Forces Drive Patterning of Liver Progenitor Cell Differentiation in 3D

Berg

Mohagheghian

Habing

et al. 2021

Adv Healthcare Materials

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3D microenvironments provide a unique opportunity to investigate the impact of intrinsic mechanical signaling on progenitor cell differentiation. Using a hydrogel‐based microwell platform, arrays of 3D, multicellular microtissues in constrained geometries, including toroids and cylinders are produced. These generated distinct mechanical profiles to investigate the impact of geometry and stress on early liver progenitor cell fate using a model liver development system. Image segmentation allows the tracking of individual cell fate and the characterization of distinct patterning of hepatocytic makers to the outer shell of the microtissues, and the exclusion from the inner diameter surface of the toroids. Biliary markers are distributed throughout the interior regions of micropatterned tissues and are increased in toroidal tissues when compared with those in cylindrical tissues. Finite element models of predicted stress distributions, combined with mechanical measurements, demonstrates that intercellular tension correlates with increased hepatocytic fate, while compression correlates with decreased hepatocytic and increased biliary fate. This system, which integrates microfabrication, imaging, mechanical modeling, and quantitative analysis, demonstrates how microtissue geometry can drive patterning of mechanical stresses that regulate cell differentiation trajectories. This approach may serve as a platform for further investigation of signaling mechanisms in the liver and other developmental systems.

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Nuclear envelope wrinkling predicts mesenchymal progenitor cell mechano-response in 2D and 3D microenvironments

Cited by 41 publications

References 90 publications

LINCing Nuclear Mechanobiology With Skeletal Muscle Mass and Function

LINCing Nuclear Mechanobiology With Skeletal Muscle Mass and Function

Nuclear envelope mechanobiology: linking the nuclear structure and function

Microtissue Geometry and Cell‐Generated Forces Drive Patterning of Liver Progenitor Cell Differentiation in 3D

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