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

• DOI: 10.1002/adhm.202101467
• Publication Date: 2021-09-29T03:30:41Z
• Authors: Qi Zhou; Xiaoyan Ren; Michelle K. Oberoi; Meiwand Bedar; Rachel M. Caprini; Marley J. Dewey; Vasiliki Kolliopo...; Dean T. Yamaguchi; Brendan A. C. Harley; Justine C. Lee
• Keywords: RUNX2; Mechanotransduction; Regenerative Medicine

Targeted refinement of regenerative materials requires mechanistic understanding cell-material interactions. The nanoparticulate mineralized collagen glycosaminoglycan (MC-GAG) scaffold is shown to promote skull regeneration in vivo without additive exogenous growth factors or progenitor cells, suggesting potential for clinical translation. This work evaluates modulation MC-GAG stiffness on canonical Wnt (cWnt) signaling. Primary human bone marrow-derived mesenchymal stem cells (hMSCs) are differentiated two scaffolds (noncrosslinked, NX-MC, 0.3 kPa vs conventionally crosslinked, MC, 3.9 kPa). hMSCs increase expression activated β-catenin, the major cWnt intracellular mediator, and mechanosensitive YAP protein with near complete subcellular colocalization stiffer MC scaffolds. Overall pathway inhibition reduces β-catenin osteogenic differentiation, while elevating BMP4 phosphorylated Smad1/5 (p-Smad1/5) but not NX-MC. Unlike downregulation, isolated knockdown increases differentiation mineralization specifically MC. also p-Smad1/5, Runx2, only material. Thus, stiffness-induced activation mechanotransduction pathways promotes osteogenesis MC-GAG, a limiting agent may serve as useful target readout optimal skeletal materials.