Abstract
Astrocytes provide neuroprotective effects against degeneration of dopaminergic (DA) neurons and play a fundamental role in DA differentiation of neural stem cells. Here we show that light illumination of astrocytes expressing engineered channelrhodopsin variant (ChETA) can remarkably enhance the release of basic fibroblast growth factor (bFGF) and significantly promote the DA differentiation of human embryonic stem cells (hESCs) in vitro. Light activation of transplanted astrocytes in the substantia nigra (SN) also upregulates bFGF levels in vivo and promotes the regenerative effects of co-transplanted stem cells. Importantly, upregulation of bFGF levels, by specific light activation of endogenous astrocytes in the SN, enhances the DA differentiation of transplanted stem cells and promotes brain repair in a mouse model of Parkinson’s disease (PD). Our study indicates that astrocyte-derived bFGF is required for regulation of DA differentiation of the stem cells and may provide a strategy targeting astrocytes for treatment of PD.
Highlights
Astrocytes provide neuroprotective effects against degeneration of dopaminergic (DA) neurons and play a fundamental role in DA differentiation of neural stem cells
We studied the effect of conditioned medium (CM) on the proliferative potential of human embryonic stem cells (hESCs):the 5-ethynyl-2-deoxyuridine (EdU) incorporation assay showed that the percentage of EdU-positive cells in the ChETA þ light group increased significantly compared with Control group (Supplementary Fig. 2d)
In the current study we investigated the effects of optogenetically activated astrocytes on the DA differentiation of human embryonic stem cells (ESCs) and the underlying mechanisms, we further explored the effects of specific activation of the endogenous astrocytes on the differentiation of transplanted stem cells and functional brain repair
Summary
Astrocytes provide neuroprotective effects against degeneration of dopaminergic (DA) neurons and play a fundamental role in DA differentiation of neural stem cells. Upregulation of bFGF levels, by specific light activation of endogenous astrocytes in the SN, enhances the DA differentiation of transplanted stem cells and promotes brain repair in a mouse model of Parkinson’s disease (PD). Basic fibroblast growth factor (bFGF), as a physiologically relevant neurotrophic factor, plays an essential role in embryonic development and neural lineage specification of ESCs11,12. It is one of the crucial elements specifying DA differentiation of ESCs that is widely used to induce the tyrosine hydroxylase (TH)-producing DA neurons[13,14]. Here,we hypothesized that specific activation of the midbrain astrocyte population may increase the synthesis or release of bFGF, which may play a role in promoting the DA differentiation of transplanted stem cells and protecting the residual DA neurons in the PD model. To our knowledge, we are the first to demonstrate that specific activation of endogenous astrocytes in the SN through an optogenetic approach promoted the astrocytespecific bFGF release in situ, which substantially enhanced the DA differentiation of transplantedstem cells and promoted the regenerative effects in a mouse model of PD
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