Multiple sclerosis is an autoimmune disease characterized by demyelination and axonal loss throughout the central nervous system. No regenerative treatment exists for patients who fail to respond to conventional immunosuppressive and immunomodulating drugs. In this scenario, stem cell therapy poses as a rational approach for neurological regeneration. Transplantation of embryonic-derived oligodendrocyte progenitor cells (OPCs) has been shown to promote remyelination and ameliorate animal models of neurodegenerative diseases. However, its therapeutic application is limited due to potential transplant rejection. In multiple sclerosis, an added concern is that transplant rejection would be most pronounced at sites of previous lesions, exacerbating a hyperactive immune response which could prevent remyelination and precipitate additional demyelination. Routine systemic immunosuppression may not be sufficient to prevent transplant rejection-associated immune reactions in the cerebral microenvironment. Mesenchymal stem cells (MSCs), due to their homing properties and inherent immunosuppressive nature, are a promising tool for clinical application targeted toward immunosuppression at sites of injury. In this study, we used a co-transplantation strategy to investigate the effect of syngeneic MSCs on the survival and remyelination abilities of allogeneic OPCs in adult nonimmunosuppressed shiverer mice. At all time points examined, cotransplantation with MSCs increased OPC engraftment, migration, and maturation in myelinating oligodendrocytes, which produced widespread myelination in the host corpus callosum. In addition, MSCs reduced microglia activation and astrocytosis in the brain of transplanted animals as well as T-cell proliferation in vitro. These data suggest that combining the immunomodulatory and trophic properties of MSCs with the myelinating ability of OPCs might be a suitable strategy for promoting neurological regeneration in demyelinating diseases.
Bone regeneration following injury is initiated by inflammatory signals and occurs in association with infiltration by sensory nerve fibers. Together, these events are believed to coordinate angiogenesis and tissue reprogramming, but the mechanism of coupling immune signals to reinnervation and osteogenesis is unknown. Here, we found that nerve growth factor (NGF) is expressed following cranial bone injury and signals via p75 in resident mesenchymal osteogenic precursors to affect their migration into the damaged tissue. Mice lacking Ngf in myeloid cells demonstrated reduced migration of osteogenic precursors to the injury site with consequently delayed bone healing. These features were phenocopied by mice lacking p75 in Pdgfra + osteoblast precursors. Single-cell transcriptomics identified mesenchymal subpopulations with potential roles in cell migration and immune response, altered in the context of p75 deletion. Together, these results identify the role of p75 signaling pathway in coordinating skeletal cell migration during early bone repair.
The outer coverings of the skeleton, which is also known as the periosteum, are arranged in concentric layers and act as a reservoir for tissue-specific bone progenitors. The cellular heterogeneity within this tissue depot is being increasingly recognized. Here, inducible PDGFRα reporter animals were found to mark a population of cells within the periosteum that act as a stem cell reservoir for periosteal appositional bone formation and fracture repair. During these processes, PDGFRα reporter+ progenitors give rise to Nestin+ periosteal cells before becoming osteoblasts and osteocytes. The diphtheria toxin-mediated ablation of PDGFRα reporter+ cells led to deficits in cortical bone formation during homeostasis and a diminutive hard callus during fracture repair. After ossicle transplantation, both mouse PDGFRα reporter+ periosteal cells and human Pdgfrα+ periosteal progenitors expand, ossify, and recruit marrow to a greater extent than their counterpart periosteal cells, whereas PDGFRα reporter− periosteal cells exhibit a predisposition to chondrogenesis in vitro. Total RNA sequencing identified enrichment of the secreted factors Fermt3 and Ptpn6 within PDGFRα reporter+ periosteal cells, which partly underlie the osteoblastogenic features of this cell population.
Cross-sectional survey and retrospective review of prospectively collected data. Objective. To explore how patients perceive their decision to pursue spine surgery for degenerative conditions and evaluate factors correlated with decisional regret. Summary of Background Data. Prior research shows that onein-five older adults regret their decision to undergo spinal deformity surgery. However, no studies have investigated decisional regret in patients with degenerative conditions. Methods. Patients who underwent cervical or lumbar spine surgery for degenerative conditions (decompression, fusion, or disk replacement) between April 2017 and December 2020 were included. The Ottawa Decisional Regret Questionnaire was implemented to assess prevalence of decisional regret. Questionnaire scores were used to categorize patients into low (< 40) or medium/high ( ≥ 40) decisional regret cohorts. Patient-reported outcome measures (PROMs) included the Oswestry Disability Index, Patient-reported Outcomes Measurement Information System, Visual Analog Scale (VAS) Back/Leg/Arm, and Neck Disability
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