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Volume adaptation controls stem cell mechanotransduction

Recent studies have found discordant mechanosensitive outcomes when comparing 2D and 3D, highlighting the need for tools to study mechanotransduction in 3D across a wide spectrum of stiffness. A gelatin methacryloyl (GelMA) hydrogel with a continuous stiffness gradient ranging from 5 to 38 kPa was dev...

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Main Authors: Major, Luke G. (Author) , Holle, Andrew W. (Author) , Young, Jennifer (Author) , Hepburn, Matt S. (Author) , Jeong, Kwanghee (Author) , Chin, Ian L. (Author) , Sanderson, Rowan W. (Author) , Jeong, Ji Hoon (Author) , Aman, Zachary M. (Author) , Kennedy, Brendan F. (Author) , Hwang, Yongsung (Author) , Han, Dong-Wook (Author) , Park, Hyun Woo (Author) , Guan, Kun-Liang (Author) , Spatz, Joachim P. (Author) , Choi, Yu Suk (Author)
Format: Article (Journal)
Language:English
Published: November 12, 2019
In: ACS applied materials & interfaces
Year: 2019, Volume: 11, Issue: 49, Pages: 45520-45530
ISSN:1944-8252
DOI:10.1021/acsami.9b19770
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1021/acsami.9b19770
Verlag, lizenzpflichtig, Volltext: https://pubs.acs.org/doi/10.1021/acsami.9b19770
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Author Notes:Luke G. Major, Andrew W. Holle, Jennifer L. Young, Matt S. Hepburn, Kwanghee Jeong, Ian L. Chin, Rowan W. Sanderson, Ji Hoon Jeong, Zachary M. Aman, Brendan F. Kennedy, Yongsung Hwang, Dong-Wook Han, Hyun Woo Park, Kun-Liang Guan, Joachim P. Spatz, and Yu Suk Choi
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Summary:Recent studies have found discordant mechanosensitive outcomes when comparing 2D and 3D, highlighting the need for tools to study mechanotransduction in 3D across a wide spectrum of stiffness. A gelatin methacryloyl (GelMA) hydrogel with a continuous stiffness gradient ranging from 5 to 38 kPa was developed to recapitulate physiological stiffness conditions. Adipose-derived stem cells (ASCs) were encapsulated in this hydrogel, and their morphological characteristics and expression of both mechanosensitive proteins (Lamin A, YAP, and MRTFa) and differentiation markers (PPARγ and RUNX2) were analyzed. Low-stiffness regions (∼8 kPa) permitted increased cellular and nuclear volume and enhanced mechanosensitive protein localization in the nucleus. This trend was reversed in high stiffness regions (∼30 kPa), where decreased cellular and nuclear volumes and reduced mechanosensitive protein nuclear localization were observed. Interestingly, cells in soft regions exhibited enhanced osteogenic RUNX2 expression, while those in stiff regions upregulated the adipogenic regulator PPARγ, suggesting that volume, not substrate stiffness, is sufficient to drive 3D stem cell differentiation. Inhibition of myosin II (Blebbistatin) and ROCK (Y-27632), both key drivers of actomyosin contractility, resulted in reduced cell volume, especially in low-stiffness regions, causing a decorrelation between volume expansion and mechanosensitive protein localization. Constitutively active and inactive forms of the canonical downstream mechanotransduction effector TAZ were stably transfected into ASCs. Activated TAZ resulted in higher cellular volume despite increasing stiffness and a consistent, stiffness-independent translocation of YAP and MRTFa into the nucleus. Thus, volume adaptation as a function of 3D matrix stiffness can control stem cell mechanotransduction and differentiation.
Item Description:Gesehen am 16.04.2020
Physical Description:Online Resource
ISSN:1944-8252
DOI:10.1021/acsami.9b19770

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