The lung, a vital respiratory organ, is distinguished by its unique alveolar-capillary structure, forming the fundamental respiratory units. This intricate architecture makes the lungs the most vascularized organ in the body. Bloodstream-borne immune cells navigate within this dense capillary network, poised for rapid transmigration into the alveoli upon encountering lung injury or infection. This intimate association between blood vessels, alveolar epithelial cells, and immune cells fosters a unique microenvironment within the lung parenchyma, known as the vascular niche.

The Zhou Laboratory is dedicated to elucidating the signaling pathways within the vascular niche and their influence on lung injury, repair, and regeneration. Supported by multiple NIH R01 grants and institutional funding, our active research programs delve into the following aspects:

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1. Vascular Niche for Lung Stem Cells and Regeneration. Capillaries envelop alveoli, ensuring efficient gas exchange between alveolar spaces and the bloodstream while forming a vascular niche for epithelial stem/progenitor cells. One focus in the Zhou lab is investigating how this vascular niche orchestrates lung stem cells and regeneration following injury. For instance, our newly funded R01 grant explores the role of capillary aerocytes — a unique capillary endothelial population recently identified in the lung, specialized for gas exchange and leukocyte trafficking, and situated on the outer surface of the alveolar epithelium — in regulating stem cell and alveolar epithelial regeneration.                                                                                                                                                             

2. Vascular Niche for Immune Dynamics and Inflammation Orchestration. As a respiratory organ constantly exposed to the external environment, the lung is at the frontline of immune defense and houses abundant immune cells. Inflammation caused by immune dysfunction is a hallmark of critical lung conditions like ARDS. Following injury and infection, immune cells traffic into the lungs via blood vessels, highlighting the close association between the vascular niche and immune cells. Another focus in the Zhou lab is exploring how the vascular niche affects immune cells, influencing their phenotype and functional dynamics, and how these interactions are linked to the initiation and resolution of inflammation. For example, our findings revealed that the vascular niche orchestrates macrophage phenotype and inflammation resolution following lung injury via R-spondin3, a critical angiocrine factor released by endothelial cells (Nature Immunology).                                                                                                                                                     

3. Perivascular Cells in Supporting Endothelial Regeneration and Vascular Repair. Disruption of the vascular endothelium is a hallmark of severe lung injury in acute respiratory distress syndrome (ARDS), a primary cause of mortality in severe COVID-19 patients and other forms of viral or bacterial pneumonia. Restoring the vascular endothelium is thus central to resolving and repairing lung injury. Resident endothelial cells are the primary cellular source for re-endothelialization and vascular repair after injury. However, the mechanisms leading to the reactivation of endothelial regeneration are not yet well understood. Defining these mechanisms is crucial for developing novel therapies to restore blood vessels and promote recovery from ARDS. The Zhou lab is interested in dissecting how perivascular cells regulate endothelial regeneration and vascular repair following lung injury. For example, currently supported by an active NIH R01 grant, the Zhou lab investigates perivascular macrophages (PVMs), a specialized subset of interstitial macrophages recently discovered near the abluminal surface of blood vessels, in regulating lung vascular function as well as endothelial regeneration and vascular repair following lung injury.                                                                                                                                                                  

4. Epigenetic and Metabolic Basis for Cell Plasticity and Transition in the Lung Vascular Niche. Epigenetic programs, which govern gene expression profiles, and metabolic programs, which provide energy, are fundamental driving forces for cell fate. We are interested in elucidating the underlying epigenetic and metabolic mechanisms responsible for cell plasticity and functional diversity within the lung vascular niche. This includes exploring endothelial heterogeneity, macrophage plasticity, and epithelial cell regenerative remodeling.                                                                                                                                                              

Our research aims to uncover the complex signaling networks and cellular interactions within the vascular niche, providing insights that could lead to novel therapeutic strategies for lung diseases.