What is Stem Cell ?
The definition of stem cells must be on a functional basis. Even as the identification of structural attributes of stem cells at the morphological or molecular levels becomes possible [current candidates include high levels of expression of the multidrug resistance gene and certain combinations of integrin expression], it will always be the seductive function of stem cells that will be their defining feature.
Functionally, stem cells are the multipotential, self-renewing cells that sit at the top of the lineage hierarchy and proliferate to make differentiated cell types of a given tissue in vivo.
It is important to restrict this definition to single cells that, once developed, self-renew for the lifetime of the organism in order to distinguish stem cells from the many types of more transient progenitor cells (with limited self-renewal life-spans) that are present, especially in complex organisms. This may be more than semantic classification, because stem and progenitor cells defined by self-renewal ability may constitute different classes of cells under different molecular regulation across tissue types. In vivo in adult organisms, stem cells can divide repeatedly to replenish a tissue or may be more quiescent, as in the mammalian brain. Rather than considering stem cells as undifferentiated cells, it may be more productive to think of them as appropriately differentiated for their specific tissue niches, with perhaps the ability to display more potential phenotypes in alternate niches. Stem cells can divide symmetrically during development to expand their numbers and asymmetrically to self-renew and give rise to a more differentiated progeny. Indeed, as suggested for mammalian hematopoietic stem cells, the differentiation of specific blood progenitors from the asymmetric division of stem cells may be stochastic, with only the rate of proliferation of the stem cells under specific regulation.
Development of the concept "Stem Cell"
The concept of a stem cell, now nearing its hundredth year as one of the organizing principles of developmental biology, shows no sign of losing its youthful luster. At a time when the transfer of biological concepts to clinical practice drives much of science, the properties of stem cells in various tissues are attracting increasing levels of interest. This attention is not restricted to the germ line and blood, the traditional domain of stem cells as defined by early 20th-century studies on animal development, but has been extended to tissues not typically thought to turn over. As novel sites, properties, and functions have been identified for these cells, the definition of a stem cell has shifted repeatedly. Like some stem cells, this concept has expanded greatly and has displayed a remarkable degree of plasticity.
The origins of the concept
The recognition that tissues vary in their capacity to regenerate and the identification of tissues that can self-renew over an organism’s complete life span are rooted in 19th-century biological and medical science. The existence of a stem cell, viewed as the ultimate origin of self-renewal in self-renewing tissues, was perhaps first postulated by Regaud based on his studies of sperma-togenesis. Concurrently, the hematologists Weidenreich, Dantschakoff, and Maximow provoked a hot debate, sustained by Ferrata and Pappenheim, proposing that all blood cells derive from a common stem cell. These astute observers, without the advantages of current technologies, recognized that for spermatogenesis to occur or for blood cells to be replenished throughout the lifespan of the organism, there must be a self-renewing ancestral cell. Thus, historically, the concepts of stem cells and tissue self-renewal became closely linked. Later, the establishment of appropriate hematological assays and the finding that the progeny of certain clonogenic progenitors could completely reconstitute hematopoiesis following lethal irradiation more clearly delineated the role of the stem cell, providing the basis for the most conspicuous translation to date of stem cell biology into medical treatment: bone marrow transplantation. Consequently, the ability of a stem cell to reconstitute a dependent tissue for the life-span of an organism also became a part of the generic definition of a cell’s "stemness."
Both of these "classical" facets of a stem cell’s character, self-renewal and tissue reconstitution, are currently being challenged. Today, as discussed in several articles in this Perspective series, tissues typically regarded as non–self-renewing (such as nervous tissue), slowly self-renewing (such as bone), or non–self-renewing but endowed with a limited capacity to repair (such as skeletal muscle) are all said to include stem cells. However, in all of these cases, there is no clear evidence — such as exists for stem cells in the hematopoietic system — that the putative stem cells undergo self-renewal in vivo. In most cases, progenitor cells, which have sometimes been presumed equivalent to endogenous stem cells, can be isolated and expanded extensively, allowing for impressive, but not necessarily unlimited, amounts of the dependent tissues to be generated.
The implicit linkage of unlimited self-renewal in vivo to extensive expansion ex vivo represents a remarkable and often unnoticed shift in thinking. This shift merits careful scrutiny, however, since it invites us to define the stem cell on the basis of a biological property that exists only under experimental conditions. Likewise, clonogenicity, or the ability of a single cell to proliferate independently to form a colony, is another property commonly ascribed to stem cells, although many clonogenic cells are limited in their capacity for expansion ex vivo. As with expandability, clonogenicity is defined solely on the basis of an ex vivo assay. Thus, we have learned to recognize stem cells, not necessarily by what they do in their dependent tissues within an organism, but rather by what we can do with them in the laboratory. These two parameters, ex vivo expansion and clonogenicity, have provided us the novel perspective that even tissues that never apparently turn over have stem cells, a remarkable advance in our understanding.
In traditional thinking, stem cells have been generally recognized as undifferentiated cells with varying degrees of potency — a measure of the number and range of phenotypes that they can develop into. Studies of cell populations during embryonic development have lead to the identification of cells that are totipotent, that is, a single cell can by itself give rise to an entire organism. However, totipotency is fleeting, disappearing after the early divisions of a fertilized oocyte, but reappearing after formation of the inner cell mass, which contains embryonic stem (ES) cells that can participate in forming every tissue of the organism. However, they are only totipotent within an environmental context, either during development or upon transplantation into a postnatal organism; a single ES cell, unlike a zygote, cannot form a complete organism by itself. As development proceeds, other stem cells emerge with more limited proliferative and differentiative capabilities. Each new cell formed becomes progressively more and more restricted, based on the reactions of its ancestors to a changing environment, and following the general rule that differentiation is accompanied by decreased proliferation.
