Shear regulated differentiation of hPSCs to brain endothelial cells
hPSC 向脑内皮细胞的剪切调节分化
基本信息
- 批准号:8723321
- 负责人:
- 金额:$ 18.42万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-09-01 至 2016-08-31
- 项目状态:已结题
- 来源:
- 关键词:Active Biological TransportAffectAnimal ModelAntibodiesAstrocytesBloodBlood - brain barrier anatomyBlood VesselsBlood flowBrainCD31 AntigensCell Differentiation processCell MaintenanceCell modelCellsCoculture TechniquesCuesDevelopmentDiffusionDiseaseDrug TransportElectrical ResistanceElementsEmbryoEndothelial CellsEvaluationExhibitsFunctional disorderGeneticHealthHumanIn VitroKnowledgeLeadMaintenanceMechanicsMediatingMembrane ProteinsMethodologyModelingMonitorNutrientOutcomePericytesPharmaceutical PreparationsPharmacologic SubstancePhenotypePluripotent Stem CellsPopulationPreclinical Drug EvaluationPropertyProteinsProtocols documentationReceptor InhibitionRegenerative MedicineRegulationResearchResistanceRoleSomatic CellSpecific qualifier valueStagingSystemTestingTherapeuticTight JunctionsTissue EngineeringToxicity TestsToxicologyTransport ProcessWorkadult stem cellbasecadherin 5cell dedifferentiationcell typeclinical applicationdesignembryonic stem cellfluid flowhuman embryonic stem cellhuman tissueimprovedin vitro Modelin vivoinduced pluripotent stem cellintercellular communicationmolecular transportermonolayernerve stem cellnervous system disorderneurovascular unitnovelpluripotencypreventprogenitorreceptorrelating to nervous systemresponseself-renewalshear stresssmall moleculestem cell biologystem cell differentiationtool
项目摘要
DESCRIPTION: Human pluripotent stem cells (hPSCs), including embryonic stem cells and induced pluripotent stem cells, provide a unique combination of infinite self-renewal potential and pluripotency, two properties which impart a powerful system for generating normal human somatic cells for developmental studies, toxicity testing, and cellular therapies. Brain microvascular endothelial cells (BMECs) are a particularly promising cell type that can be derived from hPSCs since BMECs cannot easily be obtained from human tissue or adult stem cells and are of tremendous importance in neurological disease and pharmaceutical evaluation of transport across the blood-brain barrier (BBB). Recently, our team developed a protocol to differentiate hPSCs to BMECs by co- differentiating a mixed population of neural and endothelial progenitors, and then selectively subculturing the endothelial progenitors, which acquire BMEC phenotypes. These hPSC-derived BMECs express brain-specific markers including tight junction proteins and molecular transporters. When co-cultured with astrocytes, hPSC- derived BMEC monolayers generate transendothelial electrical resistance comparable to that found in vivo and exhibit polarized transport of nutrients and drugs that correlate with BBB transport in an animal model. These hPSC-derived BMECs provide the first in vitro human BBB model that recapitulates key in vivo BBB phenotypes, and provide a novel platform for understanding BMEC development and regulation. However, the hPSC-derived BMECs lack in vivo levels of BBB marker expression and transporter activity, perhaps as a consequence of the in vitro differentiation microenvironment failing to incorporate key cues present during BBB development. Several studies have implicated fluid flow as an important regulator of vascular function, including barrier formation in BMECs. In this application we will test the hypothesis tha shear stress provides inductive cues on BBB differentiation at specific developmental stages and is important in maintaining the differentiated phenotypes of hPSC-derived BMECs. Our team's expertise in mechanotransduction, pluripotent stem cell biology, and BBB modeling will permit us to systematically assess the role of shear stress on BMEC differentiation and maintenance of BBB phenotypes. This study will then motivate further mechanistic research in mechanotransduction during BBB development and lead to improvements in human BBB modeling for drug screening applications. Our specific aims to test the hypothesis of this application are: 1. Identify stage-specific effects of shear stress on differentiation fates of BMECs and BMEC progenitors 2. Ascertain the effects of shear stress on hPSC-derived BMEC phenotype induction and maintenance 3. Determine the roles of PECAM-1 and VE-cadherin in shear-induced differentiation of BMECs
产品说明:人多能干细胞(hPSC),包括胚胎干细胞和诱导多能干细胞,提供无限自我更新潜力和多能性的独特组合,这两种特性赋予用于产生正常人类体细胞以用于发育研究、毒性测试和细胞疗法的强大系统。脑微血管内皮细胞(BMEC)是一种特别有前途的细胞类型,可以来源于hPSC,因为BMEC无法轻易从人体组织或成人干细胞中获得,并且在神经系统疾病和跨血脑转运的药物评价中具有极其重要的意义屏障(BBB)。最近,我们的团队开发了一种方案,通过共分化神经和内皮祖细胞的混合群体,然后选择性地传代培养获得BMEC表型的内皮祖细胞,将hPSC分化为BMEC。这些hPSC衍生的BMEC表达脑特异性标志物,包括紧密连接蛋白和分子转运蛋白。当与星形胶质细胞共培养时,hPSC衍生的BMEC单层产生与体内发现的相当的跨内皮电阻,并且在动物模型中表现出与BBB转运相关的营养物和药物的极化转运。这些hPSC衍生的BMEC提供了第一个体外人BBB模型,该模型概括了关键的体内BBB表型,并为理解BMEC的发育和调控提供了新的平台。然而,hPSC衍生的BMEC缺乏体内水平的BBB标志物表达和转运蛋白活性,这可能是由于体外分化微环境未能结合BBB发育期间存在的关键线索。一些研究已经暗示流体流动作为血管功能的重要调节器,包括BMEC中的屏障形成。在本申请中,我们将测试剪切应力在特定发育阶段提供BBB分化的诱导线索并且在维持hPSC衍生的BMEC的分化表型中是重要的假设。我们团队在机械转导、多能干细胞生物学和BBB建模方面的专业知识将使我们能够系统地评估剪切应力对BMEC分化和BBB表型维持的作用。这项研究将进一步激发BBB发育过程中机械转导的机制研究,并改善药物筛选应用中的人类BBB建模。我们检验本申请假设的具体目的是:1。确定剪切应力对BMEC和BMEC祖细胞分化命运的阶段特异性影响2。确定剪切应力对hPSC衍生的BMEC表型诱导和维持的影响3.确定PECAM-1和VE-钙粘蛋白在BMEC剪切诱导分化中的作用
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Directed differentiation of human pluripotent stem cells to blood-brain barrier endothelial cells.
- DOI:10.1126/sciadv.1701679
- 发表时间:2017-11
- 期刊:
- 影响因子:13.6
- 作者:Qian T;Maguire SE;Canfield SG;Bao X;Olson WR;Shusta EV;Palecek SP
- 通讯作者:Palecek SP
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Sean P Palecek其他文献
Sean P Palecek的其他文献
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{{ truncateString('Sean P Palecek', 18)}}的其他基金
Label-free single-cell imaging for quality control of cardiomyocyte biomanufacturing
用于心肌细胞生物制造质量控制的无标记单细胞成像
- 批准号:
10675976 - 财政年份:2023
- 资助金额:
$ 18.42万 - 项目类别:
Mechanisms of Shear Induction of Blood-Brain Barrier Phenotypes in Human iPSC-derived Brain Endothelial Progenitors
人 iPSC 来源的脑内皮祖细胞血脑屏障表型的剪切诱导机制
- 批准号:
10328223 - 财政年份:2019
- 资助金额:
$ 18.42万 - 项目类别:
A Multi-Omics Approach to Discover Metabolic Critical Quality Attributes for Cardiomyocyte Biomanufacturing
发现心肌细胞生物制造代谢关键质量属性的多组学方法
- 批准号:
10435467 - 财政年份:2019
- 资助金额:
$ 18.42万 - 项目类别:
Mechanisms of Shear Induction of Blood-Brain Barrier Phenotypes in Human iPSC-derived Brain Endothelial Progenitors
人 iPSC 来源的脑内皮祖细胞血脑屏障表型的剪切诱导机制
- 批准号:
10557176 - 财政年份:2019
- 资助金额:
$ 18.42万 - 项目类别:
A Multi-Omics Approach to Discover Metabolic Critical Quality Attributes for Cardiomyocyte Biomanufacturing
发现心肌细胞生物制造代谢关键质量属性的多组学方法
- 批准号:
10218267 - 财政年份:2019
- 资助金额:
$ 18.42万 - 项目类别:
Prevention of Candida biofilms by localized delivery of aurein analogues
通过局部递送金黄色素类似物预防念珠菌生物膜
- 批准号:
9221080 - 财政年份:2016
- 资助金额:
$ 18.42万 - 项目类别:
Prevention of Candida biofilms by localized delivery of aurein analogues
通过局部递送金黄色素类似物预防念珠菌生物膜
- 批准号:
9813824 - 财政年份:2016
- 资助金额:
$ 18.42万 - 项目类别:
Shear regulated differentiation of hPSCs to brain endothelial cells
hPSC 向脑内皮细胞的剪切调节分化
- 批准号:
8619338 - 财政年份:2013
- 资助金额:
$ 18.42万 - 项目类别:
Prevention of C. Albicans Biofilms by Beta-Peptide Release From Thin Films
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- 批准号:
8681304 - 财政年份:2011
- 资助金额:
$ 18.42万 - 项目类别:
Prevention of C. Albicans Biofilms by Beta-Peptide Release From Thin Films
通过薄膜释放 β 肽来预防白色念珠菌生物膜
- 批准号:
8484784 - 财政年份:2011
- 资助金额:
$ 18.42万 - 项目类别:
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