Stem Cells by the Bedside

Abstract

Stem Cells Handbook By Stewart Sell Totowa, NJ: Humana Press (2003) 528 pp. $175.00Stem cells are specialized cells that orchestrate development, maintain somatic homeostasis, and effect tissue regeneration and repair. They are generally classified as cells that undergo self-renewal and possess the capacity to produce at least one differentiated cell type. However, the creation of a universal definition is problematic, as many described developmental stem cells do not undergo self-renewal and proposed cancer stem cells display aberrant self-renewal pathways that give rise to abnormal cell types. Stem cells of vertebrates have thus perhaps been more conveniently classified into at least five individual categories according to their capacity for self-renewal and differentiation potential. The first category is the totipotent stem cell, comprising the fertilized oocyte and premorula blastomeres. Totipotent stem cells generate all adult and extraembryonic tissues of their species, but undergo no or only limited self-renewal. The second category is the pluripotent stem cell, perhaps best represented by the in vitro cultivated mouse embryonic stem (ES) cell. Pluripotent mouse ES cells self-renew and give rise to all tissues of the adult, but only give rise to a restricted subset of the extraembryonic lineages represented during development. Because of this latter property, they cannot be termed totipotent. The third category is the multipotent stem cell represented by, for example, both neural stem cells (NSCs) and hematopoietic stem cells (HSCs). NSCs and HSCs undergo self-renewal and are capable of yielding at least two differentiated adult cell types. The fourth category is the unipotential cell, comprising, for example, the keratinocyte stem cells of the dermis that undergo self-renewal and are believed to give rise only to sets of closely related keratinocytes. Cancer stem cells make up a fifth category. Their compromised self-renewal pathways result in neoplasia with accompanying undifferentiated, partially differentiated, and/or differentiated cell types. Whether these cells may be classified as stem cells, however, remains controversial.HSCs have been used successfully for some time as therapeutic agents for the treatment of bone marrow disease and trauma. Following the report that pluripotent human ES cells could be grown in culture, however, interest in stem cell research has grown to unprecedented levels (see Thompson et al., 1998, Science 282, 1145–1147). This heightened interest is largely due to expectations that the same pluripotent developmental potential of mouse ES cells will be realized for human ES cells, thus endowing researchers and physicians with the means to supply an infinite quantity of any functional cell type for treating any type of cellular disease. It is further recognized that multiple environmental cues such as morphogens, the extracellular matrix, and cell-cell interactions regulate stem cell behavior in precise temporal and spatial fashions. It is therefore believed that studies of stem cell homeostasis and differentiation will additionally aid in the development of molecular therapies aimed at controlling and instructing cellular repair in situ. Together with appropriate ethical consideration, the use of relevant preclinical models and the development of systems addressing issues of immune intolerance, it is hoped that many more stem cell-based therapies will be rapidly (yet carefully) formulated to benefit people suffering from a wide variety of diseases.The Stem Cells Handbook by Stewart Sell covers many of the more exciting, practical, and recent developments in stem cell biology, familiarizing the reader with a plethora of information and facilitating understanding of the stem cell field at a sophisticated level. Major discussions of adult and embryonic stem cell biology encompass the topics of stem cell identification, isolation, function, and exploitation in the clinical setting with accompanying information being drawn from the related disciplines of developmental biology and cancer biology. A significant portion of the Handbook is dedicated to stem cell biology of the bone marrow and liver, and builds the reader's information base in these respective fields in a number of important ways. As general subject themes of the book, details of the developmental biology of each of these systems, changes leading to neoplasia, cis- versus trans-organ stem cell-mediated homeostasis and repair mechanisms, lineage isolation methodologies, and animal models for studying functions of specific cell populations are carefully detailed. Furthermore, relevance to the clinical setting facilitates the reader's transition from the research bench to the patient.Truly outstanding descriptions of the fields of early mammalian development, DNA methylation, neural stem cell biology, and imaging technologies help round the reader's knowledge through the use of perspicuous language and concepts. There is also an exceptionally informative section on Cre-loxP transgenics and associated tools of molecular and developmental genetics. These details are formulated into an introduction to retinal stem cell biology which concomitantly offers a fascinating insight into retinal development itself. Other sections of the book detail cardiovascular development, and although these contain excellent written explanations of cardiogenic signaling and current strategies aimed at treating cardiomyopathies, an increased number of illustrations would help the reader better visualize the systems explained. With respect to visualizing systems, the chapter on functional tissue architecture detailing the Attractor State Hypothesis and the theory of Waddington's Epigenetic Landscape provokes an interesting set of alternative symbols for imagining cellular dynamics of many biological systems.Details of Caenorhabditis, Drosophila, and human germline biology, the concepts of and cautionary notes surrounding reproductive and therapeutic cloning techniques, the regenerative systems of anurans and urodeles, and the individual chapters on pancreatic, respiratory, mammary, and intestinal stem cells, although covered relatively briefly, all make fascinating reading. The detailing of cell phenotypes within the gastrointestinal tract and their associated functional, proliferative, differentiation, and stem cell potential is especially noteworthy. Hardcore ES cell workers may be disappointed with the paucity of information (practical and theoretical) on pancreatic islet differentiation from ES cells. However, the descriptions of pancreatic genetics, organogenesis, islet cell culture, and transplantation are excellent.Although one book cannot be expected to cover all aspects of stem cell biology, dermal stem cell biology is only briefly addressed and descriptions of cord blood stem cells, telomerase, strategies addressing the immunological acceptance of grafted material, and ethical considerations of stem cell biology are either absent or rarely included. Furthermore, definitions of totipotency, pluripotency, and multipotency, as well as conceptus, embryo, and fetus, often lack consistency. Statements claiming that ES cells can be found within the inner cell mass, rather than being an in vitro derivative, are also not helpful.As will always be the case when compiling a textbook, the problem of predating the more contemporary debates arising between the time of book completion and release can be problematic. This is most noticeable in respect to the debates surrounding transdifferentiation and cell fusion. At the time of this Handbook's compilation, studies proffering cell fusion as an alternative explanation to the many reports of transdifferentiation were beginning to be considered by the scientific community (Terada et al., 2002, Nature 416, 542–545; Ying et al., 2002, Nature 416, 545–548). Since then, creative transgenics coupled with functional studies in vivo have demonstrated that at least some forms of reported transdifferentiation may be best explained in terms of a cell-cell fusion event (see Wang et al., 2003, Nature 422, 897–901; Vassilopoulos et al., 2003, Nature 422, 901–904; Alvarez-Dolado et al., 2003, Nature 425, 968–973). In a similar fashion, queries regarding claims of NSC pluripotency and the reproducibility of data detailing transdifferentiation of HSCs (at least lineage negative c-kit enriched) to cardiac lineages have been raised by studies using transgenics either alone or in combination with parabiotic models (Wagers et al., 2003, Science 297, 2256–2259; Murry et al., 2004, Nature 428, 664–668; Balsam et al., 2004, Nature 428, 668–673; see also Tropepe et al., 2001, Neuron 30, 65–78). Although discrepancies in experimental design may account for differences in experimental outcome, authors of these latter papers have highlighted the need for caution and rigorous assessment of experimental data before they should be taken as factual and transferred to medical practice.Care and additional reading are thus required before assuming that some definitions and the interpretation of some observations described are completely accurate. However, Stewart Sell's Stem Cells Handbook is of sufficient high quality to warrant purchasing as a useful reference to many aspects of stem cell biology.