Pericytes and postnatal alveolarization: Role of hypoxia inducible factors
周细胞和出生后肺泡化:缺氧诱导因素的作用
基本信息
- 批准号:10615235
- 负责人:
- 金额:$ 62.16万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-05-01 至 2026-04-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAffectAlveolarAreaBasement membraneBiologicalBirthBlood VesselsBlood capillariesBrainBronchopulmonary DysplasiaCell CommunicationCell ProliferationCellsChIP-seqChronic lung diseaseCoculture TechniquesContractsDataDevelopmentDiameterDiseaseEndothelial CellsEnterobacteria phage P1 Cre recombinaseErythropoietinExposure toGasesGene Expression ProfileGenesGeneticGoalsGrowthHyperoxiaHypoxiaHypoxia Inducible FactorImageImpairmentIn VitroIndividualInjuryKnockout MiceLifeLungLung CapacityLung diseasesMechanical ventilationMediatingMesenchymalMicrocirculationMolecularMorphogenesisMusMyofibroblastNatural regenerationNeonatalOxygenPathway interactionsPatternPericytesPhenotypePhysiologicalPlayPolysaccharidesPregnancyPremature InfantProliferatingRegulationRelaxationReporterResolutionRoleSignal TransductionSmooth Muscle MyocytesStimulusSurfaceTestingTimeVascular Endothelial CellVascular Endothelial Growth FactorsVascular Smooth Muscleangiogenesiscarbohydrate binding proteincarbohydrate receptorcell motilitycomputerized toolsexperimental studygain of functionin vivoinfancyinsightloss of functionlung developmentmigrationmouse modelneonatal exposureneonatal micenormoxiaparacrinepostnatalpostnatal developmentpreservationpreventpromoterpupsensorsingle-cell RNA sequencingtherapy developmenttranscription factortranscriptometranscriptomics
项目摘要
During alveolarization, the final stage of lung development, angiogenesis drives the exponential, postnatal
increase in gas-exchange surface area. Pericytes play a dual role in angiogenesis. Initially, pericytes stimulate
and guide endothelial cells (EC) during early microvascular growth and subsequently constrain EC proliferation
and migration during vessel stabilization. However, the molecular mechanisms that regulate pericyte phenotype
to drive these distinct roles in vascular growth and stability remain poorly defined. Addressing this gap may
motivate the development of therapies to treat neonatal lung diseases marked by compromised angiogenesis,
including bronchopulmonary dysplasia. O2-sensitive transcription factors, termed hypoxia-inducible factors (HIF)
are central regulators of angiogenesis. Our preliminary data suggest that HIF activity in select subsets of lung
mesenchymal cells (MC) is required for postnatal angiogenesis and alveolarization. Genetic gain- and loss-of-
function studies using Tagln promoter driven Cre-recombinase (a gene expressed by multiple MC including
pericytes), demonstrated that Tagln-specific HIF stabilization preserved pulmonary vascular and alveolar
growth in hyperoxia. Conversely, Tagln-specific Hif-1a deletion impaired pulmonary angiogenesis and
alveolarization even in normoxia. However, the specific Tagln-expressing MC responsible was not identified. Our
single cell transcriptomic studies point to a unique, hyperoxia-sensitive, developmental role for pericytes and
HIF signaling in pericytes during postnatal lung development. These studies identified: (i) marked changes
in the transcriptome of early (P7) versus late (P21) pericytes with blood vessel morphogenesis as the most
enriched biologic pathway; (ii) a peak in both proliferating pericytes and microvascular EC at P7; (iii) persistent
Hif-1a, -2a, and HIF downstream target expression in pericytes, including Rgs5, a gene that marks activated,
angiogenic pericytes, and Lgals1, a gene encoding a secreted, pro-angiogenic, carbohydrate-binding protein;
and (iv) hyperoxia-induced loss of ~90% of pericytes, all proliferating pericytes, and suppressed HIF-dependent,
pericyte-EC interactions. These observations suggest the overall working hypothesis that HIF-mediated
alterations in pericyte phenotype during postnatal development modulate the pulmonary angiogenesis
that drives alveolarization. that will be tested in 3 specific aims. Aim 1 will use genetic mouse models, primary
pericyte cultures, and ChIP-Seq to define the developmental role of HIF in pericytes on lung vascular growth.
Aim 2 will use primary pericyte and EC co-cultures and loss of function strategies to determine if developmental
regulation of select HIF-regulated targets in lung pericytes modulate pericyte phenotype and EC angiogenic
function. Aim 3 will use HIF reporter mice, deep scRNA-Seq and genetic lineage tracing to determine if hyperoxia
suppresses pericyte HIF-signaling, and disrupts pericytes fate and ontogeny during late lung development. By
focusing on the lung pericyte, at single cell resolution, these studies will provide insight into pulmonary vascular
development and identify strategies to promote lung growth and regeneration.
在肺泡形成期间,肺发育的最后阶段,血管生成驱动指数生长,
增加气体交换表面积。周细胞在血管生成中起双重作用。最初,周细胞刺激
并在早期微血管生长期间引导内皮细胞(EC),随后抑制EC增殖
以及血管稳定期间的迁移。然而,调节周细胞表型的分子机制
驱动这些在血管生长和稳定性中的不同作用仍然不清楚。解决这一差距可能
促进治疗以血管生成受损为标志的新生儿肺部疾病的疗法的开发,
包括支气管肺发育不良氧敏感性转录因子,称为缺氧诱导因子(HIF)
是血管生成的中心调节器。我们的初步数据表明,HIF活性在选择的亚组肺
间充质细胞(MC)是出生后血管生成和肺泡形成所必需的。遗传增益和损失
使用Tagln启动子驱动的Cre重组酶(由多个MC表达的基因,包括
周细胞),表明Tagln特异性HIF稳定化保留了肺血管和肺泡
在高氧环境中生长。相反,Tagln特异性Hif-1a缺失会损害肺血管生成,
肺泡化甚至在常氧条件下。然而,具体的Tagln表达MC负责没有确定。我们
单细胞转录组学研究指出,周细胞具有独特的、高氧敏感的发育作用,
出生后肺发育过程中周细胞中的HIF信号。这些研究发现:(一)显著变化
在早期(P7)与晚期(P21)周细胞的转录组中,血管形态发生最多
富集的生物途径;(ii)在P7时增殖的周细胞和微血管EC两者中的峰值;(iii)持续的
HIF-1a、HIF-2a和HIF下游靶向周细胞表达,包括Rgs 5,一种标志激活的基因,
血管生成周细胞,和Lgals 1,编码分泌的促血管生成碳水化合物结合蛋白的基因;
和(iv)高氧诱导的约90%的周细胞损失,所有的周细胞都在增殖,并且抑制HIF依赖性,
周细胞-EC相互作用。这些观察结果表明,总体工作假设,HIF介导的
出生后发育过程中周细胞表型的改变调节肺血管生成
导致肺泡化将在三个具体目标中进行测试。Aim 1将使用遗传小鼠模型,
周细胞培养物和ChIP-Seq来确定周细胞中HIF对肺血管生长的发育作用。
目的2将使用原代周细胞和EC共培养和功能丧失策略来确定发育是否
肺周细胞中选择的HIF调节靶的调节调节周细胞表型和EC血管生成
功能目的3将利用HIF报告小鼠、深度scRNA-Seq和遗传谱系追踪来确定高氧
抑制周细胞HIF信号传导,并在肺发育后期破坏周细胞命运和个体发育。通过
以单细胞分辨率关注肺周细胞,这些研究将提供对肺血管
发展和确定促进肺生长和再生的策略。
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Loss of prolyl hydroxylase 1 and 2 in SM22α-expressing cells prevents Hypoxia-Induced pulmonary hypertension.
SM22α 表达细胞中脯氨酰羟化酶 1 和 2 的丢失可防止缺氧引起的肺动脉高压。
- DOI:10.1152/ajplung.00428.2022
- 发表时间:2023
- 期刊:
- 影响因子:0
- 作者:Barnes,ElizabethA;Ito,Reiji;Che,Xibing;Alvira,CristinaM;Cornfield,DavidN
- 通讯作者:Cornfield,DavidN
Delivering a New Future for People With Cystic Fibrosis.
为囊性纤维化患者创造新的未来。
- DOI:10.1542/peds.2023-062985
- 发表时间:2023
- 期刊:
- 影响因子:8
- 作者:Burgener,ElizabethB;Cornfield,DavidN
- 通讯作者:Cornfield,DavidN
Hyperoxia prevents the dynamic neonatal increases in lung mesenchymal cell diversity.
- DOI:10.1038/s41598-023-50717-w
- 发表时间:2024-01-23
- 期刊:
- 影响因子:4.6
- 作者:Zanini, Fabio;Che, Xibing;Suresh, Nina E.;Knutsen, Carsten;Klavina, Paula;Xie, Yike;Domingo-Gonzalez, Racquel;Liu, Min;Kum, Alexander;Jones, Robert C.;Quake, Stephen R.;Alvira, Cristina M.;Cornfield, David N.
- 通讯作者:Cornfield, David N.
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Cristina Maria Alvira其他文献
Cristina Maria Alvira的其他文献
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{{ truncateString('Cristina Maria Alvira', 18)}}的其他基金
Pericytes and postnatal alveolarization: Role of hypoxia inducible factors
周细胞和出生后肺泡化:缺氧诱导因素的作用
- 批准号:
10467727 - 财政年份:2022
- 资助金额:
$ 62.16万 - 项目类别:
Developmental Heterogeneity of Pulmonary Endothelial Phenotype at Single Cell Resolution
单细胞分辨率肺内皮表型的发育异质性
- 批准号:
10678976 - 财政年份:2021
- 资助金额:
$ 62.16万 - 项目类别:
Developmental Heterogeneity of Pulmonary Endothelial Phenotype at Single Cell Resolution
单细胞分辨率肺内皮表型的发育异质性
- 批准号:
10211048 - 财政年份:2021
- 资助金额:
$ 62.16万 - 项目类别:
Diverse Homeostatic Roles for Distinct Macrophages in the Developing Lung Vasculature
不同巨噬细胞在发育中的肺血管系统中的多种稳态作用
- 批准号:
10583456 - 财政年份:2021
- 资助金额:
$ 62.16万 - 项目类别:
Diverse Homeostatic Roles for Distinct Macrophages in the Developing Lung Vasculature
不同巨噬细胞在发育中的肺血管系统中的多种稳态作用
- 批准号:
10362528 - 财政年份:2021
- 资助金额:
$ 62.16万 - 项目类别:
Novel pathways regulating calcium mediated contractility in the pregnant uterus
调节妊娠子宫钙介导的收缩性的新途径
- 批准号:
10373975 - 财政年份:2018
- 资助金额:
$ 62.16万 - 项目类别:
Novel pathways regulating calcium mediated contractility in the pregnant uterus
调节妊娠子宫钙介导的收缩性的新途径
- 批准号:
9893885 - 财政年份:2018
- 资助金额:
$ 62.16万 - 项目类别:
Novel Molecular Mechanisms Regulating Postnatal Pulmonary Angiogenesis
调节产后肺血管生成的新分子机制
- 批准号:
8686276 - 财政年份:2014
- 资助金额:
$ 62.16万 - 项目类别:
Novel Molecular Mechanisms Regulating Postnatal Pulmonary Angiogenesis
调节产后肺血管生成的新分子机制
- 批准号:
9059764 - 财政年份:2014
- 资助金额:
$ 62.16万 - 项目类别:
Novel Molecular Mechanisms Regulating Postnatal Pulmonary Angiogenesis
调节产后肺血管生成的新分子机制
- 批准号:
9265926 - 财政年份:2014
- 资助金额:
$ 62.16万 - 项目类别:
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