Abstract
Focal brain injury in the form of a needlestick (NS) results in cell death and induces a self-protective response flanking the lesion. Myo/Nog cells are identified by their expression of bone morphogenetic protein inhibitor Noggin, brain-specific angiogenesis inhibitor 1 (BAI1) and the skeletal muscle specific transcription factor MyoD. Myo/Nog cells limit cell death in two forms of retinopathy. In this study, we examined the acute response of Myo/Nog cells to a NS lesion that extended from the rat posterior parietal cortex to the hippocampus. Myo/Nog cells were identified with antibodies to Noggin and BAI1. These cells were the primary source of both molecules in the uninjured and injured brain. One day after the NS, the normally small population of Myo/Nog cells expanded approximately eightfold within a 1 mm area surrounding the lesion. Myo/Nog cells were reduced by approximately 50% along the lesion with an injection of the BAI1 monoclonal antibody and complement. The number of dying cells, identified by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL), was unchanged at this early time point in response to the decrease in Myo/Nog cells. However, increasing the number of Myo/Nog cells within the lesion by injecting BAI1-positive (+) cells isolated from the brains of other animals, significantly reduced cell death and increased the number of NeuN+ neurons compared to brains injected with phosphate buffered saline or exogenous BAI1-negative cells. These findings demonstrate that Myo/Nog cells rapidly react to injury within the brain and increasing their number within the lesion is neuroprotective.
Highlights
MATERIALS AND METHODSMicrohemorrhages contribute to the pathogenesis of central nervous system disorders, including Alzheimer’s disease and cerebral amyloid angiopathy (Cullen et al, 2005, 2006; Stone, 2008; Stone et al, 2015)
Myo/Nog cells were first discovered in the early chick embryo by their expression of the bone morphogenetic protein (BMP) inhibitor Noggin (Gerhart et al, 2000, 2004, 2006), the skeletal muscle specific transcription factor MyoD and brain-specific angiogenesis inhibitor 1 (BAI1) (Gerhart et al, 2020a)
Sections were double labeled with the BAI1 monoclonal antibody (mAb) and a goat anti-mouse polyclonal antiserum to Noggin diluted 1:200 (R&D Systems, Minneapolis, MN, United States)
Summary
MATERIALS AND METHODSMicrohemorrhages contribute to the pathogenesis of central nervous system disorders, including Alzheimer’s disease and cerebral amyloid angiopathy (Cullen et al, 2005, 2006; Stone, 2008; Stone et al, 2015). Animal models that induce microhemorrhages are useful for defining the cellular responses to injury and testing approaches to reduce neuronal damage One such model, developed by Purushothuman et al (2013), involves insertion of a needle into the posterior parietal cortex and hippocampus of the rat brain. Myo/Nog cells were first discovered in the early chick embryo by their expression of the bone morphogenetic protein (BMP) inhibitor Noggin (Gerhart et al, 2000, 2004, 2006), the skeletal muscle specific transcription factor MyoD and brain-specific angiogenesis inhibitor 1 (BAI1) (Gerhart et al, 2020a). Release of Noggin from Myo/Nog cells restricts the field of BMP signaling and is essential for normal development of the central nervous system, eyes and skeletal, and cardiac muscle (Gerhart et al, 2006, 2009). Malformations are largely prevented with their reintroduction into the blastocyst or addition of Noggin-soaked beads into the mesoderm (Gerhart et al, 2006, 2009, 2011)
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