Acute Response and Neuroprotective Role of Myo/Nog Cells Assessed in a Rat Model of Focal Brain Injury

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.

Myo/Nog Cells Give Rise to Myofibroblasts During Epiretinal Membrane Formation in a Mouse Model of Proliferative Vitreoretinopathy

“…Support for this hypothesis comes from our previous studies showing Myo/Nog cell accumulation in areas of cell death and their phagocytosis of cell corpses. 34 , 36 , 38 , 40 , 43 …”

“…Adult tissues also contain Myo/Nog cells that become activated by stress and injury. 31 , 33 , 36 – 40 Cataract surgery induces the expansion and migration of the resident Myo/Nog population and their differentiation into myofibroblasts expressing multiple contractile proteins. 31 , 33 Contractions of myofibroblasts produce wrinkles in the lens capsule that impair vision in a condition called posterior capsule opacification (PCO).…”

“… 39 Similar neuroprotective activity of Myo/Nog cells was observed after focal injury to the rat brain. 40 Thus, the effects of Myo/Nog cells can be beneficial or pathologic depending on the environment and stimuli that trigger their activation. 25 , 31 , 33 , 35 , 38 , 39 , 43 …”

Myo/Nog Cells: The Jekylls and Hydes of the Lens

“…The next phase of our exploration of Myo/Nog cells involved characterizing their behaviors in normal and diseased tissues of adult mammals. Similar to the chick embryo, Myo/Nog cells are present in low numbers in all adult tissues and organs analyzed thus far, from mice to humans [ 16 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 ]. Within the eye, Myo/Nog cells are residents of the lens, cornea, ciliary body, retina and choroid [ 16 , 62 , 63 , 66 , 67 , 68 , 70 , 71 , 72 ] ( Figure 4 ).…”

“…Under homeostatic conditions, Myo/Nog cells are either slowly or non-dividing and synthesize Noggin without detectable translation of MyoD mRNA or expression of skeletal muscle proteins [ 9 , 13 , 15 , 29 , 30 ]. Several stimuli, including cell death, hypoxia, the presence of foreign material and wounding that occurs from surgical excision, abrasion, puncture and light damage, promote the expansion and migration of Myo/Nog cells [ 32 , 59 , 61 , 62 , 64 , 67 , 69 , 70 , 71 , 72 ]. The rapidity of their activation in adults was demonstrated in the lens in response to cataract surgery [ 66 ], the brain after focal injury [ 69 ] and in the skin where Myo/Nog cells emerge from their niche associated with hair follicles and populate the wound within 24 h of epidermal abrasion [ 61 ].…”