RESUMO
Synthetic Notch (synNotch) receptors are genetically encoded, modular synthetic receptors that enable mammalian cells to detect environmental signals and respond by activating user-prescribed transcriptional programs. Although some materials have been modified to present synNotch ligands with coarse spatial control, applications in tissue engineering generally require extracellular matrix (ECM)-derived scaffolds and/or finer spatial positioning of multiple ligands. Thus, we develop here a suite of materials that activate synNotch receptors for generalizable engineering of material-to-cell signaling. We genetically and chemically fuse functional synNotch ligands to ECM proteins and ECM-derived materials. We also generate tissues with microscale precision over four distinct reporter phenotypes by culturing cells with two orthogonal synNotch programs on surfaces microcontact-printed with two synNotch ligands. Finally, we showcase applications in tissue engineering by co-transdifferentiating fibroblasts into skeletal muscle or endothelial cell precursors in user-defined micropatterns. These technologies provide avenues for spatially controlling cellular phenotypes in mammalian tissues.
Assuntos
Diferenciação Celular , Receptores Notch , Transdução de Sinais , Engenharia Tecidual , Receptores Notch/metabolismo , Engenharia Tecidual/métodos , Animais , Humanos , Camundongos , Matriz Extracelular/metabolismo , Fibroblastos/metabolismo , Fibroblastos/citologia , Proteínas da Matriz Extracelular/metabolismo , Proteínas da Matriz Extracelular/genética , Ligantes , Alicerces Teciduais/química , Músculo Esquelético/metabolismo , Músculo Esquelético/citologia , Células Endoteliais/metabolismo , Células Endoteliais/citologia , Células HEK293RESUMO
Spinal cord injury (SCI) often causes loss of sensory and motor function resulting in a significant reduction in quality of life for patients. Currently, no therapies are available that can repair spinal cord tissue. After the primary SCI, an acute inflammatory response induces further tissue damage in a process known as secondary injury. Targeting secondary injury to prevent additional tissue damage during the acute and subacute phases of SCI represents a promising strategy to improve patient outcomes. Here, we review clinical trials of neuroprotective therapeutics expected to mitigate secondary injury, focusing primarily on those in the last decade. The strategies discussed are broadly categorized as acute-phase procedural/surgical interventions, systemically delivered pharmacological agents, and cell-based therapies. In addition, we summarize the potential for combinatorial therapies and considerations.
