Stiffness of Nanoparticulate Mineralized Collagen Scaffolds Triggers Osteogenesis via Mechanotransduction and Canonical Wnt Signaling

Zhou, Qi; Lyu, Shengyu; Bertrand, Anthony A.; Hu, Allison C.; Chan, Candace H.; Ren, Xiaoyan; Dewey, Maynard M.; Tiffany, Aleczandria S.; Harley, Brendan A.C.; Lee, Justine C.

doi:10.1002/mabi.202000370

Cited by 34 publications

(31 citation statements)

References 33 publications

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“…Cultured human MSCs on crosslinked substrates showed higher expression of osteogenic genes and proteins compared to non-crosslinked versions. This was maintained via the mechanotransduction mediators YAP/TAZ and the Wnt signaling pathway [149].…”

Section: Collagenmentioning

confidence: 99%

Effect of Polymeric Matrix Stiffness on Osteogenic Differentiation of Mesenchymal Stem/Progenitor Cells: Concise Review

et al. 2021

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Mesenchymal stem/progenitor cells (MSCs) have a multi-differentiation potential into specialized cell types, with remarkable regenerative and therapeutic results. Several factors could trigger the differentiation of MSCs into specific lineages, among them the biophysical and chemical characteristics of the extracellular matrix (ECM), including its stiffness, composition, topography, and mechanical properties. MSCs can sense and assess the stiffness of extracellular substrates through the process of mechanotransduction. Through this process, the extracellular matrix can govern and direct MSCs’ lineage commitment through complex intracellular pathways. Hence, various biomimetic natural and synthetic polymeric matrices of tunable stiffness were developed and further investigated to mimic the MSCs’ native tissues. Customizing scaffold materials to mimic cells’ natural environment is of utmost importance during the process of tissue engineering. This review aims to highlight the regulatory role of matrix stiffness in directing the osteogenic differentiation of MSCs, addressing how MSCs sense and respond to their ECM, in addition to listing different polymeric biomaterials and methods used to alter their stiffness to dictate MSCs’ differentiation towards the osteogenic lineage.

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Section: Collagenmentioning

confidence: 99%

Effect of Polymeric Matrix Stiffness on Osteogenic Differentiation of Mesenchymal Stem/Progenitor Cells: Concise Review

et al. 2021

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“…Our findings are consistent with this observation, suggesting increased OPG secretion by hMSCs in MC-HB composites may be due to increased release of Calcium and Phosphate ions during degradation (vs. MC scaffolds or MC-Fluffy composites). This indicates that inclusion of Hyperelastic Bone 3D-prints could not only regenerate bone through increased stiffness, which has been linked with greater mechanotransduction-induced bone formation in mineralized collagen scaffolds [88], but also provide additional inorganic ions to safely elevate OPG levels without the need of gene therapy or growth factors [56]. The timing of increased OPG production during significant Hyperelastic Bone degradation further suggests that the Hyperelastic Bone reinforcement structure may play an active role in promoting an osteogenic response in addition to passive mechanical reinforcement.…”

Section: Discussionmentioning

confidence: 95%

Inclusion of a 3D-printed Hyperelastic Bone mesh improves mechanical and osteogenic performance of a mineralized collagen scaffold

et al. 2021

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Regenerative repair of craniomaxillofacial bone injuries is challenging due to both the large size and irregular shape of many defects. Mineralized collagen scaffolds have previously been shown to be a promising biomaterial implant to accelerate craniofacial bone regeneration in vivo. Here we describe inclusion of a 3D-printed polymer or ceramic-based mesh into a mineralized collagen scaffold to improve mechanical and biological activity. Mineralized collagen scaffolds were reinforced with 3D-printed Fluffy-PLG (ultraporous polylactide-co-glycolide copolymer) or Hyperelastic Bone (90wt% calcium phosphate in PLG) meshes. We show degradation byproducts and acidic release from the printed structures have limited negative impact on the viability of mesenchymal stem cells. Further, inclusion of a mesh formed from Hyperelastic Bone generates a reinforced composite with significantly improved mechanical performance (elastic modulus, push-out strength). Composites formed from the mineralized collagen scaffold and either Hyperelastic Bone or Fluffy-PLG reinforcement both supported human bone-marrow derived mesenchymal stem cell osteogenesis and new bone formation. Strikingly, composites reinforced with Hyperelastic Bone mesh elicited significantly increased secretion of osteoprotegerin, a soluble glycoprotein and endogenous inhibitor of osteoclast activity. These results suggest that architectured meshes can be integrated into collagen scaffolds to boost mechanical performance and actively instruct cell processes that aid osteogenicity; specifically, secretion of a factor crucial to inhibiting osteoclast-mediated bone resorption. Future work will focus on further adapting the polymer mesh architecture to confer improved shape-fitting capacity as well as to investigate the role of polymer reinforcement on MSC-osteoclast interactions as a means to increase regenerative potential.

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“…After confirmation that both IWR1 and IWP2 were effective inhibitors of osteogenic differentiation and β-catenin activation in primary hMSCs in monolayer cultures, we then evaluated the inhibitors on NX-MC (0.34 ± 0.11 kPa) and MC (3.90 ± kPa) materials ( Figure 2A ). The two materials, as we previously described, have the exact same composition and are fabricated in an identical manner with the exception of increased stiffness in MC secondary to crosslinking performed after fabrication ( 8 ). Using WST-1 assays, we first determined whether either inhibitor affected viability and proliferation of hMSCs cultured on the two materials ( Figure 2B ).…”

Section: Resultsmentioning

confidence: 99%

“…In addition, MC-GAG has both a direct and indirect inhibitory effect on primary human pre-osteoclasts ( 6, 7 ). While the trigger for such effects remains to be elucidated, we recently reported that stiffness of MC-GAG scaffolds resulted in activation of the mechanosensitive Yes- associated protein (YAP) and transcription activator with PDZ-binding motif (TAZ) signaling pathway with a concomitant increased expression of activated, non- phosphorylated β-catenin (non-p-β-catenin), the major intracellular mediator of the canonical Wingless-related integration site (cWnt) pathway ( 8 ). These data suggested that cWnt signaling may play an integral role in osteogenesis induced by MC-GAG in a stiffness-dependent manner.…”

Section: Introductionmentioning

confidence: 99%

β-Catenin Limits Osteogenesis on Regenerative Materials in a Stiffness-Dependent Manner

Zhou

Ren

Oberoi

et al. 2021

Preprint

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Targeted refinement of regenerative materials requires mechanistic understanding of cell-material interactions. The nanoparticulate mineralized collagen glycosaminoglycan (MC-GAG) scaffold is a porous biomaterial that promotes regenerative healing of calvaria defects in vivo without addition of exogenous growth factors or progenitor cells, suggesting its potential as an off-the-shelf implant for reconstructing skull defects. In this work, we evaluate the relationship between material stiffness, a tunable MC-GAG property, and activation of the canonical Wnt (cWnt) signaling pathway. Primary human bone marrow-derived mesenchymal stem cells (hMSCs) were differentiated on two MC-GAG scaffolds varying by stiffness (non-crosslinked, NX-MC, 0.3 kPa vs. conventionally crosslinked, MC, 3.9 kPa). hMSCs exhibited increased expression of activated β-catenin, the major cWnt intracellular mediator, and the mechanosensitive YAP protein with near complete subcellular colocalization in stiffer MC scaffolds. Small molecule Wnt pathway inhibitors reduced activated β-catenin and YAP protein quantities and colocalization, osteogenic differentiation, and mineralization on MC, with no effects on NX-MC. Concomitantly, Wnt inhibitors increased BMP4 and phosphorylated Smad1/5 (p-Smad1/5) expression on MC, but not NX-MC. Unlike non-specific Wnt pathway downregulation, isolated canonical Wnt inhibition with β-catenin knockdown increased osteogenic gene expression and mineralization specifically on the stiffer MC. β-catenin knockdown also increased p-Smad1/5, Runx2, and BMP4 expression only on the stiffer MC material. Our data indicates stiffness-induced activation of the Wnt and mechanotransduction pathways promotes osteogenesis in MC-GAG scaffolds. However, activated β-catenin is a limiting agent and may serve as a useful target or readout for optimal modulation of stiffness in skeletal regenerative materials.

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Stiffness of Nanoparticulate Mineralized Collagen Scaffolds Triggers Osteogenesis via Mechanotransduction and Canonical Wnt Signaling

Cited by 34 publications

References 33 publications

Effect of Polymeric Matrix Stiffness on Osteogenic Differentiation of Mesenchymal Stem/Progenitor Cells: Concise Review

Effect of Polymeric Matrix Stiffness on Osteogenic Differentiation of Mesenchymal Stem/Progenitor Cells: Concise Review

Inclusion of a 3D-printed Hyperelastic Bone mesh improves mechanical and osteogenic performance of a mineralized collagen scaffold

β-Catenin Limits Osteogenesis on Regenerative Materials in a Stiffness-Dependent Manner

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