22 April 2008

Neurons are treated by fusion

Pyotr Smirnov, "Newspaper.Ru»Stem cells never cease to amaze scientists who still do not understand very well how these "soldiers of medicine of the future" work.

One more mechanism has been added to the two main mechanisms proposed so far – replacement of cells of the damaged organ with stem cells and stimulation of cell division of its preserved parts.

At least some of the stem cells are able to fuse with some neurons, forming amazing binuclear formations. In response to chronic inflammation, which signals the body about the disease, blood stem cells rush into the brain and merge with one of the types of neurons 100 times more intensively than previously thought.

According to scientists, this may at least partially explain the numerous positive clinical effects described so far, as well as become a new direction for cell therapy.

This is not the first time that hematopoietic stem cells have surprised scientists. At the beginning of the last century, the St. Petersburg scientist Alexander Maksimov suggested the presence in the bone marrow of a small population of cells with the ability to form all other blood cells. These "generalists", later called hematopoietic stem cells, became the first stem cells known to science.

Later, the work of Alexander Friedenstein and his colleagues from the Siberian Branch of the Academy of Medical Sciences proved the existence of the ability to transform for the so-called stromal cells of the bone marrow. Finally, it was only in the last decade that scientists not only discovered a large content of hematopoietic cells in the blood of experimental animals and humans, but also proved that they can turn not only into red and white blood cells, but also into cells of other body tissues.

All these features formed the basis of modern regenerative medicine.

However, until now, the contribution of various mechanisms to the really significant effect achieved by transplantation of various stem cells remains unclear. In particular, scientists still argue that the effect is stronger – the embedding of stem cells into a damaged organ or their influence on cells preserved in integrity.

Now scientists hungry for truth will have to choose among three mechanisms – the list has been replenished with a "merger", "rediscovered" by Helen Blau and her colleagues at Stanford University.

They showed that when chronic inflammation begins, progenitor cells rush into the brain and merge with a certain type of nerve cells 100 times more often than previously thought.

After fusion, heterokaryons (cells containing two or more nuclei) are formed, the genetic material of which, in fact, does not differ from the information recorded in the DNA sequence of other cells of the body. But regulatory mechanisms force the nucleus of the progenitor cell to express previously "silent" genes specific to the nervous tissue.

As scientists rightly noted in their work (Clas B. Johansson et al., Extensive fusion of haematopoietic cells with Purkinje neurons in response to chronic inflammation), accepted for publication in Nature Biology, this effect has already been observed for hematopoietic cells paired with neurons, liver cells and skeletal muscles. However, attention was not paid to it – the frequency of the phenomenon was too low, even in conditions of damage to the target tissue. Scientists have decided that this phenomenon has no real biological significance.

Blau and her colleagues focused on Purkinje cells, huge neurons located in one of the layers of the cerebellar cortex. Previously, the features of Purkinje cells, in addition to the huge size that distinguishes them even among neurons, included a large number of intercellular contacts and a complete lack of the ability to regenerate. Now another of their properties has been revealed – the ability to merge with progenitor cells from blood and bone marrow.

Scientists have discovered the phenomenon thanks to a new method of studying cell mergers.

Previous experiments to study this phenomenon in mice consisted in using sublethal doses of radiation, which do not kill the animal, but completely destroy the bone marrow. After that, the irradiated mouse is transplanted bone marrow from a rodent of the same lineage with the same genetic material – this is a classic experiment of the 60s, differing only in a new search method. A green fluorescent protein gene is added to the nuclei of transplanted cells, which makes it easy to find hematopoietic cells transplanted into the bone marrow and migrated to other organs.

This experiment has a significant drawback. Radiation exposure is a significant stress for the body, leading to a violation of the natural semi–permeable – the so-called blood-brain barrier between the blood and the brain. From the point of view of immunology in a healthy body, blood cells should not penetrate into the nervous tissue at all.

Blau and her colleagues corrected this flaw, at the same time complicating their work, and life for the experimental animals. They artificially connected the circulatory and lymphatic systems of two mice. At the same time, one of the mice was previously irradiated and transplanted with a "green" bone marrow. The "fusion" was supposed to be studied in the cerebellum of another, whose blood-brain barrier had not changed.

After 38 weeks, more than half of all blood cells of such a "chimera" turned "green". After that, the related mice were separated, but enough green progenitor cells remained in the blood of the non-irradiated partner, the number of which gradually decreased over time. These progenitor cells were sufficient to continue the formation of heterokaryons with Purkinje cells. However, their number remained small – only a few dozen for the entire cerebellum.

However, in some individuals, this number exceeded several hundred.

When scientists began to understand the reason for such a hundredfold increase, they found that all "exceptional" mice were sick with a severe autoimmune disease – idiopathic ulcerative dermatitis, which manifests itself on the skin, but affects the entire immune system, and these are billions of cells throughout the body.

As a result, experimenters got their hands on a new, very effective tool for influencing the properties of tissues, organs and individual cells, and theorists from biology and medicine got a new headache: the cause of the detected phenomenon is still unknown.

But ordinary people do not lose hope that with the explanation of the mechanism of stem cells, regenerative medicine will work better for more people. So far, her success is akin to a blind search rather than moving towards a goal set from afar.

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