Brain Birth Defects Successfully Reversed Through Stem Cell Therapy

Scientists at the Hebrew University of Jerusalem have succeeded in reversing brain birth defects in animal models, using stem cells to replace defective brain cells.

The work of Prof. Joseph Yanai and his associates at the Hebrew University-Hadassah Medical School was presented at the Tel Aviv Stem Cells Conference last spring and is expected to be presented and published nest year at the seventh annual meeting of the International Society for Stem Cell Research in Barcelona, Spain.

Involved in the project with Prof. Yanai are Prof. Tamir Ben-Hur, head of the Department of Neurology at the Hebrew University-Hadassah Medical School, and his group, as well as Prof. Ted Slotkin at Duke University in North Carolina, where Prof. Yanai is an adjunct professor.

Neural and behavioral birth defects, such as learning disabilities, are particularly difficult to treat, compared to defects with known cause factors such as Parkinson’s or Alzheimer’s disease, because the prenatal teratogen – the substances that cause the abnormalities -- act diffusely in the fetal brain, resulting in multiple defects.

Prof. Yanai and his associates were able to overcome this obstacle in laboratory tests with mice by using mouse embryonic neural stem cells. These cells migrate in the brain, search for the deficiency that caused the defect, and then differentiate into becoming the cells needed to repair the damage.

Generally speaking, stem cells may develop into any type of cell in the body, however at a certain point they begin to commit to a general function, such as neural stem cells, destined to play a role in the brain/ nervous system. At more advanced developmental stages, the neural stem cells take on an even more specific role as neural or glial (supporting) cells within the brain/ nervous system.

In the researchers’ animal model, they were able to reverse learning deficits in the offspring of pregnant mice who were exposed to organophosphate (a pesticide) and heroin. This was done by direct neural stem cell transplantation into the brains of the offspring. The recovery was almost one hundred percent, as proved in behavioral tests in which the treated animals improved to normal behavior and learning scores after the transplantation. On the molecular level, brain chemistry of the treated animals was also restored to normal.

The researchers went one step further. Puzzled by the stem cells’ ability to work even in those cases where most of them died out in the host brain, the scientists went on to discover that the neural stem cells succeed before they die in inducing the host brain itself to produce large number of stem cells which repair the damage. This discovery, finally settling a major question in stem cell research, evoked great interest and was published earlier this year in one of the leading journals in the field, Molecular Psychiatry.

The scientists are now in the midst of developing procedures for the least invasive method for administering the neural stem cells, which is probably via blood vessels, thus making the therapy practical and clinically feasible.

Normally, stem cells are derived from individuals genetically different from the patient to be transplanted, and therefore the efficacy of the treatment suffers from immunological rejection. For this reason, another important avenue of the ongoing study, toward the same goals, will be to eliminate the immunological rejection of the transplant, which will become possible by taking cells from the patient’s own body -- from a place where they are easily obtained -- by manipulating them to return to their stem cell phase of development, and then transplanting them into the patient’s brain via the blood stream. One important advantage of this approach will be to eliminate the controversial ethical issues involved in the use of embryo stem cells.

The research on the project has been supported by the US National Institutes of Health, the US-Israel Binational Science Foundation and the Israel anti-drug authorities.

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.