Loss of progenitor function accelerates lung aging

祖细胞功能丧失加速肺部衰老

• 批准号: 10579157
• 负责人: SUSAN M MAJKA
• 金额: $ 69.86万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-15 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579157
• 关键词: 5 year old; Acceleration; Address; Adult; Age; Aging; Biological Assay; Biology; Blood Vessels; Cardiovascular system; Cell Communication; Cell Count; Cell physiology; Cells; Cellular Structures; Characteristics; Chronic; Chronic Obstructive Pulmonary Disease; Chronic lung disease; Coculture Techniques; Coupled; Data; Development; Disease; Distal; Endothelium; Female; Functional disorder; Goals; Histologic; Homeostasis; Human; Immune; Impairment; In Vitro; Inflammation; Inflammatory; Inflammatory Infiltrate; Interleukin-13; Knowledge; Link; Lung; Lung Lavage Fluid; Lung diseases; Lymphoid; Lymphoid Cell; Maintenance; Medial; Mesenchymal; Modeling; Mus; Oxidation-Reduction; Patients; Phenotype; Physiological; Physiology; Plasma; Play; Population; Predisposition; Process; Prognosis; Proteins; Pulmonary Emphysema; Sampling; Senility; Smoker; Smoking; Stromal Cells; Structure; Structure of parenchyma of lung; Subgroup; Testing; Tissues; Vascular Diseases; Vascular remodeling; Work; aged; aging population; angiogenesis; cytokine; epithelial stem cell; exhaustion; exposure to cigarette smoke; human model; immune cell infiltrate; in vivo; in vivo evaluation; knock-down; male; mouse model; novel; premature; progenitor; pulmonary function; stem cell function; stem cells; transcriptomics

Aging is associated with loss of lung structure and declining function. Emphysematous loss of tissue structure is exacerbated by vasculopathy, which increases susceptibility to lung disease, and limits survival. We have previously demonstrated that the structure and function of the lung microvasculature is regulated by a specialized mesenchymal vascular progenitor cell (MVPC). We have also defined Dickkopf-related protein 1 (DKK1) as a regulator of this niche in murine and human model. Our preliminary data demonstrate that MVPC numbers decline with age in WT mice by 1 year, and that, when MVPC are depleted in young mice, lung aging is accelerated, resulting in severe emphysema at 1.5 years of age. While MVPC are key modulators of the pulmonary microvasculature in the distal lung, adventitial stem cells (ASC) influence large blood vessel homeostasis in the proximal lung. Our preliminary data identifies key similarities between MVPCs and ASCs suggesting that decline in ASC numbers and function may also result in accelerated lung aging. Given ASC function is tightly controlled by lung-resident type-2 innate lymphoid cells (ILC2) and pulmonary ILC2 are known to decrease with age, loss of ASC-ILC2 crosstalk is likely a contributor to emphysema. Similar to aging, vascular remodeling is driven by chronic activation of type 2 (Th2) inflammation. Our preliminary data support increased Th2 cytokine profiles in plasma and BAL of COPD patients. Human and murine scRNAseq data define ILC2 and MVPC populations as well as immune cell infiltrate and cytokine expression characteristic of Th2 inflammation in COPD and a smoking model. The goal of this proposal is to define the mechanisms that result in loss of adult MVPC and ILC2 progenitor function contributing to accelerated lung aging, by altering vascular structure and function, and increased susceptibility to emphysema in the aged population. We hypothesize that loss of progenitor function accelerates lung aging by altering cell interactions within vascular niches, promoting vascular remodeling and increasing susceptibility to emphysema in the aging population. We will test that decline in MVPC and ILC2 numbers and/or function in the aging lung accelerates aging via impairment of vascular homeostasis due to disruption of cell – cell interactions in their respective perivascular niches, promoting vascular remodeling and loss of tissue structure using novel conditional murine models to knock down progenitors in aged mice or young mice. We will assess the requirement of MVPC, MVPC derived DKK1, ILC2 cells, and ILC2 derived IL13 in the maintenance of vascular niche homeostasis and susceptibility to emphysema. We will use conditional models to manipulate DKK1 or IL13 expression in mice allowed to age in the presence or absence of cigarette smoke exposure both in vivo and in vitro. Lastly, we will test that loss of ILC2 and MVPC progenitors promotes lung aging and is associated with COPD and a type-2 immune endotype. This work will provide an understanding of progenitor aging, mechanisms by which loss of MVPC and ILC2 function drives vascular remodeling with a Th2 endotype contributing to lung aging and emphysema.

衰老与肺结构丧失和功能下降有关。组织结构的气肿性丧失 血管病变会加重病情，增加肺部疾病的易感性，并限制生存。我们有 先前证明肺微血管的结构和功能是由一种 特化间充质血管祖细胞（MVPC）。我们还定义了Dickkopf相关蛋白 1（DKK 1）作为该生态位的调节剂在鼠和人模型中。我们的初步数据表明， 在WT小鼠中，到1岁时，MVPC数量随年龄的增长而下降，并且当MVPC在年轻小鼠中耗尽时， 肺老化加速，导致1.5岁时严重的肺气肿。虽然MVPC是关键调制器， 在肺远端的肺微血管中，外膜干细胞（ASC）影响大血管， 近端肺内的稳态。我们的初步数据确定了MVPC和ASC之间的关键相似之处 这表明ASC数量和功能的下降也可能导致肺老化加速。鉴于ASC 功能由肺驻留的2型先天淋巴样细胞（ILC 2）严格控制，肺ILC 2是 已知ASC-ILC 2串扰随着年龄的增长而减少，ASC-ILC 2串扰的丧失可能是肺气肿的一个促成因素。与衰老相似， 血管重塑由2型（Th 2）炎症的慢性激活驱动。我们的初步数据支持 COPD患者血浆和BAL中Th 2细胞因子谱增加。人和鼠scRNAseq数据 定义ILC 2和MVPC群体以及免疫细胞浸润和细胞因子表达特征， COPD和吸烟模型中的Th 2炎症本提案的目标是确定 导致成人MVPC和ILC 2祖细胞功能的丧失，从而加速肺老化， 血管结构和功能，以及老年人群对肺气肿的易感性增加。我们 假设祖细胞功能丧失通过改变血管内细胞相互作用加速肺老化 壁龛，促进血管重塑和增加老年人群对肺气肿的易感性。我们 将测试MVPC和ILC 2数量和/或功能在老化肺中的下降通过以下方式加速老化： 由于其各自血管周围的细胞-细胞相互作用的破坏而导致的血管稳态的损害 小生境，促进血管重塑和组织结构的损失，使用新的条件性小鼠模型， 敲除老年小鼠或年轻小鼠的祖细胞。我们将评估MVPC的要求，MVPC派生 DKK 1、ILC 2细胞和ILC 2衍生的IL 13在维持血管生态位稳态和易感性中的作用 肺气肿我们将使用条件模型来操纵允许衰老的小鼠中DKK 1或IL 13的表达 在体内和体外存在或不存在香烟烟雾暴露的情况下。最后，我们将测试 ILC 2和MVPC祖细胞促进肺老化，并与COPD和2型免疫相关 内型这项工作将提供对祖细胞老化的理解，MVPC丢失的机制， ILC 2功能驱动血管重塑，Th 2内型促成肺老化和肺气肿。