Identification of the mechanisms by which age alters the mechanosensitivity of mesenchymal stromal cells on substrates of differing stiffness: Implications for osteogenesis and angiogenesis

Barreto, Sara; González-Vázquez, Arlyng; Cameron, Andrew R.; Cavanagh, Brenton; Murray, Dylan J.; O’Brien, Fergal J.

doi:10.1016/j.actbio.2017.02.031

Cited by 37 publications

(44 citation statements)

References 46 publications

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“…In our study, we observe stiffness-induced expression of JNK3 and WNT2 as well as activation of the WIF1, the inhibitor of the canonical pathway in cells from fused sutures. This suggests not only that WNT2 may be act in these cells through the non-canonical WNT pathway but also that accelerated osteogenesis is dependent on the activation of a mechano-regulated pathway through the activation of JNK3, which has been previously associated to stiffness activated osteoinduction in children-derived MSCs 53 . Consequently, we demonstrated that the accelerated bone formation in cells from fused sutures associated with craniosynostosis is linked with the stiffness-dependent activation of the MAPK-associated non-canonical WNT pathway through activation of JNK3 and WNT2.…”

Section: Discussionmentioning

confidence: 84%

Identification of stiffness-induced signalling mechanisms in cells from patent and fused sutures associated with craniosynostosis

Barreto

González-Vázquez

Cameron

et al. 2017

Sci Rep

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Craniosynostosis is a bone developmental disease where premature ossification of the cranial sutures occurs leading to fused sutures. While biomechanical forces have been implicated in craniosynostosis, evidence of the effect of microenvironmental stiffness changes in the osteogenic commitment of cells from the sutures is lacking. Our aim was to identify the differential genetic expression and osteogenic capability between cells from patent and fused sutures of children with craniosynostosis and whether these differences are driven by changes in the stiffness of the microenvironment. Cells from both sutures demonstrated enhanced mineralisation with increasing substrate stiffness showing that stiffness is a stimulus capable of triggering the accelerated osteogenic commitment of the cells from patent to fused stages. The differences in the mechanoresponse of these cells were further investigated with a PCR array showing stiffness-dependent upregulation of genes mediating growth and bone development (TSHZ2, IGF1), involved in the breakdown of extracellular matrix (MMP9), mediating the activation of inflammation (IL1β) and controlling osteogenic differentiation (WIF1, BMP6, NOX1) in cells from fused sutures. In summary, this study indicates that stiffer substrates lead to greater osteogenic commitment and accelerated bone formation, suggesting that stiffening of the extracellular environment may trigger the premature ossification of the sutures.

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Section: Discussionmentioning

confidence: 84%

Identification of stiffness-induced signalling mechanisms in cells from patent and fused sutures associated with craniosynostosis

Barreto

González-Vázquez

Cameron

et al. 2017

Sci Rep

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“…Human bone marrows donated by adults between 20–30 years of age were purchased from Lonza Biologics PLC from which mesenchymal stromal cells were isolated and characterized as described previously. [ 52 ] MSCs were expanded in standard expansion media comprised of low glucose Dulbecco's Modified Eagle Medium (DMEM), supplemented with 10% fetal bovine serum and 1% penicillin/streptomycin.…”

Section: Methodsmentioning

confidence: 99%

Activation of the SOX‐5, SOX‐6, and SOX‐9 Trio of Transcription Factors Using a Gene‐Activated Scaffold Stimulates Mesenchymal Stromal Cell Chondrogenesis and Inhibits Endochondral Ossification

Raftery

González-Vázquez

Chen

et al. 2020

Adv Healthcare Materials

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Current treatments for articular cartilage defects relieve symptoms but often only delay cartilage degeneration. Mesenchymal stem cells (MSCs) have shown chondrogenic potential but tend to undergo endochondral ossification when implanted in vivo. Harnessing factors governing joint development to functionalize biomaterial scaffolds, termed developmental engineering, might allow to prime host MSCs to regenerate mature articular cartilage in situ without requiring cell isolation or ex vivo expansion. Therefore, the aim of this study is to develop a gene-activated scaffold capable of delivering developmental cues to host MSCs, thus priming MSCs for articular cartilage differentiation and inhibiting endochondral ossification. It is shown that delivery of the SOX-Trio induced MSCs to over-express COL2A1 and ACAN and deposit a sulfated and collagen type II rich extracellular matrix while hypertrophic gene expression and collagen type X deposition is inhibited. When cell-free SOX-Trio-activated scaffolds are implanted ectopically in vivo, they induced spontaneous chondrogenesis without evidence of hypertrophy. MSCs pre-cultured on SOX-Trio-activated scaffolds prior to implantation differentiate into phenotypically stable chondrocytes as evidenced by a lack of collagen X expression or vascular invasion. This SOX-trio-activated scaffold represents a potent, single treatment, developmentally inspired strategy to prime MSCs in situ for articular cartilage defect repair.

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“…hMSCs were isolated from bone marrow aspirates obtained from the iliac crest of normal human donors 20–30 years old (Lonza Biologics PLC) according to a previously established protocol (Barreto et al, ). Human umbilical vein endothelial cells (HUVECs) were commercially acquired (pooled, CC‐2519; Lonza Switzerland).…”

Section: Methodsmentioning

confidence: 99%

Platelet‐derived growth factor stabilises vascularisation in collagen‐glycosaminoglycan scaffolds in vitro

Amaral

Cavanagh

O’Brien

et al. 2018

J Tissue Eng Regen Med

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Collagen-glycosaminoglycan (CG) scaffolds have been widely developed for a range of regenerative medicine applications. To enhance their efficacy, CG scaffolds have previously been prevascularised in vitro using human umbilical vein endothelial cells and human mesenchymal stromal cells (hMSCs); however, at later timepoints, a regression of vascularisation is observed. This is undesirable for longer preculture periods (e.g., for partial/full organ regeneration) and for in vitro vascularised tissue model systems (e.g., for drug testing/modelling). We hypothesised that delayed platelet-derived growth factor (PDGF)-BB addition could stabilise vessels, preventing their regression. In 2D, we identified 25 ng/ml as a suitable dose that enhanced hMSC metabolic activity and proliferation, without affecting endothelial cells, or migration in either cell type. In our 3D model of CG scaffold vascularisation, early addition of

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Identification of the mechanisms by which age alters the mechanosensitivity of mesenchymal stromal cells on substrates of differing stiffness: Implications for osteogenesis and angiogenesis

Cited by 37 publications

References 46 publications

Identification of stiffness-induced signalling mechanisms in cells from patent and fused sutures associated with craniosynostosis

Identification of stiffness-induced signalling mechanisms in cells from patent and fused sutures associated with craniosynostosis

Activation of the SOX‐5, SOX‐6, and SOX‐9 Trio of Transcription Factors Using a Gene‐Activated Scaffold Stimulates Mesenchymal Stromal Cell Chondrogenesis and Inhibits Endochondral Ossification

Platelet‐derived growth factor stabilises vascularisation in collagen‐glycosaminoglycan scaffolds in vitro

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