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:8619338
- 负责人:
- 金额:$ 22.23万
- 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 2015-08-31
- 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
PROJECT SUMMARY
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, 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 proposal we will test the hypothesis that 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 proposal 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
项目摘要
人多能干细胞(hPSC),包括胚胎干细胞和诱导多能干细胞,
提供了无限自我更新潜力和多能性的独特组合,这两种特性赋予了
强大的系统,用于生成正常人体细胞,用于发育研究,毒性测试,
细胞疗法脑微血管内皮细胞(BMEC)是一种特别有前途的细胞类型,
由于BMEC不能容易地从人组织或成体干细胞获得,
在神经系统疾病和药物评估中具有巨大的重要性,
血脑屏障(BBB)。最近,我们的团队开发了一种方案,通过共培养将hPSC分化为BMEC,
分化神经祖细胞和内皮祖细胞的混合群体,然后选择性地继代培养神经祖细胞和内皮祖细胞。
内皮祖细胞,其获得BMEC表型。这些hPSC衍生的BMEC表达脑特异性
标记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,
衍生的BMEC单层产生与体内发现的相当的跨内皮电阻,
在动物模型中显示与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,其重现了关键的体内BBB
表型,并提供了一个新的平台,了解BMEC的发展和调控。但
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纳入BBB期间存在的关键线索的结果
发展一些研究已经暗示流体流动是血管功能的重要调节器,
包括在BMEC中形成屏障。在这个建议中,我们将测试剪切应力提供的假设,
在特定的发育阶段对BBB分化的诱导线索,并在维持BBB分化中起重要作用。
hPSC衍生的BMEC的分化表型。我们团队在机械传导、多能性
干细胞生物学和血脑屏障建模将使我们能够系统地评估切应力对BMEC的作用
BBB表型的分化和维持。这项研究将激发进一步的机制研究
在BBB发育过程中的机械转导中,并导致用于药物的人BBB建模的改进
筛选应用程序。
我们检验这一提议假设的具体目标是:
1.确定剪切应力对BMEC和BMEC分化命运的阶段特异性影响
祖细胞
2.确定切应力对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(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(1)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Sean P Palecek其他文献
Sean P Palecek的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
$ 22.23万 - 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:
$ 22.23万 - 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:
$ 22.23万 - 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:
$ 22.23万 - 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:
$ 22.23万 - 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:
$ 22.23万 - 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:
$ 22.23万 - 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:
8723321 - 财政年份:2013
- 资助金额:
$ 22.23万 - 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:
8681304 - 财政年份:2011
- 资助金额:
$ 22.23万 - 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:
$ 22.23万 - 项目类别:
相似海外基金
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
- 批准号:
BB/Z514391/1 - 财政年份:2024
- 资助金额:
$ 22.23万 - 项目类别:
Training Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
- 批准号:
2312555 - 财政年份:2024
- 资助金额:
$ 22.23万 - 项目类别:
Standard Grant
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
- 批准号:
2327346 - 财政年份:2024
- 资助金额:
$ 22.23万 - 项目类别:
Standard Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
- 批准号:
ES/Z502595/1 - 财政年份:2024
- 资助金额:
$ 22.23万 - 项目类别:
Fellowship
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
- 批准号:
23K24936 - 财政年份:2024
- 资助金额:
$ 22.23万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
- 批准号:
ES/Z000149/1 - 财政年份:2024
- 资助金额:
$ 22.23万 - 项目类别:
Research Grant
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
- 批准号:
2901648 - 财政年份:2024
- 资助金额:
$ 22.23万 - 项目类别:
Studentship
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
- 批准号:
488039 - 财政年份:2023
- 资助金额:
$ 22.23万 - 项目类别:
Operating Grants
New Tendencies of French Film Theory: Representation, Body, Affect
法国电影理论新动向:再现、身体、情感
- 批准号:
23K00129 - 财政年份:2023
- 资助金额:
$ 22.23万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
The Protruding Void: Mystical Affect in Samuel Beckett's Prose
突出的虚空:塞缪尔·贝克特散文中的神秘影响
- 批准号:
2883985 - 财政年份:2023
- 资助金额:
$ 22.23万 - 项目类别:
Studentship