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Cell differentiation The search for the holy grail
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Cell differentiation The search for the holy grail Editorial overview Elaine Dzierzak* and Fiona M Wattt Addresses *Facultat der Geneeskunde en Gezondheitswetenschappen, dr. Molewaterplein 50 Postbus 1738, 3000 DR Rotterdam, The Netherlands; e-mail: dzierzak@chl .fgg.eur.nl *Imperial Cancer Research Fund, Lincoln's Inn Fields, London WC2A 3PX, UK Current Opinion in Cell Biology 1998, 10:685-686
signals and gradients of factors all provide the cues for proliferation and/or differentiation; however, even as specialiscd tissues emerge during development, undifferentiated precursors and stem cells must be preserved. This suggests the existence of specialized microenvironmental niches for the sequestration of limited numbers of lineagespecific stem cells.
http://biomednet.com/elecref/0955067401000685 © Current Biology Ltd ISSN 0955-0674
Stem cells are the 'holy grail' of research into cellular differentiation: long sought, yet frustratingly elusive. In both embryo and adult they are characterised as relatively undifferentiated cells with the capacity to self-renew and to generate differentiated daughters. During embryonic development, stem cells are the founders of virtually all tissues of the organism. In the adult, stem cells continuously replenish normal tissues and allow repair of damage. Implicit in our search for a better understanding of stem cells in mammals, and particularly in humans, is the potential for application within clinical medicine. If stem cells can be grown to infinite numbers in culture, allowing for ex vivo genetic manipulation and lasting gene repair through homologous recombination, and if stem cells can be reimplanted in vivo to undergo normal differentiation, then some genetic diseases could be permanently alleviated. This can be considered the long-term practical goal of research into stem cells. T h e basic biological mechanisms by which cells are kept in an undifferentiated state also stimtdate intense intellectual curiosity. T h e whole organism, which harbours a wide variety of stem cells, is the result of the differentiation of the ultimate stem cell, the egg. T h e egg (or germline stem cell) possesses unrestricted potential, producing the enormous array of cells necessary for generating the entire organism, while maintaining the ability to give rise to another egg for the production of future generations. Further down the differentiation pathway of the egg are more specialised stem cells which are the founders and constant providers of the blood, nervous and intestinal epithelial systems, as well as the epithelium of the skin. Such restricted stem cells are a very efficient means for an adult organism to replenish both rapidly-renewing and slowly-regenerating functional cell types. T h e adult harbours limited numbers of restricted stem cells which possess common characteristics such as high proliferative potential, self-renewability and ability to give rise to differentiating daughter cells. During ontogeny, positional information within the embryo leads to specification and cell-fate determination resulting in growth and morphogenesis. Regional
In this section of Current Opinion in Cell Biologg,, some of the models and mechanisms involved in the establishment, maintenance, self-renewal, and differentiation of stem cell populations are presented. Two reviews on germline stem cells, which provide the source of gametes in diverse organisms, discuss some of the possible mechanisms by which stem cells self-renew, and homeostasis in stem cell number may be achieved. T h e review on the self-renewing mechanism of Drosophila germline stem cells by Lin (pp 687-693) provides interesting insights into asymmetric stem cell division. Lin distinguishes between 'stereotypic' germline stem cells, in which each division invariantly produces one stem cell and one differentiated daughter, and 'populational' stem cells in which a balance between stem cell maintenance and differentiation is achieved on a population basis, even though individual cells do not divide asymmetrically. Stereotypic germline stem cell division in Drosophila is controlled by both intracellular mechanisms (such as a structure known as the spectrosome) and by signals from neighbouring cells. In Drosophila three genes have recently been identified as being required cellautonomously for maintenance of female germline stem cells and the correct differentiation of their progeny. Some interesting similarities and contrasts to Drosophila germline stem cells emerge in the review by de Rooij and Grootegoed (pp 694-701) on nonprimatc mammalian germline stem cells. T h e specific topographical arrangement of the cells appears to be highly important in rodent spermatogonial multiplication and self-renewal. Asymmetry of cell fate is maintained on a population basis and stereotypic asymmetric division does not occur. Various signals necessary for spermatogonial differentiation are discussed, along with the possible clinical applications of spermatogonial stem cell transplantation. Finally, in the rodent model system transgenic technology has been exploited to explore the role of apoptosis in germ cell density regulation. T h e issue of stem cell self-renewal and density regulation, this time in the mouse intestinal epithelium, is also covered by Stappenbeck et al. (pp 702-709). T h e intestinal crypt again exemplifies the importance of spatial orientation in the maintenance of undifferentiated cells and the subsequent differentiation events leading to the well
686
Cell differentiation
ordered production of four epithelial cell lineages. T h e technology for creating transgenic mice has revealed many aspects of normal and abnormal regulation of intestinal cell proliferation. T h e genes involved in these processes are classified conceptually according to their putative functions as 'gatekeepers', 'caretakers' or 'landscapers' and include genes of the Wnt pathway. Epithelial stem cells are also discussed in the review by Alison (pp 710-715). Unlike the intestine, where there is a single stem cell population, there appear to be two stem-cell populations in adult mammalian liver. Liver regeneration is normally dependent on hepatocytes, at least some of which have the high self renewal capacity characteristic of stem cells. Under circumstances in which hepatocyte proliferation is impaired, however, the liver can be rescued through proliferation of bile-duct-derived hepatocyte progenitors known as oval cells. While progress is being made in understanding the signals that regulate stem-cell proliferation and fate in epithelia, the search for epithelial stem-cell markers is far from over. In contrast, stem cells in the haemopoietic system can be highly enriched by flow cytometry for cell-surface markers and these can be exploited for studies of how haemopoiesis is controlled. Jordan and Van Zant (pp 716-720) review classical genetic studies, as well as recent gene knockout investigations in the mouse, that have identified genes playing important roles in the generation, maintenance and proliferative potential of the blood stem cell compartment. T h e s e studies have revealed some overlap with, but also significant differences between, the genes necessary for adult and embryonic haemopoiesis, suggesting the importance of
microenvironment and external signals that differ between embryo and adult. Whetton and Spooncer (pp 721-726) continue on this theme in their discussion of asymmetric cell division, stem-cell adhesion, homing and chemoattraction. T h e progress made in understanding haemopoietic signal transduction, transcriptional regulators and growth factors presented in these reviews clearly points out the impact that transgenic technology has had on our understanding of haemopoietic stem-cell biology. In the final two reviews of this issue Panchision, Hazel and McKay (pp 727-733) discuss neuronal stem cells in the vertebrate nervous system and Langdale (pp 734-738) considers how cellular differentiation is controlled in the leaf. Using both in vivo and in vitro models Panchision, Hazel and McKay make the case that single extrinsic factors can control cell fate, and that there is a window of competence during which cells can respond to these signals prior to irreversible commitment to differentiation. In the leaf, the same concerns about intrinsic versus extrinsic signals and the establishment of patterned arrays of differentiated cell types also apply; it is interesting that signalling via a tumour necrosis factor-like receptor plays a role in controlling epidermal differentiation in plant tissue. Indeed in all the topics covered in this volume, issues of intrinsic programming versus responsiveness of stem cells to signals from the local microenvironment are recurring themes. It is our hope that this group of reviews on stem cell signalling in different tissues and experimental models will yield insights into the unique and shared features of this very specialized group of cells, and allow you to assess how close we are to finding the 'holy grail'.
Cell differentiation The search for the holy grail Editorial overview Elaine Dzierzak* and Fiona M Wattt Addresses *Facultat der Geneeskunde en Gezondheitswetenschappen, dr. Molewaterplein 50 Postbus 1738, 3000 DR Rotterdam, The Netherlands; e-mail: dzierzak@chl .fgg.eur.nl *Imperial Cancer Research Fund, Lincoln's Inn Fields, London WC2A 3PX, UK Current Opinion in Cell Biology 1998, 10:685-686
signals and gradients of factors all provide the cues for proliferation and/or differentiation; however, even as specialiscd tissues emerge during development, undifferentiated precursors and stem cells must be preserved. This suggests the existence of specialized microenvironmental niches for the sequestration of limited numbers of lineagespecific stem cells.
http://biomednet.com/elecref/0955067401000685 © Current Biology Ltd ISSN 0955-0674
Stem cells are the 'holy grail' of research into cellular differentiation: long sought, yet frustratingly elusive. In both embryo and adult they are characterised as relatively undifferentiated cells with the capacity to self-renew and to generate differentiated daughters. During embryonic development, stem cells are the founders of virtually all tissues of the organism. In the adult, stem cells continuously replenish normal tissues and allow repair of damage. Implicit in our search for a better understanding of stem cells in mammals, and particularly in humans, is the potential for application within clinical medicine. If stem cells can be grown to infinite numbers in culture, allowing for ex vivo genetic manipulation and lasting gene repair through homologous recombination, and if stem cells can be reimplanted in vivo to undergo normal differentiation, then some genetic diseases could be permanently alleviated. This can be considered the long-term practical goal of research into stem cells. T h e basic biological mechanisms by which cells are kept in an undifferentiated state also stimtdate intense intellectual curiosity. T h e whole organism, which harbours a wide variety of stem cells, is the result of the differentiation of the ultimate stem cell, the egg. T h e egg (or germline stem cell) possesses unrestricted potential, producing the enormous array of cells necessary for generating the entire organism, while maintaining the ability to give rise to another egg for the production of future generations. Further down the differentiation pathway of the egg are more specialised stem cells which are the founders and constant providers of the blood, nervous and intestinal epithelial systems, as well as the epithelium of the skin. Such restricted stem cells are a very efficient means for an adult organism to replenish both rapidly-renewing and slowly-regenerating functional cell types. T h e adult harbours limited numbers of restricted stem cells which possess common characteristics such as high proliferative potential, self-renewability and ability to give rise to differentiating daughter cells. During ontogeny, positional information within the embryo leads to specification and cell-fate determination resulting in growth and morphogenesis. Regional
In this section of Current Opinion in Cell Biologg,, some of the models and mechanisms involved in the establishment, maintenance, self-renewal, and differentiation of stem cell populations are presented. Two reviews on germline stem cells, which provide the source of gametes in diverse organisms, discuss some of the possible mechanisms by which stem cells self-renew, and homeostasis in stem cell number may be achieved. T h e review on the self-renewing mechanism of Drosophila germline stem cells by Lin (pp 687-693) provides interesting insights into asymmetric stem cell division. Lin distinguishes between 'stereotypic' germline stem cells, in which each division invariantly produces one stem cell and one differentiated daughter, and 'populational' stem cells in which a balance between stem cell maintenance and differentiation is achieved on a population basis, even though individual cells do not divide asymmetrically. Stereotypic germline stem cell division in Drosophila is controlled by both intracellular mechanisms (such as a structure known as the spectrosome) and by signals from neighbouring cells. In Drosophila three genes have recently been identified as being required cellautonomously for maintenance of female germline stem cells and the correct differentiation of their progeny. Some interesting similarities and contrasts to Drosophila germline stem cells emerge in the review by de Rooij and Grootegoed (pp 694-701) on nonprimatc mammalian germline stem cells. T h e specific topographical arrangement of the cells appears to be highly important in rodent spermatogonial multiplication and self-renewal. Asymmetry of cell fate is maintained on a population basis and stereotypic asymmetric division does not occur. Various signals necessary for spermatogonial differentiation are discussed, along with the possible clinical applications of spermatogonial stem cell transplantation. Finally, in the rodent model system transgenic technology has been exploited to explore the role of apoptosis in germ cell density regulation. T h e issue of stem cell self-renewal and density regulation, this time in the mouse intestinal epithelium, is also covered by Stappenbeck et al. (pp 702-709). T h e intestinal crypt again exemplifies the importance of spatial orientation in the maintenance of undifferentiated cells and the subsequent differentiation events leading to the well
686
Cell differentiation
ordered production of four epithelial cell lineages. T h e technology for creating transgenic mice has revealed many aspects of normal and abnormal regulation of intestinal cell proliferation. T h e genes involved in these processes are classified conceptually according to their putative functions as 'gatekeepers', 'caretakers' or 'landscapers' and include genes of the Wnt pathway. Epithelial stem cells are also discussed in the review by Alison (pp 710-715). Unlike the intestine, where there is a single stem cell population, there appear to be two stem-cell populations in adult mammalian liver. Liver regeneration is normally dependent on hepatocytes, at least some of which have the high self renewal capacity characteristic of stem cells. Under circumstances in which hepatocyte proliferation is impaired, however, the liver can be rescued through proliferation of bile-duct-derived hepatocyte progenitors known as oval cells. While progress is being made in understanding the signals that regulate stem-cell proliferation and fate in epithelia, the search for epithelial stem-cell markers is far from over. In contrast, stem cells in the haemopoietic system can be highly enriched by flow cytometry for cell-surface markers and these can be exploited for studies of how haemopoiesis is controlled. Jordan and Van Zant (pp 716-720) review classical genetic studies, as well as recent gene knockout investigations in the mouse, that have identified genes playing important roles in the generation, maintenance and proliferative potential of the blood stem cell compartment. T h e s e studies have revealed some overlap with, but also significant differences between, the genes necessary for adult and embryonic haemopoiesis, suggesting the importance of
microenvironment and external signals that differ between embryo and adult. Whetton and Spooncer (pp 721-726) continue on this theme in their discussion of asymmetric cell division, stem-cell adhesion, homing and chemoattraction. T h e progress made in understanding haemopoietic signal transduction, transcriptional regulators and growth factors presented in these reviews clearly points out the impact that transgenic technology has had on our understanding of haemopoietic stem-cell biology. In the final two reviews of this issue Panchision, Hazel and McKay (pp 727-733) discuss neuronal stem cells in the vertebrate nervous system and Langdale (pp 734-738) considers how cellular differentiation is controlled in the leaf. Using both in vivo and in vitro models Panchision, Hazel and McKay make the case that single extrinsic factors can control cell fate, and that there is a window of competence during which cells can respond to these signals prior to irreversible commitment to differentiation. In the leaf, the same concerns about intrinsic versus extrinsic signals and the establishment of patterned arrays of differentiated cell types also apply; it is interesting that signalling via a tumour necrosis factor-like receptor plays a role in controlling epidermal differentiation in plant tissue. Indeed in all the topics covered in this volume, issues of intrinsic programming versus responsiveness of stem cells to signals from the local microenvironment are recurring themes. It is our hope that this group of reviews on stem cell signalling in different tissues and experimental models will yield insights into the unique and shared features of this very specialized group of cells, and allow you to assess how close we are to finding the 'holy grail'.