Pulin Li

Question

How and why do cells organize into spatial patterns within tissues?

Approach

Tissues are not random clusters of cells. Instead, cells of different types are carefully arranged in space, forming intricate patterns that define a tissue’s structure and function. Much like a city’s layout, where the placement of infrastructure must be carefully planned to optimize how the city operates, tissue patterning ensures that specific cell types and cell functions are positioned properly. For example, the lung is a tree-like network of airways ending in tiny sacs called alveoli, lined with over 50 types of cells placed in just the right spots to enable breathing. Amazingly, this complex structure starts in the embryo as just two small buds made of a few cells. How do these simple beginnings lead to such intricate patterns? Can we use these insights to grow better tissues in the lab? The Li lab tackle these questions through three interconnected research directions:

Rebuilding how cells talk to each other: Cells use signaling proteins to communicate and guide development. These proteins spread through tissues in patterns that shape where different cells go and what they become. But these patterns are hard to see in real tissues. The Li lab pioneered a new way to rebuild these signaling patterns in Petri dishes, using synthetic biology tools and guided by mathematical models. This approach led to the discovery that signals mostly spread by simple diffusion—often slowly along cell surfaces—and that other molecules can tweak how signals travel. These findings help explain how similar signals can build organs of very different sizes, and offer new ways to design targeted therapies.

Decoding cell-cell communication in real tissues: To truly map how cells communicate in natural tissues, the Li lab is developing computational tools to infer cell-cell communication using genomic data. For example, the lab has developed IRIS, a machine-learning based tool, to learn how cells change their gene expression when different signals are turned on. By recognizing these features, one can tell whether a signaling pathway is active or not in each cell within a mouse embryo, a task that would have taken decades with traditional methods. Such approach can help us understand normal development and may reveal signaling patterns that go wrong in diseases like cancer. 

Understanding the lung’s hidden support system: Inside organs like the lung, a supportive tissue called the stroma plays a critical role. It starts from mesenchymal progenitors—immature cells that later become blood vessels, fibroblasts, and more. Yet little is known about how these supportive cells are patterned. The Li lab studies how patterns emerge in the lung and investigates their functional roles, using a combination of quantitative imaging, mouse genetics, single-cell analysis and stem cell engineering. A fundamental understanding of these processes will facilitate the development of more complex and realistic organ models in a dish (“organoids”) that can be used for studying respiratory diseases and drug discovery.

The long-term goal of the lab is to bridge biological scales spanning over five orders of magnitude — from the nanometer-sized molecules that carry information between cells to tissue structures that are hundreds of microns across. This will allow us to uncover the fundamental rules that build life’s intricate architecture, and construct quantitative, predictive models that can be used for guiding tissue engineering and therapeutic intervention. 
 

Bio

Li earned a bachelor’s degree in life sciences from Peking University and a Ph.D. in Chemical Biology at Harvard University in the lab of Leonard Zon. She became a Whitehead Institute Member and an assistant professor of biology at Massachusetts Institute of Technology in 2019, after completing a postdoctoral fellowship with Michael B. Elowitz at California Institute of Technology.