Extracellular Matrix Induction of Renal Stem and Progenitor Cell Development
肾干细胞和祖细胞发育的细胞外基质诱导
基本信息
- 批准号:10200365
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-10-01 至 2022-09-30
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAcute Renal Failure with Renal Papillary NecrosisAddressAdultAffectAmericanBindingBiological MarkersBiomedical EngineeringBioreactorsBladderBladder DysfunctionCardiovascular systemCell Differentiation processCell MaturationCellsChronic Kidney FailureClinicalCoculture TechniquesCollagenCommunitiesComplexControlled EnvironmentCuesDevelopmentDiabetes MellitusDialysis procedureDifferentiation and GrowthDiseaseE-CadherinElderlyElementsEnd stage renal failureEnvironmentEvaluationExcisionExpenditureExtracellular MatrixFGF2 geneFibroblastsFinancial HardshipFutureGeneral PopulationGenomic medicineGeographyGoalsGrowthGrowth FactorHealthHemodialysisHigh PrevalenceHumanHypertensionImmunosuppressionIn VitroIndividualInjuryIntercellular JunctionsInterventionInvestigationKidneyKidney DiseasesKidney FailureKidney TransplantationLaboratoriesLamininLigandsLiving DonorsMediatingMedicalMedicareMesenchymeMethodsModelingModificationMonitorMorbidity - disease rateNatural regenerationNephronsOrganOrgan Culture TechniquesOrgan SizeOrgan TransplantationOrganogenesisParacrine CommunicationPathway interactionsPatientsPeptidesPerfusionPeripheral Vascular DiseasesPopulationProcessPublic HealthRenal TissueRenal functionRenal tubule structureRodentRoleServicesSignal TransductionSkinStem Cell DevelopmentStructural ProteinStructureSystemTechnologyTestingTherapeutic UsesTimeTissue EngineeringTissue TransplantationTissuesTransplantationUrsidae FamilyVascular Endothelial Growth FactorsVeteransWaiting Listsbasecell typediabetic ulcerembryonic stem cellfirst-in-humanhealth administrationhigh throughput screeninghuman pluripotent stem cellimprovedinduced pluripotent stem cellinjury and repairinnovationmortalitypersonalized medicinepreservationpreventprogenitorpublic health relevancereconstitutionrepairedresponsescaffoldstemstem cell biologystem cell differentiationstem cell technologystem cellsthree dimensional cell culturetissue regenerationtissue support frametooltwo-dimensional
项目摘要
DESCRIPTION (provided by applicant):
Acute kidney injury (AKI) and chronic kidney disease (CKD) are critical health problems in the Veteran community. In the absence of sufficient tubule repair after injury and despite the best medical therapy, decreasing kidney function often leads to dialysis and significant morbidity and mortality. The growing gap between the increasing demand and limited supply of transplantable organs is now the chief limiting obstacle preventing extension of kidney transplantation to all patients and veterans with end-stage renal disease. Stem cell biology, and in particular induced pluripotent stem cell (iPSC) technology, provides new strategies via innovative advances in genomic and personalized medicine to decode the mechanisms of renal repair and pathways influencing tissue regeneration, to offer an opportunity for future clinical intervention to repair
injured renal tubules or replace failed renal tissue. We address the current limitation in stem cel technology-to delineate and target mechanisms of stem cell maturation in three-dimensional (3D) tissue. To define these fundamental parameters we developed and characterized acellular 3D scaffolds from decellularized rodent kidneys, which allow study of growth and differentiation of stem and progenitor cells toward metanephric mesenchyme, and ultimately a mature renal lineage. Evidence from our group, as well as others, indicate that signals from 3D extracellular matrix (ECM) scaffolds induce stem cell maturation. Our findings show stem cell differentiation in a geographically-specific manner with maturation and expression of E-cadherin centered around matrix-lined tubules. Our 3D scaffolds are bioactive, consisting of natural tissue- specific
ECM with structural proteins (e.g. collagens, laminins) and growth factors (e.g. VEGF, bFGF) known to mediate renal organogenesis. We will test the hypothesis that signals from 3D renal ECM tissue are a prerequisite to direct proper stem and renal progenitor cell differentiation to form nephron segments. The cellular complexity of the kidney prompts us to specifically focus on tubulogenesis within acellular matrix scaffolds and determine the requirements for regeneration and tissue formation in vitro. We will use two renal stem/progenitor populations: an early kidney-derived, adult renal progenitor cell capable of intercalating into developing nephrons, and a population of pluripotent reprogrammed human iPSCs and embryonic stem cells that differentiate to form early metanephric tissue. Our overall goal using 3D scaffolds and stem cells is to elucidate the elements of stem cell-matrix interactions that drive differentiation Aim 1 will investigate stem/progenitor cell response to modification of the renal ECM in a high-throughput system using small ECM scaffolds to rapidly screen conditions favoring differentiation. In this process we identify the requisite matrix-bound growth factors and test the
role of ECM remodeling by renal stroma fibroblasts. Aim 2 will assess scalability by analyzing the requirements for stem/progenitor growth in larger-scale organ-sized scaffolds and explore tubule formation within a perfusion bioreactor. This system serves as a model for nephron development within a full-scale kidney scaffold and establishes the requirements for stem cell differentiation and scaffold repopulation within normal and diseased ECM. This investigative strategy uses innovative matrix technology to modify tissue scaffolds with fibroblasts and bioactive ligands to delineate mechanisms of differentiation in 3D. Our systematic investigation is highly significant because it will decode the critical factors involved in nephron reconstitutio, which are critical next steps in tubule repair and renal tissue regeneration.
描述(由申请人提供):
急性肾损伤(阿基)和慢性肾病(CKD)是退伍军人社区的严重健康问题。在损伤后缺乏足够的肾小管修复的情况下,尽管有最好的药物治疗,肾功能下降往往导致透析和显著的发病率和死亡率。日益增长的需求和有限的可移植器官供应之间的差距越来越大,现在是阻碍肾移植扩展到所有终末期肾病患者和退伍军人的主要限制性障碍。干细胞生物学,特别是诱导多能干细胞(iPSC)技术,通过基因组和个性化医学的创新进展提供了新的策略,以解码肾脏修复的机制和影响组织再生的途径,为未来的临床干预提供机会,以修复肾脏。
损伤的肾小管或替换衰竭的肾组织。我们解决了目前干细胞技术的局限性,即在三维(3D)组织中描绘和靶向干细胞成熟的机制。为了定义这些基本参数,我们开发并表征了来自脱细胞啮齿动物肾脏的脱细胞3D支架,其允许研究干细胞和祖细胞向后肾间充质的生长和分化,并最终形成成熟的肾脏谱系。来自我们小组以及其他人的证据表明,来自3D细胞外基质(ECM)支架的信号诱导干细胞成熟。我们的研究结果表明,干细胞分化的地理特异性的方式与成熟和表达的E-钙粘蛋白围绕基质内衬小管。我们的3D支架具有生物活性,由天然组织特异性
ECM与已知介导肾器官发生的结构蛋白(例如胶原蛋白、层粘连蛋白)和生长因子(例如VEGF、bFGF)。我们将测试来自3D肾ECM组织的信号是指导适当的干细胞和肾祖细胞分化以形成肾单位片段的先决条件的假设。肾脏的细胞复杂性促使我们特别关注脱细胞基质支架内的小管形成,并确定体外再生和组织形成的要求。我们将使用两个肾干细胞/祖细胞群:一个早期肾源性的,成年肾祖细胞能够嵌入到发育中的肾单位,和一个多能重编程的人iPSC和胚胎干细胞群,分化形成早期后肾组织。我们使用3D支架和干细胞的总体目标是阐明驱动分化的干细胞-基质相互作用的要素。目标1将研究干/祖细胞对使用小ECM支架的高通量系统中的肾ECM修饰的反应,以快速筛选有利于分化的条件。在这个过程中,我们确定了必要的基质结合生长因子,并测试了
肾间质成纤维细胞ECM重塑的作用。目标2将通过分析干细胞/祖细胞在大规模器官大小的支架中生长的要求来评估可扩展性,并探索灌注生物反应器内的小管形成。该系统用作全尺寸肾支架内肾单位发育的模型,并建立了正常和患病ECM内干细胞分化和支架再增殖的要求。这项研究策略使用创新的基质技术,用成纤维细胞和生物活性配体修饰组织支架,以描绘3D分化机制。我们的系统研究是非常重要的,因为它将解码参与肾单位重建的关键因素,这是肾小管修复和肾组织再生的关键下一步。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Ensuring the safe and effective FDA regulation of fecal microbiota transplantation.
- DOI:10.1093/jlb/lsv032
- 发表时间:2015-07
- 期刊:
- 影响因子:3.4
- 作者:Sachs RE;Edelstein CA
- 通讯作者:Edelstein CA
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JASON A WERTHEIM其他文献
JASON A WERTHEIM的其他文献
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{{ truncateString('JASON A WERTHEIM', 18)}}的其他基金
Repairing the Kidney Endothelium via Targeted Extracellular Matrix Modifiers
通过靶向细胞外基质修饰剂修复肾内皮
- 批准号:
10213014 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Repairing the Kidney Endothelium via Targeted Extracellular Matrix Modifiers
通过靶向细胞外基质修饰剂修复肾内皮
- 批准号:
10454117 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Repairing the Kidney Endothelium via Targeted Extracellular Matrix Modifiers
通过靶向细胞外基质修饰剂修复肾内皮
- 批准号:
10205482 - 财政年份:2020
- 资助金额:
-- - 项目类别:
ShEEP Request for Enabling 3D Nano-Printer Technology
ShEEP 请求启用 3D 纳米打印机技术
- 批准号:
10179144 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Repairing the Kidney Endothelium via Targeted Extracellular Matrix Modifiers
通过靶向细胞外基质修饰剂修复肾内皮
- 批准号:
9449094 - 财政年份:2018
- 资助金额:
-- - 项目类别:
Optimization and control of hepatocyte activity via biofunctional modification
通过生物功能修饰优化和控制肝细胞活性
- 批准号:
9246530 - 财政年份:2014
- 资助金额:
-- - 项目类别:
Optimization and control of hepatocyte activity via biofunctional modification
通过生物功能修饰优化和控制肝细胞活性
- 批准号:
8679763 - 财政年份:2014
- 资助金额:
-- - 项目类别: