Postnatally, the distinction between progenitors and stem cells becomes somewhat unclear, because of our changing views of what defines these cells. Progenitor cells associated with postnatal somatic tissues are generally seen as committed cells left over from development and, as such, would be expected to be capable of a limited number of divisions and to generate differentiated cells of only the phenotypes expected for a given tissue. Stem cells, conversely, should be capable of sustained renewal and tissue regeneration. Such postnatal cells may be unipotent, giving rise to a singular phenotype, or pluripotent where progeny have multiple distinct phenotypes. By this standard, pluripotency of the kind seen in hematopoietic stem cells (HSCs) is not an obligatory property of stem cells, but it is plausibly seen as being limited to them. It is generally assumed that the mechanisms of lineage restriction observed during development apply to the progeny of postnatal stem cells. However, development is a system of differentiation, not renewal, and it is not certain that all stem cells found in the postnatal organism are governed by the same principles that dictate stem cell activity during development. Nevertheless, some postnatal stem cells clearly behave like developmental stem cells, since a decrease in proliferation, coupled with a progressive commitment and lineage restriction, governs the formation of blood cells from HSCs in adult animals.
In contrast to the pluripotent nature of the HSC, the fates of its progeny are restricted. Thus, a monocyte may become an alveolar macrophage or a Kupffer cell, but it will never become an erythrocyte. However, such restrictions do not apply in other tissues, where differentiated cells display plasticity, the ability to alter their phenotypes in response to changes in their local environment. This property was first noted in studies on skeletal stem cells found in the bone marrow stroma, where shifts in phenotypes of even differentiated cells were observed earlier both in vivo and in vitro. Furthermore, in some tissues, more differentiated cells can give rise to stem cells and may even replenish the stem cell population. The need for nonplastic and plastic cells may derive from the economics of tissue homeostasis. In tissues where rapid renewal is essential, such as blood, skin, and intestine, it is far more efficient to continuously generate a series of cells with dedicated phenotype; conversely, in tissues that turn over more slowly, such as hard and soft connective tissues, plasticity is essential to accommodate growth and response to injury.
Just as there are degrees of potency among stem cells, both they and their progeny display degrees of plasticity. As shown in the bone marrow stromal system, differentiated cells shift between osteoblastic cells, myelosupportive stroma, and adipocytes, within the context of the bone/marrow organ environment. However, striking experimental observations indicate there is also plasticity at the stem cell level. For example, neural and muscle stem cells can give rise to blood, and marrow stroma-derived stem cells can generate neural tissue. Some stem cells thus display a higher level of plasticity upon removal from their normal confines, when they take on the phenotypes of cells indigenous to the new context in which they are placed. This lack of cellular fidelity to a specific tissue or lineage violates classical expectations about developmental pathways. Perhaps, however, it should no longer surprise us after the recent spectacular demonstrations that a nucleus transplanted from a differentiated somatic tissue can contribute to all the cells of a complete organism. The cloning of a whole animal, as was seen with the sheep, Dolly, and a number of animals of several mammalian species, clearly calls into question the notion that differentiation is terminal, although it remains unclear whether adult cells that maintain their plasticity are in some way exceptional. In fact, the majority of nuclear transfers are unsuccessful, and there are no criteria for predicting which nuclei can be used to generate a totipotent cell. These findings may indicate that stem cells with embryonic character persist throughout life, whether they are actually used in tissue turnover or not. Plasticity of differentiated cells and stem cells has become a new frontier of cell biology. Understanding to what extent the two types of plasticity exist, and in what tissues, in what cells, at what ages, is a major challenge to the field.
Nature and nurture
The role of environmental cues, as opposed to genetic determination, in the specification of a cell’s fate has long been debated. More than two decades ago, before molecular descriptions of gene regulation or an understanding of cell-environment interactions were developed, a remarkable flavor of a "Darwinism vs. Lamarckism" contest was attached to the debate. We now know that environmental cues play a central role in cell differentiation during development, postnatal growth, and maintenance of cell populations in a tissue. Postnatal stem cells are extremely sensitive to the physical nature of their environments. Even HSCs are initially regulated in such fashion through their interaction with cells of the bone marrow stroma, but after being induced to proliferate and differentiate, hematopoietic cells are solitary. Their further differentiation occurs in a predominantly fluid, matrix-free environment and is driven by soluble factors and the intrinsic character of the cells themselves. In solid tissues, conversely, cell-cell and cell-matrix interactions exert powerful and continuous effects, not only in directing a cell’s development and behavior, but also in maintaining its state of differentiation. The significance of these environmental cues is further confirmed by the recent unexpected finding that altering the physical location of certain stem cells causes a complete reprogramming of their phenotypic expression patterns.
The plasticity of differentiated cells and stem cells in the postnatal organism poses important questions concerning the role of environmental cues. What mechanisms allow a stem cell to escape developmental pressures and maintain its "stemness"? What macro- or microenvironmental cues maintain a cell in its differentiated state? If cells associated with adult tissues and organs retain the ability to differentiate along both orthodox (tissue- or lineage-restricted) and unorthodox (unrestricted) pathways, what specific environmental cues do they respond to? If we can determine these mechanisms and cues, can we alter them to our benefit, to stimulate stem cell recruitment, proliferation, and induction into a desired phenotype in vivo? Other important questions relate to the developmental origin of postnatal stem cells and their possible relationships, as well as the role of symmetrical and asymmetrical cell divisions that maintain stem cell compartments but allow for differentiation.
Stem cells, regeneration, and disease
The recognition that somatic stem cells can be isolated and are able to renew a particular tissue motivated immediate efforts to apply these cells in the clinic. Bone marrow transplantation, albeit not successful in all circumstances, has become a mainstay in the treatment of hematological and some nonhematological diseases and cancers. Extensive skin lesions are now being treated with the use of autologous and even nonautologous grafts generated by the ex vivo expansion of epidermal cells. The reconstruction of damaged articular cartilage has been attempted using ex vivo expanded chondrogenic cells. More recently, it has also been suggested that skeletal tissue, muscle, and even nervous tissue can be regenerated from stem cell populations. Potential applications extend beyond tissue regeneration, into the realm of gene transfer and gene therapy. With the advance of molecular techniques, it is envisioned that stem cells could be engineered to replace or repair a defective gene. Because of their self-renewal and ability to regenerate a tissue, transgenic stem cells could provide a long-lasting clinical benefit to a recipient. Although the precise techniques for accomplishing these goals are not yet in hand, our biotechnological imaginations have run wild with the hope of recreating organs, correcting genetic diseases, and improving the quality of life as we age.
