Science: The source of the left and right asymmetry of the human body - cilia

Although the human body is externally symmetrical on the left and right axes, there are significant left-right asymmetries in the shape and position of most internal organs, including the heart, lungs, liver, stomach, and brain
.

Left-right asymmetry is known to be established during early embryogenesis by a small group of cells called left-right organizers
.
In this organizer, active cilia (hair-like structures on the cell surface) beat rapidly, forming the direction of the flow of extracellular fluid to the left, which is the first outward marker
of left-right differences.

This early flow has proven to be the key
to distinguishing left and right.
However, how this flow is perceived and transformed into left-right asymmetry is unknown
.

A new study led by MGH researchers now reveals cilia in the organizers as creators of flow — they also act as sensors for the biomechanical forces exerted by flow to shape the left and right body planes
of the developing embryo.

The findings were published in the journal Science
.

Shiaulou Yuan, Ph.
D.
, a researcher at the Center for Cardiovascular Research at Massachusetts General Hospital, assistant professor of medicine at Harvard Medical School and senior author of the study, said: "Nearly 25 years of research by numerous research groups have shown that flow in cilia and organizers is absolutely necessary
for establishing body-left and right asymmetry.
But we don't yet have the right tools or technology to definitively study how it all works
.
”

To overcome this challenge, the researchers used zebrafish as a model for left and right development and used a novel optical toolkit
consisting of custom microscopy and machine learning analysis.

Their approach is unique in that they innovatively use phototweezers — a biophysical tool that uses light to hold and move microscopic objects, similar to a traction beam — for the first time being able to precisely transmit mechanical forces to the cilia of a whole, living animal
.

Using these tools, the researchers found that cilia are mechanical sensors on the cell surface that are important
for left-right asymmetry in developing bodies and organs, such as the heart.

By using phototweezers to apply mechanical force to the cilia of the left and right organizers of zebrafish, they showed that a subset of the cilia of the organizer sensed and converted the flow force into calcium signals, controlling the left and right development
of the zebrafish.

Left-right asymmetric defects have been implicated in many human diseases, including ectopic syndrome, primary ciliary body dyskinesia, and congenital heart disease
.
Yuan said: "The knowledge gathered from this study not only advances our understanding of the fundamental cellular processes that control human development, but may also open new avenues
for novel diagnostics of these diseases.
" In addition, this work may pave the way for targeted therapies targeting cilia signaling and mechanical induction to improve outcomes
.
”

Yuan and his colleagues continue to study the molecular mechanisms
that control cilia force perception.
They also continue to develop new strategies to visualize and manipulate cilia signals, with the long-term goal of developing new tools
to treat cilia-related diseases.

"These results, along with the tools that make it possible, provide a new window into embryonic patterns of development and open Pandora's box," said Scott E.
Fraser, provost professor of biology and bioengineering at the University of Southern California and co-author of the study
.
"This reminds us that we still have a lot to learn
about how cilia signaling and mechanobiology affect development and disease.
"

MGH and other Harvard Medical School authors include Lydia Djenoune, Mohammed Mahamdeh, and Christopher Nguyen
.
Other authors include Thai V.
Truong of the University of Southern California, and Martina Brueckner and Jonathon Howard
of Yale University.