Effect of matrix stiffness on the proliferation and differentiation of umbilical cord mesenchymal stem cells

Xu, Juanjuan; Sun, Miao; Tan, Yan; Wang, Haowei; Wang, Heping; Li, Pengdong; Xu, Ziran; Xia, Yuhan; Li, Lisha; Li, Yulin

doi:10.1016/j.diff.2017.07.001

Cited by 62 publications

(43 citation statements)

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“…MSC responses to variations in ECM stiffness have been studied previously in mice [ 8 , 34 ], rats [ 35 ], and humans [ 36 , 37 ]. The present study examined this phenomenon in hMSCs to provide an accurate theoretical basis for clinical treatment.…”

Section: Discussionmentioning

confidence: 99%

Extracellular matrix stiffness controls osteogenic differentiation of mesenchymal stem cells mediated by integrin α5

et al. 2018

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BackgroundHuman mesenchymal stem cell (hMSC) differentiation into osteoblasts has important clinical significance in treating bone injury, and the stiffness of the extracellular matrix (ECM) has been shown to be an important regulatory factor for hMSC differentiation. The aim of this study was to further delineate how matrix stiffness affects intracellular signaling through integrin α5/β1, FAK, and Wnt signaling, subsequently regulating the osteogenic phenotype of hMSCs.MethodshMSCs were cultured on tunable polyacrylamide hydrogels coated with fibronectin with stiffness corresponding to a Young’s modulus of 13–16 kPa and 62–68 kPa. After hMSCs were cultured on gels for 1 week, gene expression of alpha-1 type I collagen, BGLAP, and RUNX2 were evaluated by real-time PCR. After hMSCs were cultured on gels for 24 h, signaling molecules relating to integrin α5 (FAK, ERK, p-ERK, Akt, p-Akt, GSK-3β, p-GSK-3β, and β-catenin) were evaluated by western blot analysis.ResultsOsteogenic differentiation was increased on 62–68 kPa ECM, as evidenced by alpha-1 type I collagen, BGLAP, and RUNX2 gene expression, calcium deposition, and ALP staining. In the process of differentiation, gene and protein expression of integrin α5/β1 increased, together with protein expression of the downstream signaling molecules FAK, p-ERK, p-Akt, GSK-3β, p-GSK-3β, and β-catenin, indicating that these molecules can affect the osteogenic differentiation of hMSCs. An antibody blocking integrin α5 suppressed the stiffness-induced expression of all osteoblast markers examined. In particular, alpha-1 type I collagen, RUNX2, and BGLAP were significantly downregulated, indicating that integrin α5 regulates hMSC osteogenic differentiation. Downstream expression of FAK, ERK, p-ERK, and β-catenin protein was unchanged, whereas Akt, p-Akt, GSK-3β, and p-GSK-3β were upregulated. Moreover, expression of Akt and p-Akt was upregulated with anti-integrin α5 antibody, but no difference was observed for FAK, ERK, and p-ERK between the with or without anti-integrin α5 antibody groups. At the same time, expression of GSK-3β and p-GSK-3β was upregulated and β-catenin levels showed no difference between the groups with or without anti-integrin α5 antibody. Since Akt, p-Akt, GSK-3β, and p-GSK-3β displayed the same changes between the groups with or without anti-integrin α5 antibody, we then detected the links among them. Expression of p-Akt and p-GSK-3β was reduced effectively in the presence of the Akt inhibitor Triciribine. However, Akt, GSK-3β, and β-catenin were unchanged. These results suggested that expression of p-GSK-3β was regulated by p-Akt on 62–68 kPa ECM.ConclusionsTaken together, our results provide evidence that matrix stiffness (62–68 kPa) affects the osteogenic outcome of hMSCs through mechanotransduction events that are mediated by integrin α5.Electronic supplementary materialThe online version of this article (10.1186/s13287-018-0798-0) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Extracellular matrix stiffness controls osteogenic differentiation of mesenchymal stem cells mediated by integrin α5

et al. 2018

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“…21 Besides, substrate stiffness can regulate proliferation of cells. 22 We hypothesized that substrate mechanical properties would contribute to the proliferation and osteogenic/odontogenic differentiation of DPSCs.…”

Section: Discussionmentioning

confidence: 99%

“…Neuronal differentiation of MSCs took place after culturing on a relatively soft polyacrylamide hydrogel with stiffness of 0.1‐1 kPa, whereas mesenchymal stem cells (MSCs) show preference to osteogenic lineage with stiffness of 25‐40 kPa and muscle of 8‐17 kPa . Besides, substrate stiffness can regulate proliferation of cells . We hypothesized that substrate mechanical properties would contribute to the proliferation and osteogenic/odontogenic differentiation of DPSCs.…”

Section: Introductionmentioning

confidence: 99%

Stiffness regulates the proliferation and osteogenic/odontogenic differentiation of human dental pulp stem cells via the WNT signalling pathway

et al. 2018

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“…These cellular forces can alter the structure and mechanical properties of the ECM in the proximity of the cell (4). As such, cell-ECM mechanical interactions play important roles at the cellular level, such as in migration (5,6), proliferation (6)(7)(8), differentiation (5-7, 9, 10), cancer invasion (11)(12)(13) and mineral deposition (14).…”

Section: Introductionmentioning

confidence: 99%

Elastic Anisotropy Governs the Range of Cell-Induced Displacements

Goren

Koren

et al. 2020

Biophysical Journal

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SignificanceTissues are made up of cells and an extracellular matrix (ECM), a cross-linked network of stiff biopolymers. Cells actively alter the ECM structure and mechanics by applying contractile forces, which allow them to sense other distant cells and regulate many tissue functions. We study theoretically the decay of cell-induced displacements in fibrous networks, while quantifying the changes in the elastic properties of the cell's local environment. We demonstrate that cell contraction induce an anisotropic elastic state, i.e., unequal principal elastic moduli, in the ECM which dictates the slow decay of displacements. These observations suggest a new mechanical mechanism through which cells can mechanically communicate over long distances, and may provide biomaterials design parameters to guide morphogenesis in tissue engineering. AbstractThe unique nonlinear mechanics of the fibrous extracellular matrix (ECM) facilitates long-range cell-cell mechanical communications that would be impossible on linear elastic substrates. Past research has described the contribution of two separated effects on the range of force transmission, including ECM elastic non-linearity and fiber alignment. However, the relation between these different effects is unclear, and how they combine to dictate force transmission range is still elusive. Here, we combine discrete fiber simulations with continuum modeling to study the decay of displacements induced by a contractile cell in fibrous networks. We demonstrate that fiber non-linearity and fiber reorientation both contribute to the Page 2 of 32 strain-induced anisotropy of the elastic moduli of the cell's local environment. This elastic anisotropy is a "lumped" parameter that governs the slow decay of the displacements, and it depends on the magnitude of applied strain, either an external tension or an internal contraction as a model of the cell. Furthermore, we show that accounting for artificially-prescribed elastic anisotropy dictates the displacement decay induced by a contracting cell. Our findings unify previous single effects into a mechanical theory that explains force transmission in fibrous networks. This work provides important insights into biological processes that involve the coordinated action of distant cells mediated by the ECM, such that occur in morphogenesis, wound healing, angiogenesis, and cancer metastasis. It may also provide design parameters for biomaterials to control force transmission between cells, as a way to guide morphogenesis in tissue engineering.In addition, we find in Fig. 3C that the data points of 2 / 1 for all types of fibers can be approximately fitted by a master curve if plotted versus the normalized strain, / crit . Here crit is the critical strain, a characteristic parameter of the network, in which 2 / 1 becomes smaller than 0.9, and the strain-induced elastic anisotropy is significant. The normalized strain, / crit , similar to the normalized cell contraction, / crit in cell contraction networks, is another "emergent" dimensionless p...

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Effect of matrix stiffness on the proliferation and differentiation of umbilical cord mesenchymal stem cells

Cited by 62 publications

References 55 publications

Extracellular matrix stiffness controls osteogenic differentiation of mesenchymal stem cells mediated by integrin α5

Extracellular matrix stiffness controls osteogenic differentiation of mesenchymal stem cells mediated by integrin α5

Stiffness regulates the proliferation and osteogenic/odontogenic differentiation of human dental pulp stem cells via the WNT signalling pathway

Elastic Anisotropy Governs the Range of Cell-Induced Displacements

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