Astroglia-mediated regulation of cell development in the model of neurogenic niche in vitro treated with Aβ1-42

Abstract

Neurogenesis is a complex process which governs embryonic brain development and is importants for brain plasticity throughout the whole life. Postnatal neurogenesis occurs in neurogenic niches that regulate the processes of proliferation and differentiation of stem and progenitor cells under the action of stimuli that trigger the mechanisms of neuroplasticity. Cells of glial and endothelial origin are the key regulators of neurogenesis. It is known that physiological neurogeneses is crucial for memory formation, whereas reparative neurogenesis provides partial repair of altered brain structure and compensation of neurological deficits caused by brain injury. Dysregulation of neurogenesis is a characteristics of various neurodevelopmental and neurodegenerative diseases, particularly, Alzheimer's disease which is very important medical and social problem. In the in vitro model of the neurogenic niche using hippocampal neurospheres as a source of stem/progenitor cells and astrocytes, we studied effects of astrocyte activation on the expression of markers of different stages of cell proliferation and differentiation. We found that aberrant mechanisms of development of stem and progenitor cells, caused by the beta-amyloid (Aβ1-42), can be partially restored by targeted activation of GFAP-expressing cells in the neurogenic niche.

Current progress and challenges in the development of brain tissue models: How to grow up the changeable brain in vitro?

“…7. In addition to all above mentioned characteristics, the models aimed to reproduce key events in neurogenesis and neurogenesis-coupled brain plasticity should consider the following additional tasks: 7.1. establishment of multicellular ensembles made of NSCs/NPCs and their progeny as well as fully-differentiated cells (astrocytes, BMECs, CPECs, EpCs), tight integration of functionally and phenotypically distinct compartments (neurogenic niche, NVU/brain parenchyma, and associated brain tissue barriers) on a chip mimicking the regulation of neurogenesis in (patho)physiological conditions 31 , 135 , 281 – 283 ; 7.2. reproduction of ECM composition, oxygen and nutrients supply for better cell viability and functionality, reproduction of metabolic plasticity and local humoral microenvironment supporting cell-to-cell communications, establishment of conditions supportive for neurogenesis and angiogenesis 204 , 284 – 286 ; 7.3. reconstitution of the chip microarchitecture, fluids exchange and establishment of chemical gradients that are supportive for NSCs/NPCs maintenance due to dynamic changes in the concentrations of local and “systemic” regulatory molecules (neurotransmitters, gliotransmitters, growth factors, cytokines, alarmins, metabolites) produced by the cells themselves, infused into the microfluidic device artificially, or embedded into the ECM and scaffolds 13 , 287 ; 7.4. achieving the controllable and reproducible recruitment, proliferation, differentiation, apoptosis of NSCs/NPCs, migration of neuroblasts, maturation of newly-formed neurons and their functional integration within the NVU/brain parenchyma compartment 242 , 244 , 247 , 264 , 288 , 289 ; 7.5. establishment of the molecular machinery responsible for dynamic/phasic changes in the tissue (for instance, circadian/diurnal rhythms and/or mitochondrial dynamics) that are important for determining the stem cells fate or barrier functions 136 , 290 ; 7.6. achievement of prolonged viability of the neurogenic niche in vitro model enabling long-lasting recording of “developmental” and plastic changes in the brain tissue. …”

“…7.1. establishment of multicellular ensembles made of NSCs/NPCs and their progeny as well as fully-differentiated cells (astrocytes, BMECs, CPECs, EpCs), tight integration of functionally and phenotypically distinct compartments (neurogenic niche, NVU/brain parenchyma, and associated brain tissue barriers) on a chip mimicking the regulation of neurogenesis in (patho)physiological conditions 31 , 135 , 281 – 283 ;…”

Blood–Brain Barrier and Neurovascular Unit In Vitro Models for Studying Mitochondria-Driven Molecular Mechanisms of Neurodegeneration

“…Using BMECs but not ECs of other origin as a part of the models is more physiological to reproduce the main mechanisms of BBB development and functioning. As we have shown before, specific metabolic properties of BMECs makes them an interesting object for managing the barrier permeability in BBB models, or even in tissue models based on the cerebral endothelial monolayer (i.e., neurogenic niche in vitro model) [ 123 , 139 , 140 , 141 , 142 , 143 , 144 ].…”

Novel Approaches Used to Examine and Control Neurogenesis in Parkinson′s Disease

“…Less is known about the application of optogenetics for controlling astroglia-driven regulation of adult neurogenesis. We have demonstrated before that optogenetic stimulation of niche astrocytes expressing channelrhodopsin-2 under the GFAP promoter was efficient in activating the neurogenic potential of NSCs/NPCs in the in vitro neurogenic niche model or in implanted intrahippocampal neurospheres ex vivo in experimental Alzheimer's disease [184,185]. Photostimulation of iPSC-derived ChR2-expressing astrocytes co-cultured with iPSC-derived neurons results in effective bidirectional signaling, which is important for supporting the maturation of neurons and the establishment of a functional synaptic network, even though the transcriptomic analysis confirms that iPSCsoriginated astrocytes are relatively immature compared to adult cortical astrocytes [186].…”