Matrix remodeling controls a nuclear lamin A/C-emerin network that directs Wnt-regulated stem cell fate

• Published in: Developmental cell Vol. 57; no. 4; pp. 480 - 495.e6
• Main Authors: Tang, Yi, Zhu, Lingxin, Cho, Jung-Sun, Li, Xiao-Yan, Weiss, Stephen J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 28.02.2022
• Subjects: adipogenesis; beta-catenin; Cell Differentiation - physiology; Cell Lineage - physiology; Cell Nucleus - metabolism; collagen; Cytoskeleton - metabolism; emerin; extracellular matrix; Humans; lamin; Lamin Type A - metabolism; matrix metalloproteinase; Mmp14; Nuclear Envelope - metabolism; osteogenesis; stem cells; Stem Cells - metabolism; Wnt; Wnt Signaling Pathway - physiology; beta-catenin; stem cells; lamin; adipogenesis; emerin; Mmp14; collagen; matrix metalloproteinase; osteogenesis; Wnt; extracellular matrix
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2022.01.015

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. [Display omitted] •ECM remodeling regulates Wnt signaling to control skeletal stem cell (SSC) fate•Mmp14-driven remodeling modulates lamin A/C via LINC-dependent mechanotransduction•A lamin A/C-emerin node regulates nuclear β-catenin-mediated Wnt signaling•SSC lineage is regulated by an Mmp14-nuclear lamin A/C-emerin-β-catenin network Tang et al. show that skeletal stem cells mobilize the proteolytic enzyme, Mmp14, to remodel their surrounding extracellular matrix to activate a β1 integrin signaling axis that controls canonical Wnt signaling and lineage commitment via the regulation of a nuclear lamin A/C-emerin-β-catenin network.