Abstract
Astrocytes are abundant cell types in the vertebrate central nervous system and can act as neural stem cells in specialized niches where they constitutively generate new neurons. Outside the stem cell niches, however, these glial cells are not neurogenic. Although injuries in the mammalian central nervous system lead to profound proliferation of astrocytes, which cluster at the lesion site to form a gliotic scar, neurogenesis does not take place. Therefore, a plausible regenerative therapeutic option is to coax the endogenous reactive astrocytes to a pre-neurogenic progenitor state and use them as an endogenous reservoir for repair. However, little is known on the mechanisms that promote the neural progenitor state after injuries in humans. Gata3 was previously found to be a mechanism that zebrafish brain uses to injury-dependent induction of neural progenitors. However, the effects of GATA3 in human astrocytes after injury are not known. Therefore, in this report, we investigated how overexpression of GATA3 in primary human astrocytes would affect the neurogenic potential before and after injury in 2D and 3D cultures. We found that primary human astrocytes are unable to induce GATA3 after injury. Lentivirus-mediated overexpression of GATA3 significantly increased the number of GFAP/SOX2 double positive astrocytes and expression of pro-neural factor ASCL1, but failed to induce neurogenesis, suggesting that GATA3 is required for enhancing the neurogenic potential of primary human astrocytes and is not sufficient to induce neurogenesis alone.
Highlights
Astrocytes bear multiple vital functions such as maintaining the ion homeostasis, contributing to the blood–brain barrier, restoring synaptic integrity, regulating immune response, and acting as neural stem cells (Kettenmann and Ransom, 2012)
Given that several seminal studies succeeded in converting non-neurogenic cortical astrocytes in mouse to neurons by reprogramming (Heinrich et al, 2010; Karow et al, 2012; Chen et al, 2015; Masserdotti et al, 2015; Gascon et al, 2016), enhancing neurogenic potential in human brains using endogenous reservoir cells stands as a plausible future goal
We investigated the effect of overexpression of human GATA3 in Primary Human Astrocyte (pHA) in 2D and 3D culture conditions with or without injury because Gata3 is associated with regenerative neurogenic potential of glial cells in adult zebrafish brain (Kizil et al, 2012b), and its mechanism of action is specific to the neurogenic potential of neural stem/progenitor cells after the injury (Kizil et al, 2012b; Kyritsis et al, 2012; Rodriguez Viales et al, 2015; Katz et al, 2016)
Summary
Astrocytes bear multiple vital functions such as maintaining the ion homeostasis, contributing to the blood–brain barrier, restoring synaptic integrity, regulating immune response, and acting as neural stem cells (Kettenmann and Ransom, 2012). Several studies using reprogramming and direct conversion succeeded in converting astrocyte into neuronal subtypes (Heinrich et al, 2010; Cherry and Daley, 2012; Guo et al, 2014), yet an alternative approach can still be to learn these mechanisms from regenerating vertebrate brains that can efficiently convert glial cells into neurons in case of injuries (Rolls et al, 2009; Karl and Reh, 2010; Kizil et al, 2012a; Hong et al, 2014; Cosacak et al, 2015) One such regenerative organism is zebrafish and it can regenerate its brain upon traumatic injuries and neurodegeneration (Zupanc, 2008; Fleisch et al, 2010; Kroehne et al, 2011; Baumgart et al, 2012; Kishimoto et al, 2012; Kizil et al, 2012a; Marz et al, 2012; Cosacak et al, 2015; Alunni and Bally-Cuif, 2016; Kizil, 2018; Kizil and Bhattarai, 2018). The effects of Gata on the proliferative and neurogenic ability of human astrocytes are not known
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