The lung is a vital respiratory organ defined by its highly specialized alveolar–capillary architecture, which constitutes the fundamental unit of gas exchange. This intricate structure makes the lung the most highly vascularized organ in the body. Circulating immune cells traverse an exceptionally dense capillary network, where they are strategically positioned for rapid transmigration into the alveolar space in response to injury or infection. The close physical and functional integration of blood vessels, alveolar epithelial cells, and immune cells creates a distinct microenvironment within the lung parenchyma, termed the vascular niche.

The Zhou Laboratory is dedicated to defining the signaling pathways operating within the lung vascular niche and elucidating their roles in lung injury, repair, and regeneration. Supported by multiple NIH R01 awards and institutional funding, our research focuses on the following areas:

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Vascular Niche in Lung Stem Cells and Regeneration

Pulmonary capillaries tightly wrap around alveoli, enabling efficient gas exchange while simultaneously forming a vascular niche that supports epithelial stem and progenitor cells. A major focus of the Zhou laboratory is to understand how this vascular niche regulates lung stem cell behavior and drives epithelial regeneration following injury. For example, a newly funded NIH R01 grant investigates the role of capillary aerocytes, a specialized endothelial cell population recently identified in the lung. These cells are uniquely adapted for gas exchange and leukocyte trafficking and reside along the outer surface of the alveolar epithelium. Our work explores how aerocytes contribute to stem cell regulation and alveolar epithelial regeneration during lung repair.

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Vascular Niche in Immune Dynamics and Inflammation Regulation

As an organ continuously exposed to the external environment, the lung serves as a frontline of immune defense and harbors a large and diverse immune cell population. Dysregulated inflammation is a defining feature of severe lung diseases, including acute respiratory distress syndrome (ARDS). Following injury or infection, immune cells are recruited to the lung primarily through the vasculature, underscoring the intimate relationship between immune cells and the vascular niche. The Zhou lab investigates how vascular niche–derived signals shape immune cell phenotype and function and how these interactions govern the initiation and resolution of inflammation. Notably, our work demonstrated that endothelial cell–derived R-spondin3 acts as a key angiocrine factor that regulates macrophage polarization and promotes inflammation resolution following lung injury (Nature Immunology).

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Perivascular Cells in Endothelial Regeneration and Vascular Repair

Disruption of the vascular endothelium is a hallmark of severe lung injury in ARDS, a major cause of mortality in patients with severe COVID-19 and other viral or bacterial pneumonias. Effective restoration of the endothelial barrier is therefore essential for lung repair and recovery. While resident endothelial cells are the primary source of re-endothelialization following injury, the mechanisms that trigger endothelial regeneration remain poorly understood. Defining these mechanisms is critical for developing therapeutic strategies to restore vascular integrity. The Zhou lab focuses on the role of perivascular cells in regulating endothelial regeneration and vascular repair. Supported by an active NIH R01 grant, we are investigating perivascular macrophages (PVMs)—a recently identified subset of interstitial macrophages localized to the abluminal surface of blood vessels—and their roles in lung vascular function, endothelial regeneration, and repair following injury.

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Cellular Sensing, Metabolic, and Epigenetic Reprogramming in the Lung Vascular Niche

We are also interested in understanding how cells sense signals within the lung microenvironment and how metabolic and epigenetic reprogramming mechanisms drive cellular transitions during lung injury, repair, and regeneration.

Through these research efforts, the Zhou Laboratory aims to unravel the complex cellular interactions and signaling networks within the lung vascular niche, with the ultimate goal of identifying novel therapeutic targets for the treatment of lung diseases.