Loss of progenitor function accelerates lung aging

衰老与肺结构丧失和功能衰退有关。肺气肿组织结构丧失 血管病变会加剧病情，增加肺部疾病的易感性，并限制生存。我们有 以前证明，肺微血管的结构和功能是由一种 特化间充质血管前体细胞(MVPC)。我们还定义了Dickkopf相关蛋白 1(Dkk1)在小鼠和人类模型中作为这一生态位的调节因子。我们的初步数据表明 在WT小鼠中，MVPC数量随着年龄的增长而下降1岁，当MVPC在幼鼠中耗尽时， 肺老化加速，导致1.5岁时出现严重的肺气肿。而MVPC是关键的调节器 在远端肺的肺微血管中，外膜干细胞影响大血管。 近端肺的动态平衡。我们的初步数据确定了MVPC和ASC之间的关键相似之处 提示ASC数量和功能下降也可能导致肺老化加速。给定的ASC 肺固有的2型固有淋巴样细胞(ILC2)和肺ILC2是紧密控制功能的 已知随着年龄的增长而减少，ASC-ILC2串扰的丧失可能是肺气肿的原因之一。与衰老相似， 血管重塑是由慢性激活的2型(Th2)炎症驱动的。我们的初步数据支持 COPD患者血浆和BAL中Th2细胞因子水平升高。人和小鼠的scRNAseq数据 明确ILC2和MVPC群体以及免疫细胞浸润和细胞因子表达的特征 Th2炎症在COPD和吸烟模型中的作用。这项提案的目标是定义 通过改变导致成人MVPC和ILC2祖细胞功能丧失，从而加速肺老化 血管结构和功能，以及老年人口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衰老 利基，促进血管重塑和增加老年人口中患肺气肿的易感性。我们 将测试老化肺中MVPC和ILC2数量和/或功能的下降通过以下方式加速衰老 由于各自血管周围细胞间相互作用的中断而导致的血管内稳态受损 利基，促进血管重塑和组织结构丢失使用新的条件小鼠模型 击倒老年小鼠或年轻小鼠的祖细胞。我们将评估MVPC的需求，MVPC派生 Dkk1、ILC2细胞和ILC2来源的IL13在维持血管生态位稳态和敏感性中的作用 致肺气肿。我们将使用条件模型来操纵Dkk1或IL13在允许衰老的小鼠中的表达 在体内和体外有或没有香烟烟雾暴露的情况下。最后，我们将测试该损失 ILC2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 ILC2功能驱动血管重构，Th2内型导致肺老化和肺气肿。

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.