The concept of stem cells emerged from research carried out in the 1950s and 1960s on the renewal of blood cells. These have a short lifespan (a human red blood cell lives 120 days) and therefore must be replaced for the entire lifetime.
Renewal is ensured by resident cells of the bone marrow, capable of self-renewal while producing, by asymmetrical division, cohorts of rapidly proliferating cells which engage in the differentiation pathways leading them to produce the whole variety of circulating blood cells. These cell renewal mechanisms exist for all tissues.
Each organ contains, alongside differentiated and functional cells, a contingent of undifferentiated cells capable of replacing dead cells and thus maintaining cell homeostasis. These stem cells originate during embryonic development where they are assigned a specific place in the body (a “niche”) and a function, that of renewing the tissue to which they belong.
Thus, the development of the embryo being completed, the task of “repairing” the tissues altered by the wear of time is delegated to these cells, few in number, but endowed, thanks to their capacity for self-renewal, with the power to produce “new” cells without losing their own population. The origin of hematopoietic stem cells in the embryo has been studied extensively. These works were reported by Françoise Dieterlen and Bruno Péault. One of the most significant recent results from these studies is the common origin of vascular endothelial cells and hematopoietic stem cells.
The demonstration of the existence of these stem cells capable of supplying the blood and endothelial lines, called hemangioblasts, has been provided in several species such as the bird, mouse and human embryo. Such cells persist in adults and can be mobilized in the process of scarring and neovascularization via the bloodstream. Another example of cells with rapid renewal in adults is that of the skin, an important organ by its size and volume (16% of body weight), the epidermis of which is the site of permanent cell renewal from ” a basal layer called generator essentially consisting of stem cells.
In addition to the epidermis, skin stem cells are also responsible for the appendages (hair, feathers, scales) and skin glands such as the sebaceous glands of mammals. Yves Barrandon by constructing chimeric hair follicles between a normal mouse and a mouse carrying a genetic marker, was able to show the dynamics of the renewal of the different cell types of the skin as well as the very extensive pluripotentiality of skin stem cells.
The muscular tissue contains next to myocytes (giant multinucleated cells provided with contractile myofibrils) undifferentiated cells called satellite cells capable of becoming themselves contractile cells. These stem cells were used by a French group represented at the Symposium by Philippe Menasché to treat lesions caused by a myocardial infarction. This is a first in human regenerative cell therapy using adult stem cells other than hematologic cells from the bone marrow or umbilical cord and skin.
Stem cells and nervous tissue
It has long been held to be true that in higher vertebrates the brain has at birth a contingent of neurons, the number of which can only decrease during life. The stopping of neurogenesis during embryonic life constituted a dogma which seemed to suffer no exceptions. A first and timid addiction to this certainty came from the study of the brains of birds whose seasonal sexual activity is accompanied by rich and varied vocalizations which they are no longer able to emit when the mating season is over. .
The nerve center of these vocalizations disappears during the sexual rest phase and reappears the following year for the breeding season. Nottebohm, by specifically marking dividing cells, has shown that the re-emergence of the song nucleus was the result of neoneurogenesis therefore occurring in the adult bird.
It wasn’t until the 1990s that it was accepted that the adult brain was the seat of production of new neurons. Studies of the rat’s olfactory bulb have effectively demonstrated a continuous death affecting certain types of neurons which therefore had to be the seat of constant renewal. We know today that adult neurogenesis, although discreet, involves other parts of the central nervous system such as the hippocampus and even the cerebral cortex.
In addition to these controversies, research on the development of the nervous system has shown that, in the embryo, the different types of cells that differentiate into neurons and glial cells in the neuroepithelium, come from the innermost layer of cells. of the primitive neural tube (the ventricular epithelium), certain elements of which appear to play the role of pluripotent stem cells. The first demonstration that the neural outline contains stem cells was provided for the neural crest, by Nicole Le Douarin.
The neural crest is a transient embryonic structure at the origin of the ganglia and peripheral nerves system as well as many other cell types (pigment cells, endocrine cells, cartilage, bone, connective tissue). The clonal cell culture of the neural crest of a bird embryo and later a rat has shown the existence of pluripotent cells from which colonies develop where all the cell types normally derived from this outline are represented. Thus was defined a stem cell of the neural crest encompassing the peripheral nervous system and its other derivatives.
The next step was to discover the stem cell of the central nervous system. Undifferentiated cells expressing the “nestin” gene (an intermediate cytoplasmic filament) were identified in the ventricular epithelium by Ron McKay who hypothesized that they could be putative stem cells of the central nervous system. This hypothesis has been confirmed by numerous studies and the methods of isolating these cells were thought to be fate determined from embryonic development. Keiichi Fukuda isolated a line of cardiomyocytes from stromal cells in the bone marrow.
The sensational and unexpected nature of these results opened up the columns of newspapers reputed to be selective in their choices. For these reasons, should they benefit from our unconditional membership?
What are the extent and limits of the multipotentiality of adult stem cells?
Several papers from this symposium recommended caution with regard to the generalization of the pluripotentiality of specialized stem cells from adult tissues. Different tissues, including the endodermal epithelium of the intestine and bronchi, can contribute not only to the blood line but also to the intestinal and bronchial epithelium. Margaret Goodell shows that, even in the hands of competent and careful researchers, misinterpretations can be made to these complex experiences.
His article published in PNAS in 1999 showed that cells from the muscle could, if injected into an irradiated mouse, participate in the hematopoietic reconstruction of the host. This role, attributed to neural stem satellite cells from embryonic and adult brains (in many species including humans), is now well developed. Stefan Momma, Perry Bartlett, and Angelo Vescovi discussed the isolation of brain stem cells, their characterization, their culture in the form of neurospheres and their ability to differentiate into a wide variety of cell types when subjected at appropriate environmental conditions.
Several articles have been published in recent years showing the plasticity of stem cells which embryologists who follow the fate of cells in the embryo during development know that one of the important elements in determining cells towards a particular destiny is their belonging to one of the three embryonic layers. One of the most striking phenomena resulting from recent experiments on adult stem cells is that the extent of their plasticity exceeds the virtual boundaries of the sheets.
The experiments of Neil Theise are spectacular in this respect because they tend to show that hematopoietic stem cells (HSC) injected into a mouse irradiated lethally and consequently depleted in cells which ensure the rapid renewal of muscle cells whose role in muscle neogenesis throughout life is well known. Using a chimeric system in which the cells injected come from a mouse carrying a genetic marker allowing them to be recognized from the host cells, she recently concluded that despite the precautions taken during her experiments, the composition of the cells injected although coming from the muscle was not homogeneous but contained alongside the muscle stem cells, resident hematopoietic stem cells whose characteristics it was able to identify and which are in fact at the origin of the blood cells which appeared in the host irradiated.
We must welcome the continuation of the work accomplished by Margaret Goodell to identify with an ever greater degree of certainty the nature of the cells injected. The main difficulty of these experiences lay in fact in the purity of the inoculate. Contamination by a single cell of an unwanted type can lead to major interpretation errors, given the significant proliferation power of certain cells if they are placed in a context that is favorable to them. Irving Weissman recalls these precautions.
His work has defined, in the past, the molecular characteristics of hematopoietic stem cells which make it possible to identify and know their migrations, which is all the more critical during the conference as it follows shortly the publication of two articles in Nature of April 4, 2002 in which the authors show that if stem cells are cultivated in the presence of other cells of adult origin (eg, bone marrow or cells of the central nervous system), they have a hitherto unsuspected tendency to generate spontaneously somatic hybrids by cell fusion.
These hybrids have a chromosomal formula double the chromosomal stock of the species and display the cytoplasmic characteristics of the differentiated cells with which the stem cells have fused. Although these experiments were carried out in vitro, they cast additional doubt on the interpretation given to the results of certain previous experiments which concluded that the plasticity of stem cells in adults is wide.