How are stem cells brought to reproduce identically and to self-differentiate into as many specialized cells necessary for the proper functioning of the organism? No doubt they are genetically programmed to behave this way. But signals emitted by neighboring cells are also there to encourage them to do so.
These vital interactions between stem cells and partner cells occur in very precise anatomical locations, true spaces of cellular communication: the “niches”.
The hypothesis of a niche influencing the biology of hematopoietic stem cells was first proposed in 1978 by an English hematologist (Schofield).
Since then, multiple niches have been located in adults: in the ovaries, the testes, the hematopoietic marrow, the hair follicles, the intestinal epithelium or even the nervous system.
They are made up of a set of cells located in a part of the organ specialized in maintaining a stock of stem cells which are “immobilized” there and which receive a multitude of complex signals which control their self-renewal. Despite these commonalities, the nature of the cells participating in the niche is different depending on the organ considered. And the signals exchanged are probably not completely identical …
Hematopoietic Niches
After birth, blood cells are permanently produced in the marrow located in the cavities of the bone under the control of other cells whose exact role is not yet fully understood. We have seen that stem cells are specifically located near the bone. Why do they settle so close to the bone? And why do they stay there? In this region, there are osteoblasts which are the cells responsible for building bones. However, it has recently been shown that some of them also create niches for stem cells.
They produce substances called chemokines which act as a magnet attracting stem cells. They also have so-called adhesion molecules which bind to molecules located on the surface of stem cells which are thus fixed there. It has also been observed that other molecules allow the stem cell to adhere to a matrix probably produced by osteoblasts.
Why do stem cells divide so little? Why are they able to renew themselves? Why are they not differentiated? Here again, the adhesion of stem cells to their osteoblastic partners and to the matrix seems essential to control proliferation. Other “receptor-ligand” interactions allow the stem cell to retain its self-renewing properties, induce an increase in the production of adhesion molecules and inhibit divisions.
Finally, osteoblasts produce other killer factors involved in maintaining the properties of stem cells, but whose role is not yet fully understood. How do stem cells leave their niche and what do they become? Enzymes produced in the osteoblastic zone activate a molecule (Kit-ligand) which stimulates the proliferation of stem cells which, simultaneously, lose their adhesion molecules, which allows them to move away from osteoblasts.
They proliferate, gradually lose their capacity for self-renewal, differentiate and migrate to the blood vessels. On their way, they encounter a wide variety of cells probably involved in the control of all these phenomena: for example, the endothelial cells which line the blood vessels contribute to the survival of the differentiating cells, which has led to suspect the existence of a vascular niche.
Is it possible that hematopoietic stem cells also participate actively in the creation of the niche? Communication between the stem cell and its partner cell appears to be a two-way street: stem cells control the production of certain cytokines by osteoblasts, and progenitor cells would do the same with endothelial cells. These mechanisms and their importance are still far from being elucidated.
The niches: a new avenue for oncology
Cancer stem cells share certain properties with normal stem cells: they self-renew and give rise to highly proliferative progenitors. We know that the niche inhibits the division of stem cells: a mutation that would make them insensitive to control of the niche or a change in the signals emitted by the niche could perhaps contribute to the development of cancer.
In their niche, stem cells are protected against a whole series of attacks and are resistant, among other things, to certain anti-cancer drugs; some leukemia cells are also resistant to these drugs: are they protected by a niche? Is it possible to get them out and make them more vulnerable? To answer these questions, it will be necessary not only to identify all the potential players in the niche, but also to understand how they coordinate their actions.