An international group of scientists under the supervision of a staff member of Sechenov University (Russia) and Karolinska Institute (Sweden) found out that earlier views on the mechanisms that provide and regulate skeletal growth were wrong. Previously, scientists used to believe that at birth a body had a certain number of cells to grow the skeleton, and when this amount was over, the growth stopped. However, the authors of the work discovered a special area of the growth plate (a structure that enables longitudinal growth of bones) called a stem niche that can theoretically produce infinite numbers of new cells. The scientists believe that growth stops not when all growth cells are used, but when the stem niche is destroyed. This discovery changes the whole concept of growth and may suggest new method of growth disorder treatment in children. The article of the team was published in Nature.
Skeletal growth in children is secured by the growth plate - an area of dividing and growing cartilage tissue cells or chondrocytes. The plates are narrow disks around 1 mm thick. They are located at each end of a bone between the head and the main part (except for several skull, pelvis, and scapula bones). Inside a growth plate there are progenitor cells (the precursors of chondrocytes). They are differentiated into chondrocytes, and the latter divide, grow bigger, and die leaving behind a mineralized carcass made of the intercellular substance that bone tissue later bases on. This process enables the children's growth, and any disorders in it may lead to various growth anomaly, including stunted growth and microplasia.
Previously, it was believed that progenitor cells were used during the whole process of longitudinal skeletal growth, and when there were no more such cells in the growth plate, the growth stopped. However, the life of such cells in short, and the number of divisions is limited. Therefore it was difficult to understand how they were able to produce numerous chondrocytes that were required to secure the growth of bone tissue for many years.
To monitor the division and growth of progenitor cells, the scientists used the so-called Confetti mice. Their cells glow with different colors under UV rays. The genes that code the glowing proteins are inherited when the cells are divided. Therefore, one may identify the progeny (clone) of each marked cell. The authors of the work traced the progeny of each progenitor cell in the growth plate and found out that the clones differed depending on the age of the mice. In embryos and newborns each progenitor cell divided only 2 or 3 times and formed small clones. Starting from the age when the mice were able to walk and run, their progenitor cells divided in a slower, but a more consistent pattern and formed big and stable clones.
Having modelled the division and development of the cells (see the results of the modeling on the web-site of the lab), the scientists found out that this type of clone formation was only possible in the case of self-renewing progenitors. Such behavior of these cells is typical in the tissues that have to produce numerous cells, such as skin, blood, or intestines. It is known that for such progenitors (the so-called adult stem cells) to have special favorable conditions for constant updating, they have to be surrounded by other cells and the extracellular matrix. The total of such conditions is called a stem niche. The authors of the work verified this hypothesis and confirmed that specific genes typical for stem niches were expressed in the growth plate. The new stem niche was called an epiphyseal one.
The authors of the article believe that the niche might have appeared due to the formation of a secondary ossification (calcification) center in the head of the bone that happens in mice at the age of three weeks, and in people - by the end of their first year.
The research was carried out on mice, and it will take time and additional studies to understand whether it is applicable to people. However, if it is confirmed that human children grow based on the same growth plate functioning principles, scientists will be able to reconsider the methods of treatment for the children with growth disorders. Current results already explain the observed cases of unconstrained growth in several patients with genetic disorders. Moreover, the results obtained by the scientists may explain the reasons why the growth of children stops after trauma or chemotherapy and suggest new treatment methods.
"In our article we point out that skeletal growth is based on the so-called stem niche principle that we discovered and characterized. It suggests completely new approaches to the treatment of children with growth disorders. When we understand how the niche is controlled, we'll be able to regulate it and let the kids with growth disorders grow as high as they want to be", said Andrei Chagin, the head of the Laboratory for the Regeneration of Skeletal Tissues of Sechenov University.
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Journal
Nature