The Role of Astrocytes in Neuroprotection after Brain Stroke: Potential in Cell Therapy

Abstract

Astrocytes are commonly involved in negative responses through their hyperreactivity and glial scar formation in excitotoxic and/or mechanical injuries. But, astrocytes are also specialized glial cells of the nervous system that perform multiple homeostatic functions for the survival and maintenance of the neurovascular unit. Astrocytes have neuroprotective, angiogenic, immunomodulatory, neurogenic, and antioxidant properties and modulate synaptic function. This makes them excellent candidates as a source of neuroprotection and neurorestoration in tissues affected by ischemia/reperfusion, when some of their deregulated genes can be controlled. Therefore, this review analyzes pro-survival responses of astrocytes that would allow their use in cell therapy strategies.

Keywords: astrocytes; cell therapy; cerebral ischemia; excitotoxicity; neuroprotection.

FIGURE 1

Role of astrocytes in a micro-environment dependent-mode. (A) Functions of the astrocytes in physiological conditions, which are in favor of the homeostasis of the nervous tissue. (B) Reactive astrocytosis, which has a double function highly discussed, one for cell death and one for pro-neuroprotection probably in a context dependent-mode. (C) Astrocytes with genetic modifications by reduced expression of some upregulated genes, which would allow preserve them as a neuroprotective source for promoting neuronal survival; although the mechanism of how they could maintain this state of neuroprotection for longer time is still unknown (?).

FIGURE 2

Possible mechanisms of neuroprotection induced by astrocytes’ cell therapy after brain stroke. Following brain ischemia, transplantation of genetically modified astrocytes could trigger endogenous neuroprotective mechanisms as neurogenesis, angiogenesis, and regulation of inflammation. These mechanisms are regulated by a paracrine activity, where the astrocyte participates as an intermediary between neurons, endothelial cells, pericytes, microglia, and neural progenitor cells; through the release of neurotrophic factors (BDNF, GDNF, VEGF, GDNF), lower proinflammatory cytokines, and increased reuptake excitatory neurotransmitters, thus avoiding excitotoxicity and, promoting long-term neuronal survival. Arrow, soluble growth factors release by transplanted genetically modified astrocytes (“green cells,” e.g., Figure 1C), stimulate endogens astrocytes and endothelial cells, preserving the neurovascular integrity.