Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
Dev Cell. 2022 Feb 28;57(4):480-495.e6. doi: 10.1016/j.devcel.2022.01.015. Epub 2022 Feb 11.
Skeletal stem cells (SSCs) reside within a three-dimensional extracellular matrix (ECM) compartment and differentiate into multiple cell lineages, thereby controlling tissue maintenance and regeneration. Within this environment, SSCs can proteolytically remodel the surrounding ECM in response to growth factors that direct lineage commitment via undefined mechanisms. Here, we report that Mmp14-dependent ECM remodeling coordinates canonical Wnt signaling and guides stem cell fate by triggering an integrin-activated reorganization of the SCC cytoskeleton that controls nuclear lamin A/C levels via the linker of nucleoskeleton and cytoskeleton (LINC) complexes. In turn, SSC lamin A/C levels dictate the localization of emerin, an inner nuclear membrane protein whose ability to regulate β-catenin activity modulates Wnt signaling while directing lineage commitment in vitro and in vivo. These findings define a previously undescribed axis wherein SSCs use Mmp14-dependent ECM remodeling to control cytoskeletal and nucleoskeletal organization, thereby governing Wnt-dependent stem cell fate decisions.
骨骼干细胞 (SSCs) 位于三维细胞外基质 (ECM) 隔室中,并分化为多个细胞谱系,从而控制组织维持和再生。在这种环境中,SSCs 可以通过未定义的机制对周围的 ECM 进行蛋白水解重塑,以响应指导谱系定向的生长因子。在这里,我们报告 MMP14 依赖性 ECM 重塑通过触发 SCC 细胞骨架的整联蛋白激活重组来协调经典 Wnt 信号,并通过核骨架和细胞骨架的连接体 (LINC) 复合物来指导干细胞命运,从而控制核层粘连蛋白 A/C 水平。反过来,SSC 层粘连蛋白 A/C 水平决定了核膜内蛋白 emerin 的定位,其调节β-连环蛋白活性的能力调节 Wnt 信号,同时指导体外和体内的谱系定向。这些发现定义了一个以前未描述的轴,其中 SSCs 使用 MMP14 依赖性 ECM 重塑来控制细胞骨架和核骨架组织,从而控制 Wnt 依赖性干细胞命运决定。