The first step to better addressing lung injury and repair is to understand how the lung develops, says Jennifer Sucre, M.D., a neonatologist at Vanderbilt University Medical Center.
“If we know how the lung forms, then that’s a playbook for how to reform it and regenerate it after injury.”
“If we know how the lung forms, then that’s a playbook for how to reform it and regenerate it after injury,” Sucre said. “Those processes of development and regeneration are linked.”
Sucre researches lung injury, a major cause of morbidity and mortality in neonates.
Her work involves a deep dive into the lung cell landscape. Using single-cell RNA sequencing, her team has been able to capture and appreciate the nuances of lung cells, particularly as they ebb and flow from one state to another.
Free Online Atlas
Together with research partner Jonathan Kropski, M.D., a pulmonologist at Vanderbilt, Sucre has fully mapped gene expression in the lungs of developing mice – from embryonic day 12 through postnatal day 14.
The researchers created a comprehensive single-cell atlas of mouse lung development, with spatial context and dynamics for each gene involved.
A fervent advocate of data sharing and transparency in research, Sucre immediately made the atlas freely available online.
“One of the core values I have as a scientist is trying to lower the barriers for accessing resources,” Sucre said. “If the goal is to help human health, or help us understand the world, why can’t we just share it?”
In just a few years, the atlas has ignited research by groups investigating stress responses and cellular regeneration in the developing lung, among other types of inquires. For Sucre, the work has fueled dozens of studies into lung repair mechanisms.
Dual Roles
An overarching finding was that lung cells do not always fit neatly into alveolar type 1 or type 2 categories, as historically thought.
“We found some cells in the development atlas that were in-between, and we called them transitional cells,” Sucre said. “But, we also found these cells after injury in mice. These cells look like they have features of both type 1 and type 2 cells.”
The finding showed that “hallmark” features aren’t always specific to one kind of cell – a major departure from dogmatically assuming that certain cell types match specific genes and proteins.
“Hallmark genes don’t exist in nature to be markers. It’s a cell’s current state, not a distinct cell type.”
“Hallmark genes don’t exist in nature to be markers. Cells don’t make name tags so we can find them. That’s not how the biology works. It’s a cell’s current state, not a distinct cell type,” Sucre said.
Transition or Cell States
The finding also made Sucre question the concept of “transitional cells” entirely, which implies directionality from one cell-state to another. She and Kropski wrote more about this element recently in The Journal of Clinical Investigation.
The researchers’ article praised a recent paper that investigated the role of keratin 8, a well-known marker in identifying lung cells undergoing differentiation. The study showed alveolar type 2 cells bearing the marker weren’t transitioning but instead were accumulating in lung tissue and driving fibrosis after injury.
“They aren’t going anywhere. In fact, they’re part of the problem,” Sucre said.
Sucre and Kropski are now advocating a shift in thinking about alveolar cells both during development and after injury.
“We propose moving away from thinking about presumed transitional cell types as defined populations having a distinct identity.”
“Additional complexity is required in our understanding of these cells and of intermediate cell states,” they wrote. “We propose moving away from thinking about presumed transitional cell types as defined populations having a distinct identity.”
A Push For Change
Sucre has helped assemble a nationwide taskforce to rethink alveolar cells and to develop best practices and guidelines for their nomenclature, particularly in light of single-cell RNA sequencing.
“With single-cell RNA sequencing we are identifying cells by behavior. As this technology comes out, we are faced with different kinds of questions and standards,” she said.
Sucre also teamed up with colleagues at Vanderbilt and beyond to broaden the atlas work. Along with Vanderbilt biomedical engineer Bryan Millis, Ph.D., she is now visualizing lung development in real time. This work has led to an entirely new way of thinking about how alveoli form in utero.
Collaboration continues at the new Biodevelopmental Origins of Lung Disease Center at Vanderbilt, where Sucre is the founding director.
“We envision it as a space for people to dream big and to think about science beyond what is feasible. We are really a magnet and hub for scientists to be creative and question previously held assumptions,” Sucre said.
