Aerocyte-mediated Alveolar Epithelial Regeneration following Lung Injury

PROJECT SUMMARY / ABSTRACT Acute Respiratory Distress Syndrome (ARDS) is a life-threatening lung injury caused by various factors such as infection and trauma, currently lacking a cure. Annually, approximately 190,000 Americans are diagnosed with ARDS, a number further amplified by the COVID-19 pandemic. The primary pathology involves damage to the alveolar epithelium, necessitating innovative approaches to accelerate alveolar epithelial regeneration for treating ARDS. Alveoli, surrounded by abundant capillaries for gas exchange, remain poorly understood in their regulatory role within this intensive capillary niche. Our focus is on aerocytes, a recently identified capillary endothelial population specialized in the lungs and positioned on the outer surface of the alveolar epithelium. Given this unique location, we propose that aerocytes play a pivotal role in alveolar epithelial regeneration. Preliminary data indicate that aerocytes express the angiocrine factor R-spondin3, a Wnt signaling activator, and stem cell factor. Loss of angiocrine R-spondin3 impedes regenerative epithelial remodeling and lung repair following injury, suggesting a crucial role for aerocyte-derived signaling in lung alveolar regeneration. Our research proposal aims to establish the central role of aerocytes in regulating alveolar regeneration post lung injury, with a specific focus on the signaling molecule R-spondin3. We hypothesize that aerocytes guide regenerative alveolar remodeling through R-spondin3, enhancing Wnt signaling in alveolar epithelium, and orchestrating interstitial macrophage plasticity for the necessary regenerative niche. To rigorously test this hypothesis, we outline the following specific aims: Aim 1: Investigate the role of aerocyte-derived R-spondin3 in lung growth and recovery using loss-of- function and gain-of-function animal studies within disease-related lung injury models. Aim 2: Define the mechanisms of regenerative alveolar remodeling guided by aerocyte-derived signaling, focusing on AT2 cell renewal, transition into TSCs, and differentiation into AT1 cells using advanced techniques such as alveolar organoids. Aim 3: Examine the impact of aerocytes on interstitial macrophage plasticity in establishing a regenerative alveolar niche. By unveiling the role and mechanisms of aerocytes in alveolar epithelial regeneration, this research potentially leads to innovative therapeutic strategies for treating ARDS by targeting aerocyte-derived signaling to regenerate the alveoli, ultimately improving the health and quality of life for individuals affected by severe respiratory complications associated with COVID-19 and ARDS.