Project description:Fibrotic scar tissue formation is conserved throughout the central nervous system in humans and mice, and impairs tissue regeneration and functional recovery. However, the origin of scar-forming stromal fibroblasts is controversial. Here, we show that stromal fibroblasts found after spinal cord injury derive from two populations of perivascular cells that are anatomically and transcriptionally defined as pericytes and perivascular fibroblasts. We identify two distinct perivascular cell populations, which activate and transcriptionally converge on the generation of stromal myofibroblasts after injury. Our results suggest potential targets to improve tissue regeneration and functional recovery after central nervous system injuries.
Project description:Fibrotic scar tissue formation is conserved throughout the central nervous system in humans and mice, and impairs tissue regeneration and functional recovery. However, the origin of scar-forming stromal fibroblasts is controversial. Here, we show that stromal fibroblasts found after spinal cord injury derive from two populations of perivascular cells that are anatomically and transcriptionally defined as pericytes and perivascular fibroblasts. We identify two distinct perivascular cell populations, which activate and transcriptionally converge on the generation of stromal myofibroblasts after injury. Our results suggest potential targets to improve tissue regeneration and functional recovery after central nervous system injuries.
Project description:Fibrotic scar tissue formation is conserved throughout the central nervous system in humans and mice, and impairs tissue regeneration and functional recovery. However, the origin of scar-forming stromal fibroblasts is controversial. Here, we show that stromal fibroblasts found after spinal cord injury derive from two populations of perivascular cells that are anatomically and transcriptionally defined as pericytes and perivascular fibroblasts. We identify two distinct perivascular cell populations, which activate and transcriptionally converge on the generation of stromal myofibroblasts after injury. Our results suggest potential targets to improve tissue regeneration and functional recovery after central nervous system injuries.
Project description:In this study, by a genome-wide RNA interference screen, we identified heterogeneous nuclear ribonucleoprotein U (Hnrnpu) as an endogenous key molecule in astrocyte activation. Inhibition of Hnrnpu in astrocytes impairs the formation of astrocytic glial scar, motor function recovery, and neuronal regeneration after spinal cord injury (SCI) in mice. Therefore, we then performed gene expression profiling analysis to evalute the function of HNRNPU in human astrocytes. Our findings uncover that modulation of endogenous astrocytic function through Hnrnpu would be a promising therapeutic avenue to restore neurological function after the injury.
Project description:Scar formation is a major hindrance to central nervous system regeneration upon traumatic injury. Glial cells are key players during the wound healing process, and their reaction to injury determines the extent of tissue restoration. Here, we used the regenerative potential of the zebrafish telencephalon to identify specific molecular and cellular mechanisms regulating glial scar formation. We demonstrated that contact of the cerebrospinal fluid with the brain parenchyma after injury activates toll-like receptor 2 (Tlr2) and the chemokine receptor 3 (Cxcr3) innate immunity pathways leading to initiation of a glial scar. These pathways were critical for scarring even after ablation of microglia and infiltrating monocytes. Our data support a specific role for the injury-induced Tlr1/2 and Cxcr3 signaling pathways in controlling proliferation of the oligodendrocyte progenitors and therefore exacerbated glial reactivity, contributing to scar formation. Interference with the Tlr1/2 and Cxcr3 pathways after injury alleviated glial scar formation and improved tissue restoration.
Project description:After spinal cord injury, fibrotic scars will form, which affect tissue regeneration and functional recovery in the body. However, the differences in fibrotic scars produced by different segments of the spinal cord are still unclear. Here, we demonstrate that after the same spinal cord hemisection injury, the thoracic spinal cord produces the most scars, while the lumbar and cervical spinal cords have fewer scars, and there are also significant differences in functional recovery after injury in the three segments. By comparing the differences in fibrosis scars produced by cervical spinal cord, thoracic spinal cord, and lumbar spinal cord, as well as the different abilities of fibroblasts to promote fibrosis in vitro, the potential mechanism characteristics of injury repair in different segments of the spinal cord were revealed. This article explores the impact of spinal cord segment differences on fibrosis scar formation and their relationship with behavioral functional recovery, revealing the regional heterogeneity of spinal cord tissue fibrosis scar formation and deepening our understanding of the complexity of CNS scar formation. This provides new ideas for future targeted treatment to improve functional recovery after specific spinal cord injuries.
Project description:Deficiency in hematopoietic phosphatase Ptpn6/Shp1 hyperactivates the innate immune system and impairs control of bacterial infections in zebrafish embryos