{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:32:20Z","timestamp":1786977140800,"version":"build-2736575974"},"reference-count":67,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2022,7,30]],"date-time":"2022-07-30T00:00:00Z","timestamp":1659139200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000138","name":"U.S. Department of Education","doi-asserted-by":"publisher","award":["P200A210069"],"award-info":[{"award-number":["P200A210069"]}],"id":[{"id":"10.13039\/100000138","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Biotech &amp; Bioengineering"],"published-print":{"date-parts":[[2022,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Glioblastoma (GBM) is the most aggressive type of brain tumor that originates from glioblastoma stem cells (GSCs). In the brain, GSCs are supported by a tumor microenvironment (TME) residing in the perivascular niche and the hypoxic niche. The GBM TME is highly heterogenous and exhibits complex cell\u2010to\u2010cell interactions. Three\u2010dimensional tumorspheres cultured in stem cell\u2010enriching media is often used as an in vitro model. The GBM tumorspheres retain some of the transcriptional and translational GSC features but often fails to recapitulate intertumor heterogeneity. Here, we developed a simple, matrix\u2010free, and in vivo\u2010like GBM\u00a0organoids (GBOs) using patient\u2010derived xenograft GBM lines in small\u2010scale bioreactors. Shear stress was optimized to produce highly reproducible GBOs over 1\u2009mm diameter within 4\u20135 weeks. GBOs exhibited high stemness and strong cell\u2010to\u2010cell interactions compared to conventional tumorsphere cultures. They displayed spatial gradients of hypoxia\u2010inducible factor 1\u03b1 positive hypoxic cores where CD133\u2010positive cells resided and spatially heterogeneous expression of NOTCH and its ligands. We also observed a self\u2010established, hierarchically organized, and heterogeneous TME by GBM transdifferentiation into endothelial cells, pericytes, and astrocytes. Collectively, we demonstrate the ability to biomanufacture uniformly sized GBOs that recapitulate in vivo GBM TME\u00a0features that can serve as an improved GBM in vitro model.<\/jats:p>","DOI":"10.1002\/bit.28191","type":"journal-article","created":{"date-parts":[[2022,7,23]],"date-time":"2022-07-23T00:08:46Z","timestamp":1658534926000},"page":"3252-3274","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Biomanufacturing of glioblastoma organoids exhibiting hierarchical and spatially organized tumor microenvironment via transdifferentiation"],"prefix":"10.1002","volume":"119","author":[{"given":"Seungjo","family":"Park","sequence":"first","affiliation":[{"name":"Department of Chemical and Biological Engineering The University of Alabama Tuscaloosa Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra D.","family":"Avera","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biological Engineering The University of Alabama Tuscaloosa Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6344-1258","authenticated-orcid":false,"given":"Yonghyun","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biological Engineering The University of Alabama Tuscaloosa Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,7,30]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep24552"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/mi9030094"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.18117"},{"issue":"13","key":"e_1_2_8_5_1","first-page":"5262","article-title":"Carbonic anhydrase IX, an endogenous hypoxia marker, expression in head and neck squamous cell carcinoma and its relationship to hypoxia, necrosis, and microvessel density","volume":"61","author":"Beasley N. 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