Scaffolds for culture and transplantation of islet organoids
用于胰岛类器官培养和移植的支架
基本信息
- 批准号:10380872
- 负责人:
- 金额:$ 55.07万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-07-01 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAffectAllogenicAmericanAngiogenic FactorArchitectureBeta CellBlood GlucoseBlood VesselsCell Differentiation processCell LineCell TransplantationCellsClinicalClinical TreatmentCollaborationsConsultD CellsDevelopmentDiabetes MellitusDiabetic mouseDonor personEndocrineEngraftmentEnvironmentEventExtracellular Matrix ProteinsExtrahepaticFamily suidaeFatty acid glycerol estersFlow CytometryGene ExpressionGlucoseHepaticHeterogeneityHomologous TransplantationHumanHyperglycemiaHypoglycemiaImmune responseImmunosuppressionIn VitroInsulinInsulin-Dependent Diabetes MellitusInvestigationIslets of Langerhans TransplantationLeadLifeLiverMethodsMonitorMusOrganoidsPancreasPatientsPeritonealPolymersProcessReporterResearchResearch PersonnelRodentSiteSourceStem cell transplantStructureStructure of beta Cell of isletTechniquesTestingTherapeuticTissuesTransplantationVascularizationabdominal fatautoimmune pathogenesisbasecell typeclinically relevantclinically translatabledesigndesign and constructionendocrine pancreas developmenteuglycemiahigh riskhuman pluripotent stem cellin vivoinnovationinsulin secretionisletmouse modelorganoid transplantationpost-transplantprogenitorrestorationscaffoldstem cell differentiationtooltranscription factor
项目摘要
Allogeneic islets transplanted into the liver have shown promise clinically for treatment of Type 1 Diabetes
(T1D), yet their supply is limited. These limitations have led to the investigation of human pluripotent stem cells
(hPSC) as an unlimited source of functional β-cells. Multiple investigators have demonstrated the feasibility of
differentiating hPSC to immature β-cells in vitro and successfully transplanted these cells into rodents which
allowed further maturation into glucose-responsive insulin-producing β-cells. The main challenges of deriving
β-cells in vitro from hPSCs for transplantation are i) the efficiency and consistency of the hPSC differentiation,
and ii) previous transplants are typically performed at non-translatable sites, and the adaptation to clinically
translatable sites adds additional inefficiencies. Herein, we propose an innovative strategy of culturing the
hPSCs on microporous polymer scaffolds as a platform to obtain efficient differentiation of hPSCs to islet
organoids in vitro, which contain multiple endocrine cell types that are found within an islet. Furthermore, the
organoids can be directly transplanted on scaffolds at a clinically relevant site, namely the peritoneal fat,
without disrupting the niche that develops within the pores. PI Dr. Shea has developed the scaffolds for the
transplantation of primary islets into mice at a clinically translatable site that allows for efficient engraftment and
function, and the reversal of hyperglycemia with a minimal islet mass. co-PI Dr. Spence is a developmental
biologist with expertise in organoid culture that is collaborating on the scaffold design and analysis of in vivo
maturation. Aim 1 will test the hypothesis that the differentiation of hPSC-derived pancreatic progenitors on 3D
microporous scaffolds can increase the efficiency for forming islet organoids in vitro. Scaffolds will be created
with controlled architecture and modified with extracellular matrix (ECM) proteins to facilitate organization and
differentiation of cells into islet structures. The maturity of the organoids and cellular subpopulations will be
monitored through flow cytometry, gene expression of pancreatic makers, the activity of key transcription
factors, and insulin secretion. Established conditions for differentiating hPSC to β-cells will be used as a
control. Aim 2 will investigate the in vivo maturation and function following transplantation of scaffolds with islet
organoids in the pores. We will investigate the survival and maturation of the organoids upon transplantation
into the peritoneal fat, considered a translatable site, and observe the restoration of euglycemia in diabetic
mouse models. Dr. Jan Stegemann will consult on vascularization of the graft. In collaboration with a leading
islet biologist, Dr. Peter Arvan, we will assess the function of the transplanted islet organoids relative to that of
native islets, and analyze the cells by flow cytometry and gene expression for relevant pancreatic markers and
sub-populations that are observed. Collectively, these studies will develop scaffolds as a platform that can
facilitate manufacturing of the organoids, which can be readily transplanted while maintaining the niche that
maximally supports engraftment and function.
同种异体胰岛肝内移植治疗1型糖尿病临床应用前景看好
(T1D),然而它们的供应是有限的。这些局限性导致了对人类多能干细胞的研究
(HPSC)作为功能β细胞的无限来源。多名调查人员已经证明了
体外将人骨髓间充质干细胞分化为未成熟的β-细胞并成功地将其移植到啮齿动物体内
使其进一步成熟为对葡萄糖有反应并产生胰岛素的β细胞。派生的主要挑战
用于移植的hPSC的体外β-细胞是:1)hPSC分化的效率和一致性,
和ii)以前的移植通常是在不可移植的部位进行的,并且适应临床
可翻译网站增加了额外的低效。在这里,我们提出了一种创新的战略,培养
HPSCs在微孔聚合物支架上高效分化为胰岛的实验研究
体外有机类物质,含有在胰岛内发现的多种内分泌细胞类型。此外,
类有机物可以直接移植到临床相关部位的支架上,即腹膜脂肪,
而不会破坏毛孔内形成的小生境。派谢伊博士已经为
将初级胰岛移植到小鼠体内的临床可翻译部位,允许有效的植入和
功能,并逆转高血糖与最小的胰岛质量。联合派斯宾塞博士是一名发展中的
在有机体培养方面具有专业知识的生物学家,正在合作进行体内支架的设计和分析
成熟。目的1将验证hPSC来源的胰腺前体细胞在3d内分化的假设
微孔支架可提高胰岛类有机物的体外形成效率。将创建脚手架
具有受控的结构,并用细胞外基质(ECM)蛋白修饰,以促进组织和
细胞分化为胰岛结构。有机体和细胞亚群的成熟度将是
通过流式细胞仪监测胰腺标志物的基因表达、关键转录活性
因子和胰岛素分泌。HPSC分化为β-细胞的既定条件将被用作
控制力。目的2研究胰岛支架移植后的体内成熟和功能
毛孔里有有机化合物。我们将研究器官移植后的存活和成熟情况。
进入腹膜脂肪,被认为是可翻译的部位,并观察糖尿病患者正常血糖的恢复情况
老鼠模型。简·斯特格曼博士将为移植物的血管化提供咨询。与领先的
胰岛生物学家彼得·阿文博士,我们将评估移植的胰岛有机体相对于
原代胰岛,用流式细胞术对细胞进行分析,并对相关的胰腺标志和基因表达进行分析
观察到的亚种群。总的来说,这些研究将开发脚手架作为一个平台,可以
促进有机化合物的制造,这些有机化合物可以很容易地移植,同时保持
最大限度地支持嫁接和功能。
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)
Human Lung Organoid Culture in Alginate With and Without Matrigel to Model Development and Disease.
在含有和不含有基质胶的藻酸盐中培养人肺类器官,以模拟发育和疾病。
- DOI:10.1089/ten.tea.2022.0054
- 发表时间:2022
- 期刊:
- 影响因子:0
- 作者:Dye,BrianaR;Decker,JosephT;Hein,ReneeFC;Miller,AlyssaJ;Huang,Sha;Spence,JasonR;Shea,LonnieD
- 通讯作者:Shea,LonnieD
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Lonnie D Shea其他文献
Lonnie D Shea的其他文献
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{{ truncateString('Lonnie D Shea', 18)}}的其他基金
Scaffolds for culture and transplantation of islet organoids
用于胰岛类器官培养和移植的支架
- 批准号:
10197921 - 财政年份:2020
- 资助金额:
$ 55.07万 - 项目类别:
Scaffolds for culture and transplantation of islet organoids
用于胰岛类器官培养和移植的支架
- 批准号:
9887396 - 财政年份:2020
- 资助金额:
$ 55.07万 - 项目类别:
Microporous scaffolds for enhancing efficiency of beta-cell progenitor maturation in vitro and in vivo
用于提高 β 细胞祖细胞体外和体内成熟效率的微孔支架
- 批准号:
9331833 - 财政年份:2017
- 资助金额:
$ 55.07万 - 项目类别:
Integrated Structural BMP2 Carrier Systems for Cervical Spine Fusion
用于颈椎融合的集成结构 BMP2 载体系统
- 批准号:
8720503 - 财政年份:2011
- 资助金额:
$ 55.07万 - 项目类别:
Protein-Releasing Microporous Scaffolds for Cell Replacement Therapy
用于细胞替代疗法的蛋白质释放微孔支架
- 批准号:
8977538 - 财政年份:2010
- 资助金额:
$ 55.07万 - 项目类别:
Human islet transplantation on microporous scaffolds
微孔支架上的人胰岛移植
- 批准号:
7789811 - 财政年份:2009
- 资助金额:
$ 55.07万 - 项目类别:
Human islet transplantation on microporous scaffolds
微孔支架上的人胰岛移植
- 批准号:
7930629 - 财政年份:2009
- 资助金额:
$ 55.07万 - 项目类别:
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