{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T23:07:35Z","timestamp":1788908855647,"version":"build-2803163510"},"reference-count":35,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T00:00:00Z","timestamp":1788825600000},"content-version":"vor","delay-in-days":21,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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.<\/jats:p>","DOI":"10.1093\/stcltm\/szag070","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T11:51:02Z","timestamp":1784202662000},"source":"Crossref","is-referenced-by-count":0,"title":["Reduced mechanical shear is associated with early cortical differentiation and GDNF-GFRA1\/RET signalling in human brain organoids"],"prefix":"10.1093","volume":"15","author":[{"given":"Zizhen","family":"Zhao","sequence":"first","affiliation":[{"name":"Shenzhen Traditional Chinese Medicine Hospital, Affiliated to Nanjing University of Chinese Medicine , Shenzhen, 518033,","place":["China"]},{"name":"Department of Geriatrics, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen Traditional Chinese Medicine Hospital , Shenzhen, 518033,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingran","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, The Seventh Affiliated Hospital of Sun Yat-sen University , Shenzhen, 518107,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Yangzhou Maternal and Child Health Care Hospital Affiliated to Yangzhou University , Yangzhou, 225006,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haowen","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Anatomy, School of Medicine (Shenzhen), Sun Yat-sen University , Shenzhen, 518107,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6883-3752","authenticated-orcid":false,"given":"Hui","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Faculty of Science, University of Technology Sydney , Ultimo, NSW, 2007,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Geriatrics, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen Traditional Chinese Medicine Hospital , Shenzhen, 518033,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lihua","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Anatomy, School of Medicine (Shenzhen), Sun Yat-sen University , Shenzhen, 518107,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8686-4525","authenticated-orcid":false,"given":"Chenju","family":"Yi","sequence":"additional","affiliation":[{"name":"Department of Geriatrics, The Seventh Affiliated Hospital of Sun Yat-sen University , Shenzhen, 518107,","place":["China"]},{"name":"Guangdong Provincial Key Laboratory of Digestive Cancer Research , Shenzhen, 518107,","place":["China"]},{"name":"Shenzhen Key Laboratory of Chinese Medicine Active Substance Screening and Translational Research , Shenzhen, 518107,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9517-924X","authenticated-orcid":false,"given":"Jiachuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Shenzhen Traditional Chinese Medicine Hospital, Affiliated to Nanjing University of Chinese Medicine , Shenzhen, 518033,","place":["China"]},{"name":"Department of Geriatrics, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen Traditional Chinese Medicine Hospital , Shenzhen, 518033,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,9,8]]},"reference":[{"key":"2026090818343882900_szag070-B1","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1038\/nature12517","article-title":"Cerebral organoids model human brain development and microcephaly","volume":"501","author":"Lancaster","year":"2013","journal-title":"Nature"},{"key":"2026090818343882900_szag070-B2","doi-asserted-by":"publisher","first-page":"7302","DOI":"10.1038\/s41467-021-27464-5","article-title":"Single-cell transcriptomics captures features of human midbrain development and dopamine neuron diversity in brain organoids","volume":"12","author":"Fiorenzano","year":"2021","journal-title":"Nat 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