Mechanotransduction is a context-dependent activator of TGF-β signaling in mesenchymal stem cells

Steven Vermeulen; Nadia Roumans; Floris Honig; Aurélie Carlier; Dennie G.A.J. Hebels; Aysegul Dede Eren; Peter ten Dijke; Aliaksei Vasilevich; Jan de Boer

doi:10.1016/j.biomaterials.2020.120331

Mechanotransduction is a context-dependent activator of TGF-β signaling in mesenchymal stem cells

Steven Vermeulen, Nadia Roumans, Floris Honig, Aurélie Carlier, Dennie G.A.J. Hebels, Aysegul Dede Eren, Peter ten Dijke, Aliaksei Vasilevich, Jan de Boer (Corresponding author)

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Abstract

We previously found that surface topographies induce the expression of the Scxa gene, encoding Scleraxis in tenocytes. Because Scxa is a TGF-β responsive gene, we investigated the link between mechanotransduction and TGF-β signaling. We discovered that mesenchymal stem cells exposed to both micro-topographies and TGF-β2 display synergistic induction of SMAD phosphorylation and transcription of the TGF-β target genes SCX, a-SMA, and SOX9. Pharmacological perturbations revealed that Rho/ROCK/SRF signaling is required for this synergistic response. We further found an activation of the early response genes SRF and EGR1 during the early adaptation phase on micro-topographies, which coincided with higher expression of the TGF-β type-II receptor gene. Of interest, PKC activators Prostratin and Ingenol-3, known for inducing actin reorganization and activation of serum response elements, were able to mimic the topography-induced TGF-β response. These findings provide novel insights into the convergence of mechanobiology and TGF-β signaling, which can lead to improved culture protocols and therapeutic applications.

Original language	English
Article number	120331
Number of pages	14
Journal	Biomaterials
Volume	259
DOIs	https://doi.org/10.1016/j.biomaterials.2020.120331
Publication status	Published - Nov 2020

Funding

SV, NR, FH, DH, AD, AC, and JdB acknowledge the financial support of the Dutch province of Limburg. This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 676338 . PtD is supported by the Cancer Genomics Center Netherlands (CGC.NL). AC gratefully acknowledges her VENI grant (number 15057 ) from the Dutch Science Foundation ( NWO ). We thank Freek Bouwman, Edwin Mariman, and Midory Thorikay for expert technical assistance.

Funders	Funder number
Oncode Institute	15057
Marie Skłodowska‐Curie
European Union's Horizon 2020 - Research and Innovation Framework Programme	676338
Nederlandse Organisatie voor Wetenschappelijk Onderzoek

Keywords

Actin dynamics
Biomaterials
Mechanobiology
Mesenchymal stem cells
Scleraxis
TGF-β

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10.1016/j.biomaterials.2020.120331

1-s2.0-S0142961220305779-mainFinal published version, 9.26 MBLicence: TAVERNE

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title = "Mechanotransduction is a context-dependent activator of TGF-β signaling in mesenchymal stem cells",

abstract = "We previously found that surface topographies induce the expression of the Scxa gene, encoding Scleraxis in tenocytes. Because Scxa is a TGF-β responsive gene, we investigated the link between mechanotransduction and TGF-β signaling. We discovered that mesenchymal stem cells exposed to both micro-topographies and TGF-β2 display synergistic induction of SMAD phosphorylation and transcription of the TGF-β target genes SCX, a-SMA, and SOX9. Pharmacological perturbations revealed that Rho/ROCK/SRF signaling is required for this synergistic response. We further found an activation of the early response genes SRF and EGR1 during the early adaptation phase on micro-topographies, which coincided with higher expression of the TGF-β type-II receptor gene. Of interest, PKC activators Prostratin and Ingenol-3, known for inducing actin reorganization and activation of serum response elements, were able to mimic the topography-induced TGF-β response. These findings provide novel insights into the convergence of mechanobiology and TGF-β signaling, which can lead to improved culture protocols and therapeutic applications.",

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author = "Steven Vermeulen and Nadia Roumans and Floris Honig and Aur{\'e}lie Carlier and Hebels, \{Dennie G.A.J.\} and Eren, \{Aysegul Dede\} and \{ten Dijke\}, Peter and Aliaksei Vasilevich and \{de Boer\}, Jan",

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doi = "10.1016/j.biomaterials.2020.120331",

language = "English",

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AU - Honig, Floris

AU - Carlier, Aurélie

AU - Hebels, Dennie G.A.J.

AU - Eren, Aysegul Dede

AU - ten Dijke, Peter

AU - Vasilevich, Aliaksei

AU - de Boer, Jan

PY - 2020/11

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N2 - We previously found that surface topographies induce the expression of the Scxa gene, encoding Scleraxis in tenocytes. Because Scxa is a TGF-β responsive gene, we investigated the link between mechanotransduction and TGF-β signaling. We discovered that mesenchymal stem cells exposed to both micro-topographies and TGF-β2 display synergistic induction of SMAD phosphorylation and transcription of the TGF-β target genes SCX, a-SMA, and SOX9. Pharmacological perturbations revealed that Rho/ROCK/SRF signaling is required for this synergistic response. We further found an activation of the early response genes SRF and EGR1 during the early adaptation phase on micro-topographies, which coincided with higher expression of the TGF-β type-II receptor gene. Of interest, PKC activators Prostratin and Ingenol-3, known for inducing actin reorganization and activation of serum response elements, were able to mimic the topography-induced TGF-β response. These findings provide novel insights into the convergence of mechanobiology and TGF-β signaling, which can lead to improved culture protocols and therapeutic applications.

AB - We previously found that surface topographies induce the expression of the Scxa gene, encoding Scleraxis in tenocytes. Because Scxa is a TGF-β responsive gene, we investigated the link between mechanotransduction and TGF-β signaling. We discovered that mesenchymal stem cells exposed to both micro-topographies and TGF-β2 display synergistic induction of SMAD phosphorylation and transcription of the TGF-β target genes SCX, a-SMA, and SOX9. Pharmacological perturbations revealed that Rho/ROCK/SRF signaling is required for this synergistic response. We further found an activation of the early response genes SRF and EGR1 during the early adaptation phase on micro-topographies, which coincided with higher expression of the TGF-β type-II receptor gene. Of interest, PKC activators Prostratin and Ingenol-3, known for inducing actin reorganization and activation of serum response elements, were able to mimic the topography-induced TGF-β response. These findings provide novel insights into the convergence of mechanobiology and TGF-β signaling, which can lead to improved culture protocols and therapeutic applications.

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KW - Scleraxis

KW - TGF-β

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Mechanotransduction is a context-dependent activator of TGF-β signaling in mesenchymal stem cells

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