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Pregnancy Timeline by SemestersDevelopmental TimelineFertilizationFirst TrimesterSecond TrimesterThird TrimesterFirst Thin Layer of Skin AppearsEnd of Embryonic PeriodEnd of Embryonic PeriodFemale Reproductive SystemBeginning Cerebral HemispheresA Four Chambered HeartFirst Detectable Brain WavesThe Appearance of SomitesBasic Brain Structure in PlaceHeartbeat can be detectedHeartbeat can be detectedFinger and toe prints appearFinger and toe prints appearFetal sexual organs visibleBrown fat surrounds lymphatic systemBone marrow starts making blood cellsBone marrow starts making blood cellsInner Ear Bones HardenSensory brain waves begin to activateSensory brain waves begin to activateFetal liver is producing blood cellsBrain convolutions beginBrain convolutions beginImmune system beginningWhite fat begins to be madeHead may position into pelvisWhite fat begins to be madePeriod of rapid brain growthFull TermHead may position into pelvisImmune system beginningLungs begin to produce surfactant
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Developmental biology - Cell Function

Meet the Master Organizers of Human Embryo Growth

A unique group of cells emit molecular signals prompting other cells to specialize...


The factors that shape the destiny of a cell remain something of a mystery. Why, for example, does one stem cell in a human embryo become a neuron rather than a muscle cell? And why does another decide to build cartilage rather than cardiac tissue?

New research by a team of Rockefeller scientists under the direction of Ali H. Brivanlou PhD, illuminates the molecular circuitry that determines a cell's fate. Their work appears in the journal Nature, and establishes a new platform for studying the earliest stages of human development. It could form the basis for novel treatments of a wide range of ailments.

Organizational genius

Scientists already know embryonic stem cells can differentiate into any of a body's specialized cells such as bone, brain, lung and liver.

They also know from work done in the early 1920s by German embryologist Hans Spemann and his graduate student Hilde Mangold, that embryos of vertebrate animals transform from a hollow ball of cells into a multilayered structure organized along a central axis from head to tail. In that transition, a furrow called the primitive streak folds inward on itself, as cells along the furrow begin to mature into different cell lineages that will become all the organs and tissues of the body. These special groups of cells are also found in amphibian and fish embryos.
These cell groups are called "organizers," and emit molecular signals directing nearby cells to grow and develop in a specific order. When an organizer cell is transplanted from one embryo to another, it spurs the new host to produce a secondary spinal column and central nervous system, complete with spinal cord and brain. Ethical guidelines limit experiments like this on human embryos, so scientists did not know if a similar organizer cell system existed in humans.

To test the organizer cell concept in humans, Brivanlou and his team performed a series of experiments involving artificial human embryos. These tiny clusters of cells, roughly one millimeter across, are grown in a lab from human embryonic stem cells. Though a far cry from actual embryos, artificial human embryos contain many cells and tissues present in genuine human embryos, and can be used as experimental stand-ins for real embryos.
Previous studies reveal that three different signaling pathways drive early embryo development in animals such as mice and frogs. By activating those three pathways in artificial human embryos confined to Petri dishes, Brivanlou and colleagues identified identical molecular signals drive development in human cells. When given these signals in the correct sequence, artificial human embryos will even generate their own organizer cells.

There is a difference between what cells do in a Petri dish, and what happens inside a real embryo. To validate their initial findings, the researchers grafted artificial human embryos onto genuine chicken embryos - after tagging the human cells with a fluorescent marker to allow precise tracking of human cells under a microscope. What happened next astonished them.

Division of labor

Transplanting cells from one species to another is not easy. The researchers' previous attempts at combining artificial human embryos with mouse embryos were exceedingly difficult. No one, as yet, had successfully grafted human embryonic cells with bird embryo cells.

Yet as soon as the artificial human embryo cells were introduced into an avian host, the artificial human embryos began making a secondary spinal column and nervous system - clearly announcing a functioning human organizer cell group."To my amazement, the graft not only survived, but actually gave rise to these beautifully organized structures," said Brivanlou.
What was even more surprising was the provenance of those structures. While progenitors of cartilage and bone tissue would eventually make a second spinal column, they were composed entirely of human cells. However, the beginning of nervous tissue that ultimately became spinal cord and brain were composed exclusively of chick cells.

According to Brivanlou, the fact that human cells are capable of building new structures in the embryo of a bird - an animal more closely related to dinosaurs than to mammals - demonstrates that this particular cell design has been conserved over hundreds of millions of years of evolution. And, the fact that those same human cells were able to instruct chick cells to become nervous tissue also indicates molecules involved in cell to cell communication have been conserved for millions of years as well.
"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."

Ali H. Brivanlou PhD, Robert and Harriet Heilbrunn Professor, Laboratory of Stem Cell Biology and Molecular Embryology, The Rockefeller University, New York, NY, USA.

Moving forward by looking back

Understanding how undifferentiated stem cells become a particular kind of tissue is essential to regenerative medicine, which relies on stem-cell based technologies to heal and rejuvenate failing tissues, or replace them with newly grown cells.

These chick-based grafting methods invented by Brivanlou and his team represent a powerful new tool for studying the earliest stages of human development. By providing a window onto normal cell differentiation and tissue formation, their approach should help scientists understand when and how things go awry in the first moments of life. This could lead to new ways of preventing miscarriages and birth defects, as well as new treatments for diseases from cancer to diabetes.
"If you want to understand something, you must first understand its origins. And if we want to understand the origins of human disease, we must develop ways to work with human cells."

Ali H. Brivanlou PhD

Abstract
In amniotes, the development of the primitive streak and its accompanying ‘organizer’ define the first stages of gastrulation. Although these structures have been characterized in detail in model organisms, the human primitive streak and organizer remain a mystery. When stimulated with BMP4, micropatterned colonies of human embryonic stem cells self-organize to generate early embryonic germ layers1. Here we show that, in the same type of colonies, Wnt signalling is sufficient to induce a primitive streak, and stimulation with Wnt and Activin is sufficient to induce an organizer, as characterized by embryo-like sharp boundary formation, markers of epithelial-to-mesenchymal transition and expression of the organizer-specific transcription factor GSC. Moreover, when grafted into chick embryos, human stem cell colonies treated with Wnt and Activin induce and contribute autonomously to a secondary axis while inducing a neural fate in the host. This fulfils the most stringent functional criteria for an organizer, and its discovery represents a milestone in human embryology.

Authors: I. Martyn, T. Y. Kanno, A. Ruzo, E. D. Siggia and A. H. Brivanlou


Acknowledgements
The authors are grateful to I. Yan, F. Vieceli and M. Bronner for materials and protocols, to J. Metzger for assistance with 3D image segmentation, and to members of the A.H.B. and E.D.S. laboratories for helpful discussions. This work was supported by grants R01 HD080699, R01 GM101653, the Tri-Institutional Starr Foundation Grant 2016-007, and private funds from the Rockefeller University.


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May 29, 2018   Fetal Timeline   Maternal Timeline   News   News Archive



Researchers at The Rockefeller University have identified a small cluster of cells in the human embryo that dictates the fate of other embryonic cells - an 'organizer' cluster of developmental activity. Highlighted in RED above are a Human secondary spinal column and nervous system - announcing a functioning Human organizer cell group within this chick embryo cell group. Image credit: Laboratory of Stem Cell Biology and Molecular Embryology at The Rockefeller University.


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