Nature study finds mouse radial glia in cortical organoids show plastic lineage progression
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A Nature study reports that radial glial progenitors in mouse cortical organoids show high plasticity in proliferative potential instead of the temporally stereotyped lineage progression seen in vivo. The organoids exhibited increased lineage restriction and reduced cell-type diversity among cortical projection neuron clones, despite uniform single-cell transcriptional signatures and a unitary lineage trajectory. The authors attribute the divergence to missing non-cell-autonomous cues that are absent in self-organizing systems or the genuine stem cell niche.
RGP Lineage Plasticity
Radial glial progenitors in mouse cortical organoids did not follow the predictable sequence of symmetric proliferative and asymmetric neurogenic divisions seen in vivo. Using mosaic analysis with double markers (MADM) in mouse embryonic stem cells, the authors tracked clonal outputs and found that proliferative potential remained highly plastic. In vivo mouse RGPs generate projection neurons in units of 8–9 neurons, with birth order determining cell fate and laminar position; organoids did not replicate this stereotyped progression.
Clonal Diversity Loss
Organoid RGPs showed increased lineage restriction, and clones produced fewer cortical projection neuron subtypes than in vivo, unlike the 8–9 neuron units generated by mouse RGPs in the developing cortex. Despite this, single-cell transcriptional signatures of RGPs were uniform and the lineage trajectory appeared unitary. The authors say the mismatch indicates that non-cell-autonomous cues or the genuine stem cell niche are essential for generating clonal cortical cell-type diversity.
What's Next
The next step is to identify which non-cell-autonomous cues are sufficient to restore temporal lineage progression in cortical organoids. It remains unclear whether self-organizing systems can be engineered to replicate clonal cortical cell-type diversity without an intact stem cell niche.
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Nature study finds mouse radial glia in cortical organoids show plastic lineage progression
