MicroRNA-124-loaded nanoparticles as a new promising therapeutic tool for neural stem cell-based brain repair strategies
Year: 2017
Type: dissertation
Abstract: The subventricular zone (SVZ) represents the major neurogenic niche of the rodent brain and its modulation upon brain injury may enhance brain repair. Herein, we used biocompatible and traceable polymeric nanoparticles (NPs) to deliver microRNA-124 (miR-124) into SVZ cells. miR-124 is a key neuronal fate determinant and was recently described as anti-inflammatory and neuroprotective. Therefore, the efficiency of NPs to deliver miR-124 and prompt SVZ neurogenesis and brain repair in Parkinson’s disease (PD) and stroke models was evaluated. Firstly, we showed that miR-124 NPs were efficiently internalized by neural stem/progenitors cells and neuroblasts and promoted their differentiation into matured neurons by targeting Sox9 and Jagged1 (two stemness-related proteins) in vitro. Likewise, intracerebral administration of miR-124 NPs increased the number of migrating neuroblasts reaching the olfactory bulb, both in control mice and in mice subjected to a 6-hydroxydopamine (6-OHDA), a model for PD. Moreover, miR-124 NPs increased the levels of new neurons in the lesioned striatum of 6-OHDA-challenged mice, correlating with functional improvement. Interestingly, miR-124 NPs also demonstrated the ability to decrease cell death and enhance neuronal differentiation of SVZ cultures after oxygen and glucose deprivation, suggesting a potential beneficial role in stroke. Therefore, miR-124 NPs were intravenously injected in mice subjected to photothrombotic (PT) stroke. In contrast to intracerebral administration, miR-124 NPs were unable to promote recovery of lost neurological function in PT mice. miR-124 NPs did not affect SVZ neurogenesis nor post-stroke inflammation. We conclude that miR-124 NPs treatment modulates PD outcome in vivo, while in stroke it improves survival and neuronal differentiation of SVZ cells. However, the promising in vitro data from stroke could not be verified in vivo. Thus, we provide evidence supporting that miR-124 NPs are well tolerated and positive modulators of endogenous SVZ neurogenesis as well as their potential application in brain repair strategies.
Author: Cláudia Saraiva
Language: English
Subfield: Developmental Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
Awards: G1190076555, G1516346500, G1578237752, G1763632427, G2943657006, G3840324753, G3891694003, G5224927334, G5899416077, G612898079, Centro de Investigação em Ciências da Saúde, MicroRNA-124 encapsulado em nanopartículas: promover a neurogénese para tratar a doença de Parkinson, G7840520815, G8038595969
OpenAlex ID: W2784354456