Reduced mechanical shear is associated with early cortical differentiation and GDNF-GFRA1/RET signalling in human brain organoids.

Authors

Zizhen Zhao, Jingran Du, Shan Zhang, Haowen Shi, Hui Chen, Hong Cheng, Lihua Zhou, Chenju Yi, Jiachuan Wang

Published in

Stem cells translational medicine. Volume 15. Issue 9. Aug 18, 2026.

Abstract

Early cortical differentiation in human brain organoids is a critical step of corticogenesis, but remains poorly coordinated under conventional culture conditions. In a standard orbital shaker system, mechanical shear and variability in extracellular matrix support, can disrupt neuroepithelial organisation, leading to inconsistent early cortical differentiation. Here, we investigated how ClinoStar-associated low-shear culture conditions affect early corticogenic marker expression in brain organoids and examined GFRA1/RET-related signaling as a candidate pathway associated with these culture-related effects. Using a low-shear ClinoStar bioreactor, we observed improved neuroepithelial-like expansion, enhanced tissue organisation, and promoted early cortical differentiation during the neuroepithelial expansion stage. Compared with conventional conditions, low-mechanical shear in ClinoStar was associated with increased proliferation capacity and supported the number of TBR2+ intermediate progenitors and TBR1+ early cortical neurons. Transcriptomic analysis revealed enrichment of neuronal differentiation and neuroactive ligand-receptor interaction pathways, with increased upregulation of GDNF signalling components under reduced mechanical shear. Functional experiments showed that GDNF supplementation increased TBR2+ intermediate progenitor-associated and TBR1+ early neuronal marker-related populations in brain organoids, suggesting a positive effect on early corticogenic marker expression. Consistent with this, GFRA1/RET levels were elevated in organoids in the ClinoStar culture with low-mechanical shear stress, and manipulation of GFRA1 affected early cortical differentiation outcomes. These findings suggest that ClinoStar low-shear culture promoted early corticogenic marker expression, potentially associated with GDNF-GFRA1/RET signalling. Collectively, this study provides a refined culture framework for improving the reproducibility and structural organisation of human brain organoid models of early cortical differentiation.

PMID:
42710856
Bibliographic data and abstract were imported from PubMed on 09 Sep 2026.

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