Investigating the Role of Polyploidy in the Maturation of hiPSC-derived Cardiomyocytes
研究多倍体在 hiPSC 来源的心肌细胞成熟中的作用
基本信息
- 批准号:10647907
- 负责人:
- 金额:$ 4.01万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-01 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalATAC-seqAccelerationAdultAffectAnimal ModelArrhythmiaAutomobile DrivingBiologyBiomedical EngineeringBirthCardiacCardiac MyocytesCause of DeathCell Culture SystemCell TherapyCell fusionCellsCharacteristicsCytokinesisDevelopmentDiploidyDiseaseDisease modelDominant-Negative MutationEndowmentEpigenetic ProcessFailureFibroblastsFutureGenerationsGenesGenetic InductionGenetic MarkersGenetic studyHeartHumanImmunocompromised HostIn VitroIncidenceIschemiaLentivirusLinkMechanicsMetabolicMitochondriaMolecularMononuclearMusMuscle DevelopmentMutationMyoblastsMyocardial InfarctionMyocardial IschemiaMyocardiumOutputOxidative StressOxidative Stress InductionPatientsPhenotypePhysiologicalPloidiesPolyploidyProcessPropertyProtocols documentationRattusReperfusion InjuryResistanceRiskRodentRoleSafetySkeletal MuscleStructureTechniquesTestingTherapeuticTherapeutic EffectTissue EngineeringTissue SurvivalTissuesTransgenic AnimalsWorkZebrafishcardiac tissue engineeringcardiogenesiscardioprotectiondrug developmentexperiencefetalheart functionhuman pluripotent stem cellimplantationimprovedin vivoinduced pluripotent stem cellinduced pluripotent stem cell derived cardiomyocytesinjury and repairinnovationmyocardial injuryoverexpressionpostnatalpostnatal developmentpostnatal periodrepairedstress resiliencethree dimensional cell culturetraittranscriptometranscriptome sequencingtranscriptomics
项目摘要
Abstract
Current protocols for in vitro culture of human iPSC-CMs, including 3D tissue-engineering techniques,
produce cells and tissues with immature structural and functional properties characteristic of fetal rather than
adult myocardium. This lack of maturity significantly limits therapeutic potential of hiPSC-CMs by increasing
their arrhythmogenic risks and hinders their use in disease modeling and drug development applications.
Despite the large body of work to improve the maturation state of hiPSC-CMs, one important aspect - cell
polyploidy - has been largely understudied. In vitro cultured hiPSC-CMs are predominantly mononuclear and
diploid, while the adult human myocardium is comprised of nearly 90% polyploid CMs. Polyploidy is a
conserved trait in mammalian CMs and is strongly associated with postnatal heart maturation. However, its
physiological roles are largely unknown. Specifically, it remains unclear whether polyploidization drives
maturation of the heart via specific transcriptomic changes, or if polyploidization is a consequence of
maturation. The main hypothesis of my project is that polyploidy drives cardiac maturation, and that 3D
engineered cardiac tissues (ECTs) made from primarily polyploid hiPSC-CMs will have increased
functionality compared to tissues made from primarily diploid CMs. My promising preliminary results show
that hiPSC-CM polyploidy induced genetically via cytokinesis failure or cell fusion yields increased size,
mitochondria content, and conduction velocity of hiPSC-CMs and force generation of ECTs. In this project, I
will thoroughly characterize process of genetically induced CM polyploidization and determine transcriptomic
(RNAseq) and epigenetic (ATACseq) differences between polyploid and diploid hiPSC-CMs. Furthermore, I
will examine roles of CM polyploidization in structural, functional, and metabolic maturation of ECTs and
determine if polyploidy endows hiPSC-CMs with increased resistance to oxidative stress in vitro and
enhanced therapeutic potential in vivo. By combining basic biology and bioengineering approaches, I hope
to uncover new mechanistic links between CM polyploidy and maturation and provide innovative strategies
to improve safety and efficacy of hiPSC-CM therapies for ischemic heart disease.
摘要
目前用于体外培养人iPSC-CM的方案,包括3D组织工程技术,
产生具有胎儿特征的不成熟的结构和功能特性的细胞和组织,而不是
成人心肌这种成熟度的缺乏显著限制了hiPSC-CM的治疗潜力,
它们的致癌风险并阻碍它们在疾病建模和药物开发应用中的使用。
尽管有大量的工作来改善hiPSC-CM的成熟状态,但一个重要的方面--细胞增殖,
多倍性-已经在很大程度上研究不足。体外培养的hiPSC-CM主要是单核细胞,
成年人心肌中有近90%是多倍体CM。多倍体是一种
在哺乳动物CM中是保守的性状,并且与出生后的心脏成熟密切相关。但其
生理作用在很大程度上是未知的。具体地说,目前还不清楚多倍体化是否驱动了
通过特定的转录组学变化使心脏成熟,或者如果多倍化是
成熟我的项目的主要假设是,多倍性驱动心脏成熟,3D
由主要多倍体hiPSC-CM制成的工程化心脏组织(ECTs)将增加
与主要由二倍体CM制成的组织相比,我有希望的初步结果显示
通过胞质分裂失败或细胞融合遗传诱导的hiPSC-CM多倍性产生增加的大小,
线粒体含量和hiPSC-CM的传导速度以及ECT的力产生。在这个项目中,我
将彻底表征遗传诱导的CM多倍化过程,并确定转录组学
图1显示了多倍体和二倍体hiPSC-CM之间的RNA序列(RNAseq)和表观遗传(ATACseq)差异。而且我
将研究CM多倍化在ECTs结构、功能和代谢成熟中的作用,
确定多倍体是否赋予hiPSC-CM体外增加的抗氧化应激性,
增强体内治疗潜力。通过结合基础生物学和生物工程方法,我希望
揭示CM多倍体和成熟之间的新机制联系,并提供创新策略
改善缺血性心脏病hiPSC-CM疗法的安全性和有效性。
项目成果
期刊论文数量(0)
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{{ truncateString('Nicholas A Strash', 18)}}的其他基金
Investigating the Role of Polyploidy in the Maturation of hiPSC-derived Cardiomyocytes
研究多倍体在 hiPSC 来源的心肌细胞成熟中的作用
- 批准号:
10461716 - 财政年份:2021
- 资助金额:
$ 4.01万 - 项目类别:
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