Decellularized extracellular matrix and mesenchymal stem cells promote recovery in traumatic brain injury by synergistically enhancing neurogenesis and attenuating neuroinflammation

Abstract

• The innovative decellularization method via freeze-thaw cycles and detergent-enzymatic cycles endowed the decellularized brain with extremely few cellular immunogenic components and abundant ECM constituents. • The MSCs-encapsulated decellularized brain ECM (dBECM)-based hydrogel can effectively promote neuron compensation and neural recovery in TBI mice, owing to the capacity to up-regulate the neural-related genes and promote the neural differentiation of MSCs into NSCs and neurons. • The MSCs-encapsulated dBECM-based hydrogel can potentially regulate the neuroinflammation after TBI, since the hydrogel works synergistically with MSCs to stimulate the M1-to-M2 polarization and down-regulate the pro-inflammatory cytokines of microglia. Damaged neurons and harsh microenvironments contribute to the injury cascades following traumatic brain injury (TBI). Mesenchymal stem cell (MSC) therapy is considered a viable choice for brain injury treatment; however, its clinical use is hindered by limited engraftment, low survival ratio, and uncontrolled differentiation. Herein, the decellularized brain extracellular matrix (dBECM) was prepared through a new method as a delivery system for MSCs. dBECM-based hydrogel with favorable biochemical and biomechanical features provides a microenvironment for MSCs in nerve repair. The MSCs-encapsulated dBECM-based hydrogel is shown to improve neuron compensation and structural regeneration, alleviate neuroinflammation, and promote M1-to-M2 polarization of microglia. Our results first demonstrate that the combination of dBECM and MSCs is a critical vehicle to promote TBI repair from neurogenesis and immunoregulation, showing promise for the physiological recovery of neurogenic diseases and injuries.