Generation of mature human embryonic stem cell-derived left ventricular cardiomyocytes for transplantation in a large animal model
产生成熟的人胚胎干细胞衍生的左心室心肌细胞用于在大型动物模型中移植
基本信息
- 批准号:10202722
- 负责人:
- 金额:$ 64.41万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-07-15 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:AccountingActivinsAddressAmerican Heart AssociationAnimal ModelAreaArrhythmiaAutomobile DrivingBiologicalBlood flowCardiacCardiac MyocytesCardiovascular DiseasesCardiovascular systemCell Differentiation processCell MaturationCell TherapyCell TransplantationCellsCessation of lifeCicatrixClinical TrialsCollaborationsComputational BiologyDataDevelopmentDevelopment PlansDisease ProgressionEffectivenessElectrophysiology (science)EngraftmentEnsureEventFacilities and Administrative CostsFamily suidaeFutureGene ExpressionGene Expression ProfileGenerationsGenesGenetic TranscriptionGoalsHealthHealth Care CostsHeartHeart DiseasesHeart failureIn VitroInfarctionInjuryIschemiaLaboratoriesLeadLeftLightMediatingModelingMolecularMolecular ProfilingMonitorMorbidity - disease rateMuscleMyocardial InfarctionMyocardial Reperfusion InjuryMyocardial tissueMyocardiumNatural regenerationNodalOutcomePathway interactionsPatientsPopulationProductivityPropertyProtocols documentationRegulator GenesReportingReproducibilityResourcesRiskSafetySignal PathwaySourceStructureTestingTherapeuticTissuesTransgenic OrganismsTransplantationTretinoinVentricularadult stem cellanimal facilitybasecell injurycell typeclinical applicationclinically relevantcomputerized toolscostdifferentiation protocolefficacy testingexperiencefunctional improvementheart damageheart functionhuman embryonic stem cellhuman embryonic stem cell linehuman embryonic stem cell transplantationimaging studyimprovedinjuredinnovationinsightmortalitynodal myocytenon-invasive imagingprogenitorprotein expressionprototyperegenerativeregenerative cellself-renewalsingle cell analysissingle cell sequencingstemstem cell differentiationstem cell therapysuccesstraditional therapy
项目摘要
ABSTRACT
Human embryonic stem cells (hESCs) can be an unlimited source for generation of cardiovascular cells at
different stages of their development. The ultimate goal of cardiac stem cell therapy is to deliver therapeutically
relevant cells to damaged hearts that can repopulate the injury area, electromechanically couple with the host
myocardium, and provide functional benefit. However, the clinical application of hESC-based cell therapy is
limited by many technical challenges including the inability to deliver a pure population of cardiomyocytes that
can functionally integrate into the host myocardium without the risk of arrhythmias. Additionally, lack of
appropriate large animal models with clinically relevant injury prototype has limited our understanding of the fate
of hESC-derived cells after transplantation.
Attempts to date for delivery of hESC-derived cardiac cells has relied on differentiation protocols that result
in beating cells in a dish, which are considered cardiomyocytes for transplantation. However, their impurity, which
may include cardiomyocyte subtypes such as pacemaker cells, may lead to serious safety issues, such as
arrhythmias. Therefore, isolation of a pure population left ventricular (LV) cardiomyocytes that closely resemble
the endogenous cardiomyocytes is an important goal of cell-based therapy. Recently, we isolated and
characterized first- and second-heart filed cardiomyocytes, as well as pacemaker cells from differentiating
hESCs. Additionally, with our computational biologist collaborator, we reported how cardiovascular progenitors
make fate decisions during development. And finally, our group established the first large animal facility at UCLA
where we have performed hESC-derived transplantation in porcine infarct hearts. We believe the expertise and
experience of our group along with the available resources will contribute to the success of the proposed project.
We hypothesize that hESC-derived LV cardiomyocytes can engraft into the host myocardium and provide
functional benefit. In specific aim 1, we plan to isolate LV cardiomyocytes from differentiating hESCs by
modifying Activin/Nodal and retinoic acid signaling pathway. We will fully characterize these cells based on their
gene and protein expression, as well as electrophysiology at a single cell level. In specific aim 2, by analyzing
single cell gene expression profile of hESC-derived and endogenous cardiomyocytes at different stages of
development, we plan to explore the molecular signatures that mediate differentiation and maturation in vitro.
And finally, in specific aim 3, we propose to transplant hESC-derived LV cardiomyocytes in a clinically relevant
model of a porcine myocardial infarction. We will perform invasive and non-invasive tests to determine structural
and functional integration of the transplanted cells into the host myocardium. We believe that the success of this
project will enhance our understanding of hESC differentiation and maturation to chamber-specific
cardiomyocytes, provide insight into their fate after transplantation, and set the platform for future cell-based
therapies to treat heart disease.
摘要
人类胚胎干细胞(HESCs)可作为心血管细胞生成的无限来源
它们处于不同的发展阶段。心脏干细胞治疗的最终目标是提供治疗性的
与受损心脏相关的细胞,可以重新填充损伤区域,与宿主机电耦合
心肌,并提供功能上的好处。然而,基于hESC的细胞治疗的临床应用是
受限于许多技术挑战,包括无法提供纯净的心肌细胞群
可以在功能上整合到宿主心肌中,而不会有心律失常的风险。此外,缺乏
具有临床相关损伤原型的合适的大型动物模型限制了我们对命运的理解
移植后hESC来源细胞的数量。
迄今为止,hESC来源的心肌细胞的交付尝试依赖于分化方案,结果是
在培养皿中击打细胞,这些细胞被认为是用于移植的心肌细胞。然而,它们的杂质,即
可能包括心肌细胞亚型,如起搏细胞,可能会导致严重的安全问题,如
心律不齐。因此,分离出一种与左心室(LV)心肌细胞非常相似的纯群体
内源性心肌细胞是细胞治疗的重要目标。最近,我们分离出了
表征第一和第二心脏区域的心肌细胞以及来自分化的起搏细胞
HESCS。此外,与我们的计算生物学家合作,我们报告了心血管祖细胞是如何
在发展中决定命运。最后,我们团队在加州大学洛杉矶分校建立了第一个大型动物设施
我们在猪梗死心脏中进行了hESC来源的移植。我们相信专业知识和
我们小组的经验以及可用的资源将有助于拟议项目的成功。
我们假设hESC来源的LV心肌细胞可以移植到宿主心肌中,并为
功能效益。在特定的目标1中,我们计划通过以下方法从分化的hESCs中分离出LV心肌细胞
修饰激活素/节点和维甲酸信号通路。我们将根据这些细胞的特性来充分描述它们的特征
基因和蛋白质的表达,以及单细胞水平的电生理学。在具体目标2中,通过分析
不同时期人胚胎干细胞来源和内源性心肌细胞的单细胞基因表达谱
为了开发,我们计划探索在体外调节分化和成熟的分子签名。
最后,在特定的目标3中,我们建议将hESC来源的LV心肌细胞移植到临床相关的
猪心肌梗死模型。我们将进行侵入性和非侵入性测试,以确定结构
以及移植细胞与宿主心肌的功能整合。我们相信,这一成功
该项目将加强我们对hESC分化和成熟到特定小室的理解
心肌细胞,提供对其移植后命运的洞察,并为未来基于细胞的研究奠定平台
治疗心脏病的疗法。
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(0)
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Reza Ardehali其他文献
Reza Ardehali的其他文献
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{{ truncateString('Reza Ardehali', 18)}}的其他基金
The role of pericytes in scar formation following stroke and myocardial infarction
周细胞在中风和心肌梗死后疤痕形成中的作用
- 批准号:
10358534 - 财政年份:2020
- 资助金额:
$ 64.41万 - 项目类别:
The role of pericytes in scar formation following stroke and myocardial infarction
周细胞在中风和心肌梗死后疤痕形成中的作用
- 批准号:
9974106 - 财政年份:2020
- 资助金额:
$ 64.41万 - 项目类别:
Generation of mature human embryonic stem cell-derived left ventricular cardiomyocytes for transplantation in a large animal model
产生成熟的人胚胎干细胞衍生的左心室心肌细胞用于在大型动物模型中移植
- 批准号:
9803361 - 财政年份:2019
- 资助金额:
$ 64.41万 - 项目类别:
Generation of mature human embryonic stem cell-derived left ventricular cardiomyocytes for transplantation in a large animal model
产生成熟的人胚胎干细胞衍生的左心室心肌细胞用于在大型动物模型中移植
- 批准号:
10852455 - 财政年份:2019
- 资助金额:
$ 64.41万 - 项目类别:
Generation of mature human embryonic stem cell-derived left ventricular cardiomyocytes for transplantation in a large animal model
产生成熟的人胚胎干细胞衍生的左心室心肌细胞用于在大型动物模型中移植
- 批准号:
10430029 - 财政年份:2019
- 资助金额:
$ 64.41万 - 项目类别:
Exploring heterogeneity of cardiac fibroblasts to reverse fibrosis
探索心脏成纤维细胞的异质性以逆转纤维化
- 批准号:
8751716 - 财政年份:2014
- 资助金额:
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