Mechanism That Triggers Differentiation Of Embryo Cells Discovered

The mechanism whereby embryonic cells stop being flexible and turn into more mature cells that can develop into specific tissues has been discovered by scientists at the Hebrew University of Jerusalem. The discovery has significant consequences towards furthering research that will eventually make possible medical cell replacement therapy based on the use of embryonic cells.

At a very early stage of human development, all cells of the embryo are identical, but unlike adult cells are very flexible and carry within them the potential to become any tissue type, whether it be muscle, skin, liver or brain.

This cell differentiation process begins at about the time that the embryo settles into the uterus. In terms of the inner workings of the cell, this involves two main control mechanisms. On the one hand, the genes that keep the embryo in their fully potent state are turned off, and at the same time, tissue-specific genes are turned on. By activating a certain set of genes, the embryo can make muscle cells. By turning on a different set, these same immature cells can become liver. Other gene sets are responsible for additional tissues.

In a recent paper, published in the journal, Nature Structural and Molecular Biology, Professors Yehudit Bergman and Howard Cedar of the Hebrew University-Hadassah Medical School have deciphered the mechanism whereby embryonic cells stop being flexible and turn into more mature cells that can differentiate into specific tissues. Bergman is the Morley Goldblatt Professor of Cancer Research and Experimental Medicine and Cedar is the Harry and Helen L. Brenner Professor of Molecular Biology at the Medical School.

They found in their experiments, using embryos from laboratory mice and cells that grow in culture, that this entire process is actually controlled by a single gene, called G9a, which itself is capable of directing a whole program of changes that involves turning off a large set of genes so that they remain locked for the entire lifetime of the organism, thereby unable to activate any further cell flexibility.

Their studies shed light not only on this central process, but also can have consequences for medical treatment. One of the biggest challenges today is to generate new tissues for replacing damaged cells in a variety of different diseases, such as Parkinson’s disease or diabetes. Many efforts have been aimed at “reprogramming” readily-available adult cells, but scientists have discovered that it is almost impossible to do this, mainly because normal tissues are locked in their fixed program and have lost their ability to convert back to fully potent, flexible, embryonic cells.

Now, with the new information discovered by Bergman and Cedar, the molecular program that is responsible for turning off cell flexibility has been identified, and this may clear the way towards developing new approaches to program cells in a controlled and specific manner.

Artificial Human Bone Marrow Created In A Test Tube

This development could lead to simpler pharmaceutical drug testing, closer study of immune system defects and a continuous supply of blood for transfusions.

The substance grows on a 3-D scaffold that mimics the tissues supporting bone marrow in the body, said Nicholas Kotov, a professor in the U-M departments of Chemical Engineering; Materials Science and Engineering; and Biomedical Engineering.

The marrow is not made to be implanted in the body, like most 3-D biomedical scaffolds. It is designed to function in a test tube.

Kotov, principal investigator, is an author of a paper about the research currently published online in the journal Biomaterials. Joan Nichols, professor from the University of Texas Medical Branch, collaborated on many aspects of the project.

"This is the first successful artificial bone marrow," Kotov said. "It has two of the essential functions of bone marrow. It can replicate blood stem cells and produce B cells. The latter are the key immune cells producing antibodies that are important to fighting many diseases."

Blood stem cells give rise to blood as well as several other types of cells. B cells, a type of white blood cell, battle colds, bacterial infections, and other foreign or abnormal cells including some cancers.

Cancer-fighting chemotherapy drugs can strongly suppress bone marrow function, leaving the body more susceptible to infection. The new artificial marrow could allow researchers to test how a new drug at certain potencies would affect bone marrow function, Kotov said. This could assist in drug development and catch severe side effects before human drug trials.

Bone marrow is a complicated organ to replicate, Kotov said. Vital to the success of this new development is the three-dimensional scaffold on which the artificial marrow grows. This lattice had to have a high number of precisely-sized pores to stimulate cellular interaction.

The scaffolds are made out of a transparent polymer that nutrients can easily pass through. To create the scaffolds, scientists molded the polymer with tiny spheres ordered like billiard balls. Then, they dissolved the spheres to leave the perfect geometry of pores in the scaffold.

The scaffolds were then seeded with bone marrow stromal cells and osteoblasts, another type of bone marrow cell.

"The geometrical perfection of the polymer molded by spheres is very essential for reproducibility of the drug tests and evaluation of potential drug candidates," Kotov said. "The scaffold for this work had to be designed from scratch closely mimicking real bone marrow because there are no suitable commercially products.

"Certain stem cells that are essential for immunity and blood production are able to grow, divide and differentiate efficiently in these scaffolds due to the close similarity of the pores in the scaffold and the pores in actual bone marrow."

The researchers demonstrated that the artificial marrow gives a human-like response to an infectious New Caledonia/99/H1N1 flu virus. This is believed to be a first.

To determine whether the substance behaves like real bone marrow, the scientists implanted it in mice with immune deficiencies. The mice produced human immune cells and blood vessels grew through the substance.