Loss of progenitor function accelerates lung aging

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Aging is associated with loss of lung structure and declining function, termed senile emphysema. Emphysematous loss of tissue structure is exacerbated by vasculopathy, which substantially worsens prognosis, 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 senile emphysema. Our prior work and preliminary data suggest that a novel ILC2 subset serves as a progenitor in repopulating lung-resident ILC2. 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 and increased susceptibility to emphysema in the aged population. The novel premise of this proposal is that loss of progenitor function accelerates lung aging by altering vascular structure and function. 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, will test that paquinimod will restore progenitor numbers and function in the lungs of aged mice as well as attenuate cigarette smoke induced emphysema in aged mice. This work will provide an understanding of progenitor aging, mechanisms by which loss of MVPC and ILC2 function drives vascular remodeling contributing to aging and test a strategy to improve progenitor function in the aging population.