Discovering Communications Mechanisms Between Cells

Macrophages change their shape as they migrate inside a 3D collagen matrix. White stains collagen fibers, green stains macrophages and blue stains cell nuclei.

Day by day, we communicate with our office colleagues to accomplish tasks that are necessary to function. The more than 200 different types of cells in our bodies do the same thing, but the way they communicate with each other isn’t as simple as sending an email.

Researchers like Ioannis Zervantonakis are still trying to understand how these cells actually communicate with each other. The assistant professor of bioengineering at the University of Pittsburgh Swanson School of Engineering recently received a National Institute of General Medical Sciences Maximizing Investigators’ Research Award, and his project “Macrophage-Fibroblast Communication in Cell Migration and Extracellur Matrix Remodeling” will receive over $1.95 million in total funding for the next five years.

The Zervantonakis Microenvironment Engineering Lab integrates microfluids, systems biology modeling, and in vivo experiments to investigate the role of complex microenviroments on cell growth, migration, and response to health and disease. Typically his research focus on cancer, but this project will focus on specifically on the relationship between two types of cells: macrophages and fibroblasts.

“This is a great to understand fundamental processes by which these two cell types communicate,” Zervantonaki said. “Together they give tissues the ability to heal, to grow and to adapt to be a constantly changing environment.”

Fibroblasts are cells that create and maintain a diverse array of connective issues to support a broad range of essential organ functions, like resitance to sharp injuriries in the skin and healing of scars. Macrophages are white blood cells that help eliminate harmful substances by engulfing foreign materials and initiating an immune response. Both of these cells help regulate tissue homeostatis, or equilibrium, in the body.

One goal is to find out how these cells react to hypoxia, or lack of oxygen in a complex 3D environment. Differing from previous research in the field, this project involves novel technology development in microfluidic device engineering to precisely control oxygen flow and also use cell biosensors to study how fibroblasts and macrophages resond to extracellular matrix changes in intact tissues.

“With computational modeling and microfluidic devices, we can start to tease apart what is more important in cell-cell communications: Is oxygen more important. Are cell-generated mechanical forces in the extracellular matrix important?” Zervantonakis said. “If we have fibroblasts and machophages being overactivated, what are the proteins we can target to tone down their activation so that we can decrease inflammation and tissue scarring.”

The findings of this research will have several important impolications. One of the major problems in this area could solve is understanding how to treat various types of lung disease.

“The communication between macrophages and fibroblasts can be dysregulated in chronic pulmonary hypertension or pulmonary fibrosis,” Zervantonakis said. “When our lungs are fibrotic the oxygen level changes, so understanding how oxygen affects both of these cell types can help us find new drugs to target these diseases.”

The proteins (tetraspanins and cell-matrix adhesion receptors) that Zervantonakis’s team will study could also regular macrophage-fibroblast communication in cancer and autoimmune diseases, and could impact tissue regeneration.

“Since macorphages and fibroblasts are important to tissue development, manipulating proteins that control the mechanical behavior of fibroblasts or the motility of macrophages could be used to stimulate regeneration or understand developmental defects.”

According to Ruxuan Li, a bioengineering PhD candidate working in the lab, a unique aspect of this project is its usxe of 3D in-vitro models, a speciality of the lab that allows for a more efficient and lower cost model that animal research models.

“We use a variety of 3D in-vitro culture systems, including microfluidic chips, microwells, and 3D hydrogel co-culture systems to study cell behaviors in our lab,” Li said. “Unlike animal modesl and 2D tissue cutlure models, the 3D in-vitro models can mimic the 3D structure and microenvironment of human tissues.”

Much of the preliminary data for this proposal was supported by work from both Li and postdoctoral scholar Youngbin Cho, who also commented on the importance of 3D models.

“We plan to enhance our 3D in vitro platform to precisely capture the intricate interaction between macrophages and fibroblasts within an extracellurlar matrix,” Cho said. “Utilizing our high-resolution confocal microscope imaging system and microfluidic devices, we will observe the real-time cell-cell interaction and structural matrix remodeling driven by cells.”

Over the next five years, the goal of Zervantonakis’s MIRA is to increase the efficiency of NIGMS funding by providing investigators with greater stability and flexibility, thereby enhancing scientific productivity and the chances for important breakthroughs.

“It’s all about the fundamental questions and fundamental mechanisms: We are basically studying the dysregulation of cell-cell communication mechanisms that can have implications in many diseases,” Zervantonakis said.

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