AT2 migrating along the alveolar septum watch
current research
One cell, many fates
Regeneration asks cells to become temporarily plastic, and then to stop. After lung injury, alveolar type 2 (AT2) stem cells pass through a short-lived intermediate progenitor cell (IPC) state on their way to becoming the thin alveolar type 1 (AT1) cells that line the air sacs. When this transition resolves, the alveolus is restored. When it stalls, the same plastic state can become the starting point for chronic lung disease: fibrosis, cancer and beyond.
We study the IPC as a shared decision point: what controls how long cells stay in it, which way they leave, and whether we can steer them back toward repair. In the figure: One cell, multiple fates. IPCs (purple) arise from AT2 stem cells after injury and sit at a crossroads in the alveolus. Under persistent stress, such as smoke, pollution or infection, the same cells can drive fibrosis or give rise to cancer.
how we work
observe
We watch single cells make decisions in living tissue: through a permanent lung window with three-photon intravital microscopy, and in precision-cut lung slices kept alive for days in our custom imaging chambers.
decode
We watch single cells make decisions in living tissue: through a permanent lung window with three-photon intravital microscopy, and in precision-cut lung slices kept alive for days in our custom imaging chambers. In the figures: trajectories from AT2 through the IPC state to AT1, with a branch of aberrant IPCs (a-IPC) that leaves the repair path. Bottom: RNA (bars) and chromatin (peaks) from the same nuclei. In IPCs, injury genes such as Cldn4 and Cdkn1a switch on and their chromatin opens, while the AT2 gene Sftpc starts to close.
target
We test those regulators by timed perturbation in lung slices, mouse models and donated human lung tissue. In the figure: our Lung Explant Imaging System (LEIS) keeps lung slices alive under controlled perfusion, so we can change their conditions while imaging the same cells.
research Qs
4 Questions, one decision point
Q01: how a stem cell changes place and identity?
We discovered that AT2 stem cells migrate between alveoli after injury, and that this movement is needed for repair (Chioccioli et al., Dev Cell 2024). We now ask how moving and differentiating are coordinated: what sets how long a cell stays in the IPC state, and how a change in position is tied to a change in identity. Following single cells for days, we look for the switches that let a cell finish repair instead of getting stuck. Video: an AT2 stem cell (green) changing shape as it migrates through the surrounding lung tissue (red) after injury. Chioccioli et al., Dev Cell 2024.
Q2: how is homeostasis is maintained?
Meet the alveolar stem cell niche: Stem cells don't decide alone. Macrophages, fibroblasts and blood vessel cells surround each AT2 cell, keeping it quiet in health and licensing it to change after injury. Imaging epithelial and immune cells together, we ask which neighboring signals tell an IPC when to finish becoming AT1, starting with the macrophages that occupy the alveolus throughout repair, and how the timing of those signals separates healthy repair from disease. In the figure: he alveolar niche in health, repair and aberrant repair. When injury signals switch off on time, IPCs become new AT1 cells; when they persist, the same state is linked to fibrosis and cancer.
Q3: what is the role of IPCs in chronic lung diseases?
Lung adenocarcinoma starts in the alveolar region, but its cell of origin is still debated. We are testing whether the window of regeneration is also a window of cancer risk: whether injury-induced IPCs, because they are so plastic, are a highly effective starting point for KRAS-driven tumors. Lineage tracing places tumor initiation in cell state and time; single-nucleus multiomics asks what makes these cells permissive, and whether helping IPCs resolve lowers that risk. In the figure: a lung tumor (red) in a Kras-G12D mouse. TTF1 in green, nuclei in blue.
Q4: translating in to human lung
Findings in mouse matter only if they hold in people. We keep slices of donated human lung alive and imageable for days, so we can test our candidate regulators directly in human tissue and screen drugs in a model of early fibrosis. With Yale lung pathologists, we are mapping transitional cells across human fibrosis, pre-invasive lesions and early lung adenocarcinoma. Image: Precision-cut slices of human lung in culture.
