Abstract
The mediators in activating neural stem cells during the regenerative process of neurogenesis following stroke have not been fully identified. Milk fat globule-EGF Factor VIII (MFG-E8), a secreted glycoprotein serves several cellular functions by binding to its receptor, αv β3-integrin. However, its role in regulating neural stem cells after stroke has not been determined yet. We therefore, aim to reveal whether MFG-E8 promotes neural stem cell proliferation and migration during stroke. Stroke was induced in wild-type (Wt) and MFG-E8-deficinet (Mfge8-/-) mice by transient middle cerebral artery occlusion (tMCAO). Commercially available recombinant mouse MFG-E8 (rmMFG-E8) was used for mechanistic assays in neural stem cell line, while the in house prepared recombinant human MFG-E8 (rhMFG-E8) was used for in vivo administration into rats with tMCAO. The in vitro effects of recombinant rmMFG-E8 for the neural stem cell proliferation and migration were determined by BrdU and transwell migration assay, respectively. The expression of cyclin D2, p53 and netrin-1, was analyzed by qPCR. We report that the treatment of rhMFG-E8 significantly improved the neurological deficit score, body weight lost and neural stem cell proliferation in a rat model of tMCAO. Conversely, decreased neural stem cell proliferation was observed in Mfge8-/- mice in comparison with the Wt counterparts underwent tMCAO. rmMFG-E8 stimulated the proliferation of mouse embryonic neural stem cells via upregulation of cyclin D2 and downregulation of p53, which is mediated by αv β3-integrin. rmMFG-E8 also promoted mouse embryonic neural stem cell migration via αv β3-integrin dependent manner in upregulating netrin-1. Our findings suggest MFG-E8 to promote neural stem cell proliferation and migration, which therefore establishes a promising therapeutic strategy for cerebral ischemia.
Highlights
Neural stem cells orchestrate embryonic brain development, homeostasis and repair in the adult brain following injury
We found that intracerebroventricular administration of 0.4 μg/μl rhMFG-E8 significantly improved neurological function compared to vehicle at seven days post-transient middle cerebral artery occlusion (tMCAO) (Fig 1A)
The tMCAO rats treated with rh showed significant improvement in their body weight at seven days post-tMCAO (Fig 1B)
Summary
Neural stem cells orchestrate embryonic brain development, homeostasis and repair in the adult brain following injury. Pluripotent embryonic neural stem cells proliferate and migrate along various spatial coordinates in response to complex morphogenic gradients, followed by differentiation of the migrated cells to form the adult brain [1, 2]. Neural stem cells have been shown to contribute to brain repair after injury via the secretion of neuroprotective neurotrophic factors as well as tissue regeneration [3, 4]. Deciphering the molecular language of neural stem biology would be critical for the development of novel therapeutics for brain repair and regeneration after stroke
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