Research scientists from Rockefeller University for the first time showed that a small cluster of embryonic stem cells shapes the fate of other human embryonic cells. This discovery, which is published in Nature, creates new perspectives for studying the early stages of human development and can help in the creation of methods for treating a wide range of diseases.
Factors that determine the fate of the cell, are still a unknown. Why, for example, does one embryonic stem cell (ESC) become a neuron, somewhat than a muscle cell? And why does another decide to form cartilage, rather than cardiac tissue?
Scientists know that ESCs can differentiate into any of the body’s specialized types cells: bones and brain, lungs and liver. It is also known that special cell groups found in amphibian and fish embryos control the formation of structures in the early stages of development.
These groups, called “organizers,” emit molecular signals that in some way direct the growth and development of other cells. When the organizer cells are transplanted from one embryo to another, it will begin to form a secondary spinal column and central nervous system, including spinal cord and brain.
However, because of the ethical guidelines that restrict experimentation on human embryos, it has not been known until now if an analogous organizer existed in humans.
To study this issue, a team led by Dr. Ali H. Brivanlou performed a series of experiments involving artificial human embryos. For this purpose, clusters of cells were obtained in the laboratory, approximately one millimeter in diameter, grown from human embryonic stem cells.
And although these artificial embryos are far from natural counterparts, they contain many of the cells and tissues that are present in genuine human embryos, and therefore they can be used as an experimental model.
Previous studies have shown that the early stages of embryonic development in mice and frogs are controlled by three different signaling pathways. By activating these pathways in artificial human embryos in vitro, Brivanlou and colleagues showed that these same molecular signals also control the fate of human cells. When these signals were transmitted in the correct sequence, artificial embryos even generated their own organizers.
However, there is a big difference between the processes occurring in the Petri dish and what they will do inside a real embryo.
To check the data, the cells in the human artificial embryos were labeled with a fluorescent marker, which allowed them to be visualized under a microscope. Then they were transplanted into normal chicken embryos.
Interspecific cell transplantation is fraught with difficulties: the team’s previous attempts at combining artificial human embryos with genuine mouse embryos have proved exceedingly difficult. And no one had ever successfully grafted human embryonic cells onto an early bird embryo. However, in the current experiment, human cells immediately after transplantation began laying the base for a secondary spinal column and nervous system in the bird’s embryo – an act that clearly announced the presence of a true human organizer.
“To my amazement, the graft not only survived, but actually gave rise to these beautifully organized structures”, – Brivanlou says.
But most of all he was surprised by the origin of those structures. Cells of cartilage and bone tissue, from which the second spinal column eventually developed, originated entirely from human ESC, but the rudiments of the nerve tissue that was to develop into the brain and spinal cord consisted exclusively of the chickens cells.
According to Brivanlou, the fact that human cells are capable of building new structures in the embryos of birds (animals that are closer to dinosaurs than to us) shows that the ability of animal cells to choose a particular fate has been conserved over hundreds of millions of years of evolution.
In addition, the fact that human cells are able to direct the development of chick cells to become nervous tissue also suggests that the molecules involved in cellular communications – the signals that cells send to each other to control development – have survived since ancient times.
“Once you transplant the human organizer into a chicken embryo, the language it uses to instruct the bird cells to establish the brain and nervous system is exactly the same as the one used by amphibians and fish”, – Brivanlou says.
Understanding how undifferentiated stem cells become a particular kind of tissue is essential to regenerative medicine, which relies on stem-cell based technologies to restore and rejuvenate failing tissues, or even replace them with freshly grown ones.
In addition, the chick-based method of transplantation, developed by Brivanlou and his colleagues, represents a powerful tool for studying the earliest stages of human development, which the team from the Rockefeller University is already using in other studies.