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Traditional theory limits cell communication to chemical exchange via the cell wall.

How tissue grows

Carnegie Mellon engineers make a key discovery about how cells communicate, finding that mechanics must combine with biology to make tissues grow.

When the body forms new tissues while healing from injury, cells must be able to communicate with each other. For years, scientists believed this communication happened primarily through chemical signals. Now scientists at Carnegie Mellon University and the University of Pittsburgh have found that another dimension – mechanical communication – is equally, if not more, crucial to cell communication.

The findings, published in this week's issue of the Proceedings of the National Academy of Sciences, could lead to advancements in treatment for birth defects and therapies for cancer patients.

"It's like 19th century scientists discovering electricity and magnetism are the same force. The key here is using mechanical engineering tools and frameworks to reverse-engineer how these biological systems work, thereby giving us a better chance to develop methods that affect this cellular communication process and potentially treat various diseases related to tissue growth."

Lance Davidson PhD, Associate Professor, Bioengineering, University of Pittsburgh, and study co-leader.

"We answered this very important biological question by building a new tool that enabled us to see these mechanical processes at the cell level," said Philip LeDuc, professor of Mechanical Engineering at Carnegie Mellon, who co-led the study with Davidson.

The researchers developed a microfluid control system to deliver chemicals at an extremely low flow rate over very small, specific areas of groups of cells. They hypothesized that in addition to using chemical signals to communicate with each other, embryo or regenerative cells also use mechanical processes – pushing and pulling on each other – to stimulate a response.

"In order to identify these mechanical processes, we really had to control small parts of multi-cellular tissue; today's technology can finally allow us to do this," Davidson explains.

For example, a tissue sample two millimeters across may contain up to 8,000 cells. The microfluid device enables researchers to "touch" as few as three or four cells and visibly see the mechanical process of protein movement inside those cells — using a high resolution laser scanning microscope.

"We proved that mechanical processes are absolutely important along with chemical processes," LeDuc adds.

When the researchers disabled the mechanical connections between cells using microfluids, communication between cells dropped substantially.

Although cells also communicated through chemical signaling, mechanical connections – their ability to push and pull on each other – were dominant in transmitting protein signals.

Understanding this new dimension could impact future research in tissue regeneration, from embryo development to cancer growth.

LeDuc: "If you are dealing with someone who has a birth defect, and a heart that didn't form correctly, the question is — how do you target that? This discovery leads us to believe there is a mechanical way to influence tissue development — and one day help cells better communicate with each other to heal the body."

Significance
This study shows how cell contractility is triggered within an embryonic epithelial sheet by local ligand stimulation and coordinates a long-range contraction response. The stimulation–response circuit exposed here provides a better understanding of how morphogenetic processes integrate responses to stimulation and how intercellular responses are transmitted across multiple cells. Understanding the systems-level behavior of biological signaling networks may allow us to control biological actuators with engineered spatiotemporal stimulation. Our findings will provide a better understanding of contractility-dependent morphogenetic movements as well as the intercellular communication pathways critical during developmental biology, synthetic morphogenesis, and multicellular mechanotransduction signaling.

Abstract
Spatiotemporal regulation of cell contractility coordinates cell shape change to construct tissue architecture and ultimately directs the morphology and function of the organism. Here we show that contractility responses to spatially and temporally controlled chemical stimuli depend much more strongly on intercellular mechanical connections than on biochemical cues in both stimulated tissues and adjacent cells. We investigate how the cell contractility is triggered within an embryonic epithelial sheet by local ligand stimulation and coordinates a long-range contraction response. Our custom microfluidic control system allows spatiotemporally controlled stimulation with extracellular ATP, which results in locally distinct contractility followed by mechanical strain pattern formation. The stimulation–response circuit exposed here provides a better understanding of how morphogenetic processes integrate responses to stimulation and how intercellular responses are transmitted across multiple cells. These findings may enable one to create a biological actuator that actively drives morphogenesis.

Other researchers included YongTae Kim, now an assistant professor of biotechnology at Georgia Institute of Technology; Sagar D. Joshi, now a research scientist at Air Liquide; William C. Messner, now the Department Chair and Professor of Mechanical Engineering at Tufts University School of Engineering; Carnegie Mellon Research Assistants Melis Hazar Haghgoui and Jiho Song; and Pitt research assistants Timothy R. Jackson and Deepthi Vijayraghavan.

About Carnegie Mellon University:
Carnegie Mellon is a private, internationally ranked university with programs in areas ranging from science, technology and business to public policy, the humanities and the arts. More than 12,000 students in the university's seven schools and colleges benefit from a small faculty-to-student ratio and an education characterized by its focus on creating and implementing solutions for real world problems, interdisciplinary collaboration and innovation. A global university, Carnegie Mellon's campus in the United States is in Pittsburgh, Pa. It has campuses in California's Silicon Valley, Qatar, and programs in Africa, Asia, Australia, Europe and Mexico.

About the Swanson School of Engineering
The University of Pittsburgh's Swanson School of Engineering is one of the oldest engineering programs in the United States and is consistently ranked among the top 50 engineering programs nationally. The Swanson School has excelled in basic and applied research during the past decade and is on the forefront of 21st century technology including sustainability, energy systems, bioengineering, micro- and nanosystems, computational modeling, and advanced materials development. Approximately 120 faculty members serve more than 2,600 undergraduate and graduate students and Ph.D. candidates in six departments, including Bioengineering, Chemical and Petroleum Engineering, Civil and Environmental Engineering, Electrical Engineering, Industrial Engineering, Mechanical Engineering, and Materials Science.

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