Cilia in Embryo Control Left-Right Asymmetry

Scientists at the Massachusetts General Hospital have made a significant discovery about how left-right asymmetry is established in the human body during early embryogenesis. Though the human body is externally symmetric across the left-right axis, there are notable differences in the shape and positioning of internal organs, including the heart, lungs, liver, stomach, and brain.

Left-right asymmetry is known to be established during early embryogenesis by a small cluster of cells called the left-right organizer. Within this organizer, motile cilia, hair-like structures on the cell surfaces, beat rapidly to create a leftward directional flow of extracellular fluid, which is the first outward sign of a left-right difference.

A new study led by researchers at the Massachusetts General Hospital found that cilia in the organizer not only create the flow, but also act as sensors for the biomechanical forces exerted by the flow to shape the left-right body plan of the developing embryo. 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.

Their approach was unique as they developed and deployed optical tweezers, a biophysical tool that uses light to hold and move microscopic objects, which 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 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, they 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 numerous human disorders, including heterotaxy syndrome, primary ciliary dyskinesia and 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, but it may also open new avenues for the development of novel diagnostics for these disorders. Additionally, this work may pave the way for targeted therapies on cilia signaling and mechanosensing to improve outcomes.

Senior author Shiaulou Yuan, an investigator in the Cardiovascular Research Center at Massachusetts General Hospital and assistant professor of medicine at Harvard Medical School, explains, "Nearly 25 years of work by numerous groups have shown that cilia and flow in the organizer are absolutely essential for establishing body left-right asymmetry. But we haven't had the right tools or techniques to definitively study how this all works."

Yuan and his colleagues continue to investigate the molecular mechanisms that govern cilia force sensing and develop new strategies to visualize and manipulate cilia signaling, with the long-term goal of developing novel tools for treating cilia-associated disorders.

"These results, and the tools that made it possible, have provided a new window into the developmental patterning of the embryo, and also opened Pandora's box," says co-author Scott E. Fraser, the Provost Professor of Biology and Bioengineering at the University of Southern California. "It reminds us that we have so much more to learn about how cilia signaling and mechanobiology impact development and disease."

The findings are published in the journal Science.