Striatal astrocytes transdifferentiate into functional mature neurons following ischemic brain injury

Abstract

To determine whether reactive astrocytes stimulated by brain injury can transdifferentiate into functional new neurons, we labeled these cells by injecting a glial fibrillary acidic protein (GFAP) targeted enhanced green fluorescence protein plasmid (pGfa2‐eGFP plasmid) into the striatum of adult rats immediately following a transient middle cerebral artery occlusion (MCAO) and performed immunolabeling with specific neuronal markers to trace the neural fates of eGFP‐expressing (GFP+) reactive astrocytes. The results showed that a portion of striatal GFP+ astrocytes could transdifferentiate into immature neurons at 1 week after MCAO and mature neurons at 2 weeks as determined by double staining GFP‐expressing cells with βIII‐tubulin (GFP+‐Tuj‐1+) and microtubule associated protein‐2 (GFP+‐MAP‐2+), respectively. GFP+ neurons further expressed choline acetyltransferase, glutamic acid decarboxylase, dopamine receptor D2‐like family proteins, and the N‐methyl‐d‐aspartate receptor subunit R2, indicating that astrocyte‐derived neurons could develop into cholinergic or GABAergic neurons and express dopamine and glutamate receptors on their membranes. Electron microscopy analysis indicated that GFP+ neurons could form synapses with other neurons at 13 weeks after MCAO. Electrophysiological recordings revealed that action potentials and active postsynaptic currents could be recorded in the neuron‐like GFP+ cells but not in the astrocyte‐like GFP+ cells, demonstrating that new GFP+ neurons possessed the capacity to fire action potentials and receive synaptic inputs. These results demonstrated that striatal astrocyte‐derived new neurons participate in the rebuilding of functional neural networks, a fundamental basis for brain repair after injury. These results may lead to new therapeutic strategies for enhancing brain repair after ischemic stroke. GLIA 2015;63:1660–1670

Are astrocytes executive cells within the central nervous system?

“…They modulate the myelinating capacity of the oligodendrocytes 4 , the synaptic cross-talk amongst neurons 5 , the homeostasis of the CNS extracellular medium 6 , the initiation of the inflammatory and immune responses 7 and the building up of barriers between normal and damaged tissues 8 . Astrocytes can behave like phagocytic cells 9 , they sense the partial pressure of O 2 within the CNS 10 and they can transform into neurons when the brain is in need of rebuilding damaged functional neural networks contributing to nervous tissue repair 11 . Therefore, we believe that the astrocyte deserves to be considered, in its own right, one of the main players orchestrating fundamental functions within the CNS.…”

Stars from the darkest night: unlocking the neurogenic potential of astrocytes in different brain regions

“…But we and others have recently found that parenchymal astrocytes residing in the striatum can also generate neurons (Magnusson et al, 2014;Nato et al, 2015;Luzzati et al, 2014;Duan et al, 2015;Shen et al, 2015). These striatal astrocytes are triggered by certain injuries, such as stroke, to activate latent neurogenic properties and produce neurons in a burst of proliferation (Fig.…”

“…3). As mentioned, the similarities between parenchymal astrocytes and neural stem cells even extend to an intrinsic capacity of parenchymal astrocytes to generate neurons, at least when it comes to striatal astrocytes in vivo (Magnusson et al, 2014;Nato et al, 2015;Duan et al, 2015;Luzzati et al, 2014) and cortical astrocytes when isolated and cultured in vitro (Buffo et al, 2008;Shimada et al, 2012;Sirko et al, 2013). But the relatedness between the two cell types might go even further than that.…”

Programmed cell death acts at different stages of Drosophila neurodevelopment to shape the central nervous system

“…In favor of this argument, glial cells in multiple contexts have been shown to maintain mitotic activity (Doetsch 2003). This capacity may reveal itself immediately by the amplification of the glial population, or later upon activation in adulthood (Guo, Zhang et al 2014, Duan, Liu et al 2015, Sammut, Cook et al 2015). This difference in proliferative capacity may be mediated by the different levels of Prospero inherited by the terminally dividing neuroblast to its progeny.…”