[ad_1]
Every year, 9 months of dreams and anticipation shared by millions of expectant parents turn to despair and fear when they learn that their child is born with a conbad anomaly; an often devastating event affecting one in every 20 children born in the world. The formation of our organs, our limbs and our face results from a movement and behavior carefully choreographed by millions of cells, much like the dancers of a troupe. If even a few cells do not reach the right position and do not do their job properly, the end result is a conbad anomaly. Yet the fact that each cell knows what to do at the right time and in the right place is largely a mystery.
In a new study published in the scientific journal Nature, a team of researchers from the Gladstone Institutes, in collaboration with the Luxembourg Center for Biomedicine Systems (LCSB) of the University of Luxembourg, reveals for the first time the full spectrum of cells that unite to form a heart from the early stages of embryo formation. They also discovered how cells are controlled and how a mutation of a single gene can have catastrophic consequences by affecting a small group of cells that make up the organ.
Conbad heart defects are the most common and deadly human birth defects. With the advent of a powerful new technology called single-cell RNA sequencing, researchers have finally been able to discern the role of tens of thousands of individual cells in the formation of the heart, which is essential for to determine how genetic mutations cause disease. .
"With genome sequencing, we can now more easily find genetic variants that we believe contribute to disease," said Deepak Srivastava, president and principal investigator of Gladstone, who led the study. "The big challenge is to determine the specific cell type in which this variant works and its impact on the cells.This has been particularly difficult for conbad anomalies, since genetic variants affect only a small sub – all the cells of the organ – unicellular technologies, we can finally begin to understand the mechanisms underlying the defects for which we know the genetic cause ".
The catalog compiled by Srivastava and his team contains all the active genes during the various stages of cardiac development and identifies the cells in which they are located. It represents the first step in establishing the link between a genetic variant and a specific cell type.
"This can tell us, among other things, which subset of cells performs essential functions in specific regions of the heart and contributes to the underlying cause of a disease badociated with genetic mutations," explained Yvanka De Soysa, postgraduate student. in the laboratory of Srivastava and first author of the study.
A rich source of data on heart development
To complete the repository, researchers studied nearly 40,000 individual cardiac cells from a mouse model of cardiac development. The technology that made this study possible is the sequencing of single-cell RNA. This sophisticated method, commercially available for only 3 years in its current form, has allowed scientists to collect data on thousands of individual cells at a time.
"This sequencing technique allowed us to see all the different types of cells present at different stages of heart development and helped us identify the genes that were activated and deleted along the way," said Casey A. Gifford, PhD, researcher at Gladstone. is a senior author on paper. "We have not only been able to discover the existence of unknown cell types, but we have also gained a better understanding of the function and behavior of individual cells – information we would never have access to before. "
Once they identified the many types of cells involved in developing the heart, the team wanted to learn how these various types of cells are generated. To do this, they teamed up with LCSB computer scientists who specialize in the use of single-cell RNA sequencing data to uncover the molecular inducers of different cell types.
"Our group has a long history of developing computer models to understand cell conversion," said Antonio Del Sol, head of the LCSB's Computer Biology Group and Professor Ikerbasque at the CIC bioGUNE Research Center in Bilbao, Spain. "We have the expertise to study entire networks of genes that control cell identity." When we joined the project, we applied our method to predict, without any prior knowledge, what molecular factors govern the cellular identity. destiny of these different cardiac cells. "
A discovery that lasts 20 years
Computer badysis has predicted the genes involved in the generation of specific cell types in the heart, which illuminate the function of these cells. The badysis also highlighted a major player, a gene called Hand2, able to control the activity of thousands of other genes, and that Srivastava discovered and named more than two decades ago .
As a young researcher, Srivastava has spent years studying the role of this gene and its main regulator. He finally discovered that it was one of the most important genes for heart formation. However, about 10 years ago, in trying to understand how this gene actually affects the heart cells that make up the organ, his work found himself in a dead end because the scientific tools to further research did not exist. Today, his efforts have finally been revived thanks to new technologies.
By applying single-cell RNA sequencing, he and his collaborators were able to get a much more detailed and comprehensive picture of how Hand2 loss causes dysregulation of different cell populations.
Mice lacking the Hand2 gene fail to form the right ventricle chamber, which pumps blood to the lungs. Surprisingly, the new prediction made by Luxembourgish researchers suggests that Hand2 is not necessary for cells to be ordered to become right ventricular cells, but that it is essential for training cells of the output tract, the structure where the main blood vessels coming out of the heart occur.
"It made no sense in the light of earlier findings," De Soysa said. "However, we found that in fact, Hand2 has very distinct functions for different types of cells."
The computer prediction has turned out to be correct. The team discovered that hearts without the Hand2 gene never made the cells of the output tract, but manufactured the right ventricular cells. In the choreography of the heart, it is not enough to make a cell, it is also necessary to go to the right place compared to other "dancers". Without Hand2, right ventricular cells have been created but are stuck to their origin and do not reach the developing heart.
"Our collaborative results have allowed us to change the way we think about heart formation and to show how disruption of fate, migration, or cell survival can lead to heart defects," De Soysa added.
A promising future for the treatment of conbad heart disease
The study revealed the mechanisms by which relatively small cell populations are affected during development and cause defects in the formation of the heart. This also represents a discovery that would not have been possible without the single-cell RNA sequencing technology.
"Unicellular technologies can inform us about how organs form in ways that we could not understand before and can provide the underlying cause of a disease badociated with genetic variation," he said. said Gifford. "We have revealed subtle differences in very, very small subsets of cells with catastrophic consequences that could have been easily overlooked in the past, and this is the first step towards designing new treatments."
Significantly, the new cardiac cell catalog can now serve scientists and physicians interested in various aspects of cardiac development. Knowing the types of cells involved in the normal and abnormal formation of the heart, the scientific community can begin to devise strategies to correct the genetic variants responsible for conbad heart disease.
These findings could also guide therapeutic approaches aimed at helping both newborns and the growing population of adults with conbad heart disease.
"Thanks to surgical procedures, we have managed to keep most children with heart defects alive," said Srivastava, also pediatric cardiologist at UCSF Benioff Children's Hospital and professor of pediatrics at UC. San Francisco. "The result is that today we have nearly 2.5 million conbad heart disease survivors in the United States."
When children with a conbad abnormality have the chance to survive, the same genetic disorder causing the developmental problem can lead to persistent difficulties in maintaining a healthy heart throughout life .
"We are starting to see the long-term consequences for adults, and for now, we really have no way to treat them," added Srivastava. "I hope that if we can understand the genetic causes and the types of cells affected, we can potentially intervene at birth to prevent the deterioration of their condition over time."
For Srivastava, the Holy Grail would be to get a clear idea of the mechanisms involved in the occurrence of conbad heart defects, so that they could develop prevention strategies for people at risk.
"Folic acid is the best paradigm. Pregnant women now take higher levels of this vitamin and can successfully prevent nearly two-thirds of spina bifida cases," he said. "The ultimate goal is to create similar public health measures that can reduce the overall incidence of conbad anomalies through prevention, but we must first know where and how to respond."
Source link
