Substratum stiffness regulates Erk signaling dynamics through receptor-level control

Farahani, Payam E; Lemke, Sandra B.; Dine, Elliot; Uribe, Giselle; Toettcher, Jared E.; Nelson, Celeste M.

doi:10.1016/j.celrep.2021.110181

Cited by 39 publications

(62 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Earlier studies have shown that ERK/MAPK signalling plays a key role in regulation of mesenchymal stem cell differentiation (50). It is now known that stiff substrate promotes osteogenesis by activating ERK signalling pathway while soft substrate downregulates activated ERK Signalling pathway and promotes adipogenesis (51). Hence, we Investigated if VA overwrites the effect of substrate stiffness on osteo/adipo lineage specification via regulating ERK.…”

Section: Resultsmentioning

confidence: 99%

Histone deacetylase inhibitor overrides the effect of soft hydrogel on the mechanoresponse of human mesenchymal stem cells

Joshi¹,

Murlidharan²,

Yadav³

et al. 2022

Preprint

View full text Add to dashboard Cite

Human Mesenchymal cells (hMSCs) are promising in regenerative medicine for their multi-lineage differentiation capability. It has been demonstrated that lineage specification is governed by both chemical and mechanical cues. Among all the different mechanical cues known to control hMSCs fate, substrate stiffness is the most well-studied. It has been shown that the naive mesenchymal stem cells when cultured on soft gel, they commit towards adipogenic lineage while when cultured on stiff gel they become osteogenic. Soft substrates also cause less cell spreading, less traction, less focal adhesion assembly and stress fibre formation. Furthermore, chromatin condensation increases when cells are cultured on soft substrates. As the nucleus has been postulated to be mechanosensor and mechanotransducer, in this paper we asked the question how mechanosensing and mechanoresponse process will be influenced if we change the chromatin condensation by using an external chemical stimulus. To address this question, we treated hMSCs cultured on soft polyacrylamide (PA) gels with a histone deacetylase inhibitor (HDACi) called Valproic Acid (VA) which decondense the chromatin by hyperacetylation of histone proteins. We found that the treatment with VA overrides the effect of soft substrates on hMSCs morphology, cellular traction, nuclear localization of mechnosensory protein YAP, and differentiation. VA treated cells behaved as if they are on stiff substrates in all aspects tested here. Furthermore, we have shown that VA controls hMSCs differentiation via activation of ERK/MAPK pathway by increasing the p-ERK expression which inhibits adipogenic differentiation potential of mesenchymal stem cells. Collectively, these findings for the first time demonstrate that inhibiting histone acetylation can override the mechanoresponse of hMSCs. This work will help us to fundamentally understand the mechanosignalling process and to control the hMSCs differentiation in tissue engineering and regenerative medicine.

show abstract

Section: Resultsmentioning

confidence: 99%

Histone deacetylase inhibitor overrides the effect of soft hydrogel on the mechanoresponse of human mesenchymal stem cells

Joshi¹,

Murlidharan²,

Yadav³

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Additionally, despite a difference in stiffness, both 2D and 3D culture environments led to significant sarcomere disassembly in caBraf-expressing CMs. While the relatively soft ECTs could attenuate endogenous ERK signaling at the level of membrane receptors 74 , the constitutively active BRAF-driven intracellular signaling transmission and ERK activation were likely stiffness- and environment-independent. Sarcomere disassembly was also observed in mouse hearts in vivo upon transient activation of caERBB2 and ERK in CMs 21, 56 ; however, this phenotype was associated with CM hypertrophy as well as AKT co-activation, which was absent in caBRAF ECTs (Fig.…”

Section: Discussionmentioning

confidence: 99%

BRAF-V600E-Mediated Erk Activation Promotes Sustained Cell Cycling and Broad Transcriptional Changes in Neonatal Cardiomyocytes

Strash

DeLuca

Carattini

et al. 2022

Preprint

View full text Add to dashboard Cite

Mitogens capable of promoting cardiomyocyte proliferation represent important targets for functional heart regeneration following myocardial infarction. We previously described an ERK-dependent pro-proliferative tissue phenotype following overexpression of constitutively-active (ca) human ERBB2 in both neonatal rat ventricular myocytes (NRVMs) and human iPSC-derived cardiomyocytes (hiPSC-CMs). Since ERBB2 canonically regulates multiple other pathways in addition to ERK, it is unclear whether ERK activation alone can drive CM proliferation. Here, we activated ERK in a targeted fashion by CM-specific lentiviral expression of a constitutively active mutant of BRAF, BRAF-V600E (caBRAF), in cultured NRVMs and examined the effects on engineered NRVM tissue proliferation, morphology, and function. caBRAF expression induced ERK activation, tissue growth, loss of contractile function, and increased tissue stiffness, all of which were sustained for at least 4 weeks in vitro. From bulk RNA-sequencing analysis of engineered tissues, we found that caBRAF had broad transcriptomic effects on CMs and induced a shift to glycolytic metabolism. Together, this work shows that direct ERK activation is sufficient to modulate CM cycling and functional maturation in a cell-autonomous fashion and could offer a potential target for cardiac regenerative therapies.

show abstract

“…ERK may also respond to pressure and/or curvature, as reported for the lung epithelium Hirashima and Matsuda (2021) . In epithelial cells from the mammary gland, ERK activity has been found sensitive to the stiffness of the surrounding matrix Farahani et al (2021) . Whether any of this plays a role in the tracheal mesenchyme is not known.…”

Section: Control Of Cartilage Ring Formationmentioning

confidence: 99%

Tracheal Ring Formation

Iber

Mederacke

2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

The trachea is a long tube that enables air passage between the larynx and the bronchi. C-shaped cartilage rings on the ventral side stabilise the structure. On its esophagus-facing dorsal side, deformable smooth muscle facilitates the passage of food in the esophagus. While the symmetry break along the dorsal-ventral axis is well understood, the molecular mechanism that results in the periodic Sox9 expression pattern that translates into the cartilage rings has remained elusive. Here, we review the molecular regulatory interactions that have been elucidated, and discuss possible patterning mechanisms. Understanding the principles of self-organisation is important, both to define biomedical interventions and to enable tissue engineering.

show abstract

Substratum stiffness regulates Erk signaling dynamics through receptor-level control

Cited by 39 publications

References 61 publications

Histone deacetylase inhibitor overrides the effect of soft hydrogel on the mechanoresponse of human mesenchymal stem cells

Histone deacetylase inhibitor overrides the effect of soft hydrogel on the mechanoresponse of human mesenchymal stem cells

BRAF-V600E-Mediated Erk Activation Promotes Sustained Cell Cycling and Broad Transcriptional Changes in Neonatal Cardiomyocytes

Tracheal Ring Formation

Contact Info

Product

Resources

About