β-Catenin Limits Osteogenesis on Regenerative Materials in a Stiffness-Dependent Manner.
β-Catenin Limits Osteogenesis on Regenerative Materials in a Stiffness-Dependent Manner.
复制标题
DOI：
10.1002/adhm.202101467
复制
发表时间：
2021-12
影响因子：
10
通讯作者：
Lee JC
中科院分区：
文献类型：
--
作者：
Zhou Q;Ren X;Oberoi MK;Bedar M;Caprini RM;Dewey MJ;Kolliopoulos V;Yamaguchi DT;Harley BAC;Lee JC
对再生材料进行有针对性的改进需要从机理上理解细胞与材料的相互作用。纳米颗粒矿化胶原糖胺聚糖(MC-GAG)支架在体内不添加外源生长因子或祖细胞的情况下可促进颅骨再生，提示其具有临床移植的潜力。这项工作评估了MC-GAG刚性对典范WNT(CWnt)信号的调制。原代培养的人骨髓间充质干细胞(HMSCs)在两种MC-GAG支架(非交联型，NX-MC，0.3kPavs常规交联型，MC，3.9kPa)上分化。人骨髓间充质干细胞的主要细胞内介质β-连环蛋白和机械敏感的YAP蛋白的表达增加，并在坚硬的MC支架上接近完全的亚细胞共存。总体上，抑制Wnt通路减少了活化的β-连环蛋白和成骨分化，同时上调了MC上BMP4和磷酸化Smad1/5(p-Smad1/5)的表达，但不影响NX-MC的表达。与Wnt途径下调不同，单独的典型的Wnt抑制与β-catenin基因敲除一起增加了成骨分化和矿化，尤其是在较硬的MC上。β-catenin基因敲除后，p-Smad1/5、Runx2和BMP4仅在较硬的MC材料上表达增加。因此，虽然僵硬诱导的Wnt和机械转导通路的激活促进了MC-GAG上的成骨，但激活的β-catenin是一个限制剂，可以作为优化调节骨骼再生材料硬度的有用靶点或读数。
Targeted refinement of regenerative materials requires mechanistic understanding of cell-material interactions. The nanoparticulate mineralized collagen glycosaminoglycan (MC-GAG) scaffold has been shown to promote skull regeneration in vivo without additive exogenous growth factors or progenitor cells, suggesting potential for clinical translation. This work evaluates modulation of MC-GAG stiffness on canonical Wnt (cWnt) signaling. Primary human bone marrow-derived mesenchymal stem cells (hMSCs) were differentiated on two MC-GAG scaffolds (non-crosslinked, NX-MC, 0.3 kPa vs. conventionally crosslinked, MC, 3.9 kPa). hMSCs increased expression of activated β-catenin, the major cWnt intracellular mediator, and the mechanosensitive YAP protein with near complete subcellular colocalization on stiffer MC scaffolds. Overall Wnt pathway inhibition reduced activated β-catenin and osteogenic differentiation, while elevating BMP4 and phosphorylated Smad1/5 (p-Smad1/5) expression on MC, but not NX-MC. Unlike Wnt pathway downregulation, isolated canonical Wnt inhibition with β-catenin knockdown increased osteogenic differentiation 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. Thus, while stiffness-induced activation of the Wnt and mechanotransduction pathways promotes osteogenesis on MC-GAG, 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.
登录
查看更多内容
影响因子：
14
作者：
Ren X;Tu V;Bischoff D;Weisgerber DW;Lewis MS;Yamaguchi DT;Miller TA;Harley BA;Lee JC
通讯作者：
Lee JC
影响因子：
14
作者：
Damink, LHHO;Dijkstra, PJ;Feijen, J
通讯作者：
Feijen, J
影响因子：
4.9
作者：
Harley, Brendan A.;Lynn, Andrew K.;Gibson, Lorna J.
通讯作者：
Gibson, Lorna J.
影响因子：
6.2
作者：
Galea, Gabriel L.;Meakin, Lee B.;Savery, Dawn;Taipaleenmaki, Hanna;Delisser, Peter;Stein, Gary S.;Copp, Andrew J.;van Wijnen, Andre J.;Lanyon, Lance E.;Price, Joanna S.
通讯作者：
Price, Joanna S.
影响因子：
10
作者：
Lee JC;Volpicelli EJ
通讯作者：
Volpicelli EJ