A new study published in Stem Cell Research and Therapy has shown that rejuvenating the astrocyte niche in the aged brains of mice leads to improved nervous system function at both the cellular and organismal levels .
A glia-centric approach
In brain aging, neurons are quite literally only half of the story; the other half is glial cells. These are diverse non-neuronal cells that collectively sustain the homeostasis of the nervous system. In the mammalian brain, they can be broadly subdivided into macroglia (astrocytes, oligodendrocytes) and microglia. When any of these cells become dysfunctional, neurons suffer too.
Astrocytes are the jacks of all trades in the brain. They provide energy support to neurons and play important roles in neurotransmission, synaptogenesis, and axon guidance. Similarly to microglia, the resident macrophages of the nervous system, astrocytes become reactive in response to injury and even assume the role of phagocytes when microglial dysfunction occurs .
Age-associated neurodegenerative diseases, along with brain aging itself, are accompanied by morphological atrophy and the functional impairment of astrocytes. Aged astrocytes lose their ability to sustain synaptic contacts and cover brain vessels with the tips of their processes, known as endfeet, and this leads to neurovascular dysfunction. Aged astrocytes can also lead to neuroinflammation, which might cause cognitive impairment.
In this study, the researchers sought to combat the deleterious effects of aged astrocytes by engrafting glial progenitor cells, which can give rise to either astrocytes or oligodendrocytes depending on context, into aged mouse brains.
Young cells in old brains
The researchers first generated glial progenitor cells from the embryonic neural stem cells collected from the cortices of ~15-day old mice. They then confirmed that the generated glial progenitor cells acquired astrocyte identities and could generate Ca+ waves, an important prerequisite for glial functioning and neuron-glia communication.
Next, the researchers transplanted glial progenitor cells into the somatosensory cortices of adult mice (6-8 months old). This is the brain region responsible for sensory information processing. 12 months later, the animals were sacrificed and their brains dissected for histological analysis.
The majority of the transplanted cells turned into astrocytes and migrated from the injection sites. No tumors were detected. The engrafted astrocytes remained morphologically much younger (meaning structurally more complex) than the astrocytes of aged control mice. The transplanted astrocytes integrated into the aged brains and could form networks on par with young astrocytes.
The researchers describe another important morphological feature of engrafted astrocytes: they manage to establish and sustain endfeet along blood vessels. Moreover, their endfeet express the AQP4 water channel AQP4 in a highly localized manner. This is the opposute of what occurs during aging, which causes astrocytes to acquire dispersed AQP4 localization, which impairs the clearance of various solutes from the extracellular space.
Improved structure, better function
The researchers conducted behavioral tests to see if any functional improvements could be detected in mice. To this end, they employed an escape response test in which mice are placed in a cage and given a foot shock stimulation. The treated mice reacted more quickly, demonstrating a functional improvement of their somatosensory cortices.
Aging causes astrocyte morphological degeneration and functional deficiency, which impairs neuronal functions. Until now, whether age-induced neuronal deficiency could be alleviated by engraftment of glial progenitor cell (GPC) derived astrocytes remained unknown. In the current study, GPCs were generated from embryonic cortical neural stem cells in vitro and transplanted into the brains of aged mice. Their integration and intervention effects in the aged brain were examined 12 months after transplantation. Results indicated that these in-vitro-generated GPC-derived astrocytes possessed normal functional properties. After transplantation they could migrate, differentiate, achieve long-term integration, and maintain much younger morphology in the aged brain. Additionally, these GPC-derived astrocytes established endfeet expressing aquaporin-4 (AQP4) and ameliorate AQP4 polarization in the aged neocortex. More importantly, age-dependent sensory response degeneration was reversed by GPC transplantation. This work demonstrates that rejuvenation of the astrocyte niche is a promising treatment to prevent age-induced degradation of neuronal and behavioral functions.
Although this is a mouse study, it builds upon previous research in paving a way to treating various neurodegenerative diseases by transplanting glial progenitor cells. Importantly, the engrafted glial progenitor cells generated astrocytes that migrate, integrate into the existing neuro-glial networks, and fulfill their function while maintaining a younger morphology than their surrounding partners. The engrafted cells also ameliorated age-induced sensory dysfunction, which demonstrates a neuroprotective effect of the treatment.
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 Yang, Z. et al. Engrafted glial progenitor cells yield long-term integration and sensory improvement in aged mice. Stem Cell Res. Ther. 13, 1–10 (2022).
 Konishi, H. et al. Astrocytic phagocytosis is a compensatory mechanism for microglial dysfunction. EMBO J. 39, e104464 (2020).
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