Although the human body is externally symmetric across the left-right axis, there are remarkable left-right asymmetries in the shape, size, and positioning of many internal organs, including the heart, lungs, liver, stomach, and brain. These asymmetries can range from benign to serious, causing a range of conditions that affect multiple organs.
Developmental biologists have long been fascinated by how this asymmetry arises in the first place.
Scientists have long known that left-right asymmetry occurs during early embryonic development, driven by a structure called the left-right organizer, made up of a small cluster of cells. Within the “organizer,” motile cilia, hairlike structures on the surface of cells, beat rapidly to create a leftward directional flow of extracellular fluid as the first outward sign of a left-right difference.
And while research has shown that this early flow is critical in the distinction of right from left, just how this flow is sensed and translated into left-right asymmetry has remained unknown.
Science & Medicine, Delivered
Harvard Medicine magazine in your inbox
Now, a new study led by Harvard Medical School researchers at Massachusetts General Hospital answers this question.
The team’s findings reveal that cilia — as the creators of flow – also act as sensors for the biomechanical forces exerted by the flow to shape the left-right body plan of the developing embryo.
The findings are published in the journal Science.
“Nearly 25 years of work by numerous groups has shown that cilia and flow in the organizer are absolutely essential for establishing body left-right asymmetry,” said Shiaulou Yuan, assistant professor of medicine at HMS, senior author of the study, and an investigator in the Cardiovascular Research Center at Mass General. “But we haven’t had the right tools or techniques to definitively study how this all works.”
For their work, the researchers used zebrafish as a model for left-right development and employed a novel optical toolkit consisting of custom-built microscopy and machine learning analysis.
They deployed a novel tool called optical tweezers — a method that uses light to hold and move microscopic objects similar to a tractor beam. This enabled precise delivery of mechanical force onto cilia in an intact, living animal for the first time.
Utilizing these tools, the researchers discovered that cilia are cell-surface mechanosensors that are important for left-right asymmetry of the developing body and organs such as the heart.
By using optical tweezers to apply mechanical force onto cilia in the left-right organizer of zebrafish, the team showed that a subset of organizer cilia sense and translate flow forces into calcium signals that control left-right development in zebrafish.
Defects in left-right asymmetry are associated with a range of human disorders, including heterotaxy syndrome, a condition marked by abnormal positioning and structural defects of various organs; primary ciliary dyskinesia, a condition marked by recurrent respiratory infections, and several forms of congenital heart disease.
“The knowledge gleaned from this study not only advances our understanding of the fundamental cellular processes that govern the development of the human body,” Yuan said, “it may also open new avenues for the development of novel diagnostics of these disorders.”
This work may pave the way for targeted therapies on cilia signaling and mechanosensing to improve outcomes, he added.
Yuan and his colleagues continue to investigate the molecular mechanisms that govern cilia’s force sensing. They also continue to develop new strategies to visualize and manipulate cilia signaling, with the long-term goal of developing novel tools for the treatment of cilia-associated disorders.
“These results, and the tools that made them possible, have provided a new window into the developmental patterning of the embryo, and also opened Pandora’s box,” said Scott Fraser, the Provost Professor of Biology and Bioengineering at the University of Southern California and a co-author of this study. “It reminds us that we have so much more to learn about how cilia signaling and mechanobiology impact development and disease.”
Authorship, funding, disclosures
Additional Mass General and Harvard Medical School authors include Lydia Djenoune, Mohammed Mahamdeh, and Christopher Nguyen. Other authors include Thai V. Truong from the University of Southern California and Martina Brueckner and Jonathon Howard from Yale University.
This research was supported by the National Heart, Lung, and Blood Institute (grant 1R01HL165241), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (grant 1K99HD086274), the American Heart Association, the Charles Hood Foundation, the National Science Foundation (grant 1608744), the Gordon and Betty Moore Foundation, the USC Translational Imaging Center, and others.
