Purpose and regulation of stem cells: a systems‐biology view from the Caenorhabditis elegans germ line

Stem cells are expected to play a key role in the development and maintenance of organisms, and hold great therapeutic promises. However, a number of questions must be answered to achieve an understanding of stem cells and put them to use. Here I review some of these questions, and how they relate to the model system provided by the Caenorhabditis elegans germ line, which is exceptional in its thorough genetic characterization and experimental accessibility under in vivo conditions. A fundamental question is how to define a stem cell; different definitions can be adopted that capture different features of interest. In the C. elegans germ line, stem cells can be defined by cell lineage or by cell commitment (‘commitment’ must itself be carefully defined). These definitions are associated with two other important questions about stem cells: their functions (which must be addressed following a systems approach, based on an evolutionary perspective) and their regulation. I review possible functions and their evolutionary groundings, including genome maintenance and powerful regulation of cell proliferation and differentiation, and possible regulatory mechanisms, including asymmetrical division and control of transit amplification by a developmental timer. I draw parallels between Drosophila and C. elegans germline stem cells; such parallels raise intriguing questions about Drosophila stem cells. I conclude by showing that the C. elegans germ line bears similarities with a number of other stem cell systems, which underscores its relevance to the understanding of stem cells. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

[1]  J. Gurdon,et al.  The developmental capacity of nuclei taken from intestinal epithelium cells of feeding tadpoles. , 1962, Journal of embryology and experimental morphology.

[2]  B. Gondos.  Intercellular Bridges and Mammalian Germ Cell Differentiation , 1973 .

[3]  L. G. Laijtha,et al.  On the problem of differentiation in haemopoiesis. , 1974, Differentiation; research in biological diversity.

[4]  Allen Silver,et al.  Beta , 1975, The SAGE Encyclopedia of Research Design.

[5]  J. Brun,et al.  Etude Ultrastructurale Des Relations Entre Ovocytes Et Rachis Au Cours De L'Ovogenese Du Nematode Caenorhabditis Elegans , 1975 .

[6]  E. C. Zeeman,et al.  A clock and wavefront model for control of the number of repeated structures during animal morphogenesis. , 1976, Journal of theoretical biology.

[7]  M. Klass,et al.  Development of the reproductive system of Caenorhabditis elegans. , 1976, Developmental biology.

[8]  E. Wieschaus,et al.  The development and function of the female germ line in Drosophila melanogaster: a cell lineage study. , 1979, Developmental biology.

[9]  L. Lajtha.  Stem cell concepts. , 1979, Nouvelle revue francaise d'hematologie.

[10]  D. Hirsh,et al.  The postembryonic cell lineages of the hermaphrodite and male gonads in Caenorhabditis elegans. , 1979, Developmental biology.

[11]  J. White,et al.  On the control of germ cell development in Caenorhabditis elegans. , 1981, Developmental biology.

[12]  James C. Smith,et al.  Cell lineage and commitment in early amphibian development , 1985 .

[13]  Mary Anne Wheeler,et al.  Stem , 1985 .

[14]  G S Stent,et al.  The role of cell lineage in development. , 1985, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[15]  C. Potten,et al.  Cell Migration Velocities In the Crypts of the Small Intestine After Cytotoxic Insult Are Not Dependent On Mitotic Activity , 1986, Cell and tissue kinetics.

[16]  M. Raff,et al.  Clonal analysis of oligodendrocyte development in culture: Evidence for a developmental clock that counts cell divisions , 1986, Cell.

[17]  F. Watt,et al.  Measurement of the rate of epidermal terminal differentiation: expression of involucrin by S-phase keratinocytes in culture and in psoriatic plaques. , 1987, The Journal of investigative dermatology.

[18]  A. Spradling,et al.  bag-of-marbles: a Drosophila gene required to initiate both male and female gametogenesis. , 1990, Genes & development.

[19]  M. Raff,et al.  Rod photoreceptor development in vitro: Intrinsic properties of proliferating neuroepithelial cells change as development proceeds in the rat retina , 1990, Neuron.

[20]  M. Loeffler,et al.  Stem cells: attributes, cycles, spirals, pitfalls and uncertainties. Lessons for and from the crypt. , 1990, Development.

[21]  C. Stern,et al.  COMMITMENT OF MESODERM CELLS IN HENSENS NODE OF THE CHICK-EMBRYO TO NOTOCHORD AND SOMITE , 1992 .

[22]  M. Selleck,et al.  Commitment of mesoderm cells in Hensen's node of the to notochord and somite , 1992 .

[23]  H. Blau,et al.  Differentiation requires continuous active control. , 1992, Annual review of biochemistry.

[24]  Divisions , 1962, Science.

[25]  M. Loeffler,et al.  Somatic mutation, monoclonality and stochastic models of stem cell organization in the intestinal crypt. , 1993, Journal of theoretical biology.

[26]  J. Büning.  The Insect Ovary , 1994, Springer Netherlands.

[27]  J. Buning.  The insect ovary : ultrastructure, previtellogenic growth and evolution , 1994 .

[28]  J Kimble,et al.  lag-2 may encode a signaling ligand for the GLP-1 and LIN-12 receptors of C. elegans. , 1994, Development.

[29]  T. Schedl,et al.  Analysis of the multiple roles of gld-1 in germline development: interactions with the sex determination cascade and the glp-1 signaling pathway. , 1995, Genetics.

[30]  T. Schedl,et al.  gld-1, a tumor suppressor gene required for oocyte development in Caenorhabditis elegans. , 1995, Genetics.

[31]  D. Mckearin,et al.  A role for the Drosophila bag-of-marbles protein in the differentiation of cystoblasts from germline stem cells. , 1995, Development.

[32]  A. Spradling,et al.  Identification and behavior of epithelial stem cells in the Drosophila ovary. , 1995, Development.

[33]  Y. Ohkubo,et al.  Autonomous regulation of proliferation and growth arrest in mouse primordial germ cells studied by mixed and clonal cultures. , 1996, Experimental cell research.

[34]  J. Heath,et al.  EPITHELIAL CELL MIGRATION IN THE INTESTINE , 1996, Cell biology international.

[35]  J. Howe,et al.  A developmental timer regulates degradation of cyclin E1 at the midblastula transition during Xenopus embryogenesis. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[36]  P. Gönczy,et al.  The germ line regulates somatic cyst cell proliferation and fate during Drosophila spermatogenesis. , 1996, Development.

[37]  T. Schüpbach,et al.  Encore, a gene required for the regulation of germ line mitosis and oocyte differentiation during Drosophila oogenesis. , 1996, Development.

[38]  A. Spradling,et al.  The Drosophila endocycle is controlled by Cyclin E and lacks a checkpoint ensuring S-phase completion. , 1996, Genes & development.

[39]  T. Schedl,et al.  GLD-1, a cytoplasmic protein essential for oocyte differentiation, shows stage- and sex-specific expression during Caenorhabditis elegans germline development. , 1996, Developmental biology.

[40]  A. Mclaren,et al.  Entry of mouse embryonic germ cells into meiosis. , 1997, Developmental biology.

[41]  P. Gönczy,et al.  punt and schnurri regulate a somatically derived signal that restricts proliferation of committed progenitors in the germline. , 1997, Development.

[42]  M. Raff,et al.  Oligodendrocyte precursor cells count time but not cell divisions before differentiation , 1997, Current Biology.

[43]  B. Shiels,et al.  Modulation of protein synthesis relative to DNA synthesis alters the timing of differentiation in the protozoan parasite Theileria annulata. , 1997, Journal of cell science.

[44]  D. Mckearin,et al.  Ectopic expression of the Drosophila Bam protein eliminates oogenic germline stem cells. , 1997, Development.

[45]  P. Gönczy,et al.  bag-of-marbles and benign gonial cell neoplasm act in the germline to restrict proliferation during Drosophila spermatogenesis. , 1997, Development.

[46]  J. Kimble,et al.  Genetic regulation of entry into meiosis in Caenorhabditis elegans. , 1998, Development.

[47]  R. Lehmann,et al.  Nanos and Pumilio have critical roles in the development and function of Drosophila germline stem cells. , 1998, Development.

[48]  D. Hall,et al.  Ultrastructural features of the adult hermaphrodite gonad of Caenorhabditis elegans: relations between the germ line and soma. , 1999, Developmental biology.

[49]  A. Spradling,et al.  Germline cysts: a conserved phase of germ cell development? , 1999, Trends in cell biology.

[50]  A. Spradling,et al.  A niche maintaining germ line stem cells in the Drosophila ovary. , 2000, Science.

[51]  B. Reinhart,et al.  The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans , 2000, Nature.

[52]  Min Han,et al.  Mutations in cye-1, a Caenorhabditis elegans cyclin E homolog, reveal coordination between cell-cycle control and vulval development. , 2000, Development.

[53]  F R Adler,et al.  How to make a biological switch. , 2000, Journal of theoretical biology.

[54]  S. Tavaré,et al.  Investigating stem cells in human colon by using methylation patterns , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[55]  M. Wickens,et al.  A conserved RNA-binding protein controls germline stem cells in Caenorhabditis elegans , 2002, Nature.

[56]  Ting Xie,et al.  Germline Stem Cells Anchored by Adherens Junctions in the Drosophila Ovary Niches , 2002, Science.

[57]  M. Raff,et al.  Normal timing of oligodendrocyte development depends on thyroid hormone receptor alpha 1 (TRα1) , 2002, The EMBO journal.

[58]  M. Raff,et al.  Posttranscriptional regulation of p18 and p27 Cdk inhibitor proteins and the timing of oligodendrocyte differentiation. , 2002, Developmental biology.

[59]  Ingo Roeder,et al.  A novel dynamic model of hematopoietic stem cell organization based on the concept of within-tissue plasticity. , 2002, Experimental hematology.

[60]  P. Ingham,et al.  Regulation of Stem Cell Maintenance and Transit Amplifying Cell Proliferation by TGF-β Signaling in Drosophila Spermatogenesis , 2003, Current Biology.

[61]  Danielle M Maatouk,et al.  Continuing primordial germ cell differentiation in the mouse embryo is a cell-intrinsic program sensitive to DNA methylation. , 2003, Developmental biology.

[62]  T. C. Evans,et al.  Translational repression of a C. elegans Notch mRNA by the STAR/KH domain protein GLD-1 , 2003, Development.

[63]  M. White,et al.  A change in the premitotic period of the cell cycle is associated with bradyzoite differentiation in Toxoplasma gondii. , 2003, Molecular and biochemical parasitology.

[64]  R. Lehmann,et al.  Germ line stem cell differentiation in Drosophila requires gap junctions and proceeds via an intermediate state , 2003, Development.

[65]  Xin Wang,et al.  The origin and liver repopulating capacity of murine oval cells , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[66]  Laura C. Greaves,et al.  Mitochondrial DNA mutations in human colonic crypt stem cells. , 2003, The Journal of clinical investigation.

[67]  A. Spradling,et al.  An empty Drosophila stem cell niche reactivates the proliferation of ectopic cells , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[68]  Dahua Chen,et al.  Dpp Signaling Silences bam Transcription Directly to Establish Asymmetric Divisions of Germline Stem Cells , 2003, Current Biology.

[69]  T. Schüpbach,et al.  Encore facilitates SCF-Ubiquitin-proteasome-dependent proteolysis during Drosophila oogenesis , 2003, Development.

[70]  Marvin Wickens,et al.  Regulation of the mitosis/meiosis decision in the Caenorhabditis elegans germline. , 2003, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[71]  J. McCarthy,et al.  Bmp signals from niche cells directly repress transcription of a differentiation-promoting gene, bag of marbles, in germline stem cells in the Drosophila ovary , 2004, Development.

[72]  E. Matunis,et al.  Regeneration of Male Germline Stem Cells by Spermatogonial Dedifferentiation in Vivo , 2004, Science.

[73]  R. Lehmann,et al.  How different is Venus from Mars? The genetics of germ-line stem cells in Drosophila females and males , 2004, Development.

[74]  Olivier Pourquié,et al.  fgf8 mRNA decay establishes a gradient that couples axial elongation to patterning in the vertebrate embryo , 2004, Nature.

[75]  M. Casanueva,et al.  Germline stem cell number in the Drosophila ovary is regulated by redundant mechanisms that control Dpp signaling , 2004, Development.

[76]  E. Wieschaus,et al.  A study of the female germ line in mosaics ofDrosophila , 1978, Wilhelm Roux's archives of developmental biology.

[77]  A. Spradling,et al.  Differentiating germ cells can revert into functional stem cells in Drosophila melanogaster ovaries , 2004, Nature.

[78]  Tim Schedl,et al.  Multi-pathway control of the proliferation versus meiotic development decision in the Caenorhabditis elegans germline. , 2004, Developmental biology.

[79]  Tim Schedl,et al.  Control of the proliferation versus meiotic development decision in the C. elegans germline through regulation of GLD-1 protein accumulation , 2004, Development.

[80]  M. Wickens,et al.  FBF-1 and FBF-2 regulate the size of the mitotic region in the C. elegans germline. , 2004, Developmental cell.

[81]  T. Xie,et al.  Gbb/Bmp signaling is essential for maintaining germline stem cells and for repressing bam transcription in the Drosophila testis , 2004, Development.

[82]  Arthur D Lander,et al.  A Calculus of Purpose , 2004, PLoS biology.

[83]  Douglas A. Melton,et al.  How Important are Adult Stem Cells for Tissue Maintenance? , 2004, Cell cycle.

[84]  D. Inzé,et al.  B1-Type Cyclin-Dependent Kinases Are Essential for the Formation of Stomatal Complexes in Arabidopsis thaliana , 2004, The Plant Cell Online.

[85]  I. Greenwald.  LIN-12/Notch signaling in C. elegans. , 2005, WormBook : the online review of C. elegans biology.

[86]  E. Hubbard,et al.  Introduction to the germ line. , 2005, WormBook : the online review of C. elegans biology.

[87]  Jacques Demongeot,et al.  High-dimensional Switches and the Modeling of Cellular Differentiation 2.2 Mathematical Models , 2022 .

[88]  M. Matzuk,et al.  GDF11 Controls the Timing of Progenitor Cell Competence in Developing Retina , 2005, Science.

[89]  J. Kimble,et al.  Germline proliferation and its control. , 2005, WormBook : the online review of C. elegans biology.

[90]  T. Xie,et al.  Molecular mechanisms of germline stem cell regulation. , 2005, Annual review of genetics.

[91]  R. Adler.  Challenges in the study of neuronal differentiation: A view from the embryonic eye , 2005, Developmental dynamics : an official publication of the American Association of Anatomists.

[92]  Stanley Shostak,et al.  (Re)defining stem cells. , 2006, BioEssays : news and reviews in molecular, cellular and developmental biology.

[93]  H. Byrne,et al.  Crypt dynamics and colorectal cancer: advances in mathematical modelling , 2006, Cell proliferation.

[94]  Ingo Roeder,et al.  Towards an understanding of lineage specification in hematopoietic stem cells: a mathematical model for the interaction of transcription factors GATA-1 and PU.1. , 2006, Journal of theoretical biology.

[95]  M. Raff.  The mystery of intracellular developmental programmes and timers. , 2006, Biochemical Society transactions.

[96]  R. Braun,et al.  Pathway to Totipotency: Lessons from Germ Cells , 2006, Cell.

[97]  Dana T Byrd,et al.  Cellular analyses of the mitotic region in the Caenorhabditis elegans adult germ line. , 2006, Molecular biology of the cell.

[98]  T. Schedl,et al.  The regulatory network controlling the proliferation-meiotic entry decision in the Caenorhabditis elegans germ line. , 2006, Current topics in developmental biology.

[99]  Sean J. Morrison,et al.  Asymmetric and symmetric stem-cell divisions in development and cancer , 2006, Nature.

[100]  F. Cremisi,et al.  Timing the Generation of Distinct Retinal Cells by Homeobox Proteins , 2006, PLoS biology.

[101]  S. Morrison,et al.  Maintaining hematopoietic stem cells in the vascular niche. , 2006, Immunity.

[102]  Bud Mishra,et al.  Quantitative analysis of germline mitosis in adult C. elegans. , 2006, Developmental biology.

[103]  Renuka R. Nayak,et al.  Dynamics of the male germline stem cell population during aging of Drosophila melanogaster , 2006, Aging cell.

[104]  K. Moore,et al.  Stem Cells and Their Niches , 2006, Science.

[105]  D. Bryder,et al.  Prolonged Cell Cycle Transit Is a Defining and Developmentally Conserved Hemopoietic Stem Cell Property1 , 2006, The Journal of Immunology.

[106]  T. Xie,et al.  The Drosophila ovary: an active stem cell community , 2007, Cell Research.

[107]  Y. Saka,et al.  A mechanism for the sharp transition of morphogen gradient interpretation in Xenopus , 2007, BMC Developmental Biology.

[108]  Shenghui He,et al.  Haematopoietic stem cells do not asymmetrically segregate chromosomes or retain BrdU , 2007, Nature.

[109]  Sui Huang,et al.  Bifurcation dynamics in lineage-commitment in bipotent progenitor cells. , 2007, Developmental biology.

[110]  Arthur D Lander,et al.  Morpheus Unbound: Reimagining the Morphogen Gradient , 2007, Cell.

[111]  J. Kimble,et al.  Controls of germline stem cells, entry into meiosis, and the sperm/oocyte decision in Caenorhabditis elegans. , 2007, Annual review of cell and developmental biology.

[112]  O. Cinquin,et al.  Generalized, Switch-Like Competitive Heterodimerization Networks , 2007, Bulletin of mathematical biology.

[113]  A. Spradling,et al.  Male and Female Drosophila Germline Stem Cells: Two Versions of Immortality , 2007, Science.

[114]  P. Collas,et al.  Epigenetic reprogramming of nuclei using cell extracts , 2007, Stem Cell Reviews.

[115]  D. Joly,et al.  Evolution of testicular architecture in the Drosophilidae: A role for sperm length , 2008, BMC Evolutionary Biology.

[116]  Benjamin D. Simons,et al.  A single type of progenitor cell maintains normal epidermis , 2007, Nature.

[117]  Y. Nabeshima,et al.  Functional identification of the actual and potential stem cell compartments in mouse spermatogenesis. , 2007, Developmental cell.

[118]  F. Watt,et al.  Sic transit gloria: farewell to the epidermal transit amplifying cell? , 2007, Cell stem cell.

[119]  E Jane Albert Hubbard,et al.  Caenorhabditis elegans germ line: a model for stem cell biology. , 2007, Developmental dynamics : an official publication of the American Association of Anatomists.

[120]  O. Cinquin.  Understanding the somitogenesis clock: What’s missing? , 2007, Mechanisms of Development.

[121]  H. Clevers,et al.  Tracking down the stem cells of the intestine: strategies to identify adult stem cells. , 2007, Gastroenterology.

[122]  J. Vermeesch,et al.  TGF-beta1-induced cardiac myofibroblasts are nonproliferating functional cells carrying DNA damages. , 2008, Experimental cell research.

[123]  Hans Clevers,et al.  The intestinal stem cell. , 2008, Genes & development.

[124]  S. Holley,et al.  Cell cycle progression is required for zebrafish somite morphogenesis but not segmentation clock function , 2008, Development.

[125]  R. Scharfmann,et al.  β Cells Can Be Generated from Endogenous Progenitors in Injured Adult Mouse Pancreas , 2008, Cell.

[126]  Ting Xie,et al.  Differentiation-defective stem cells outcompete normal stem cells for niche occupancy in the Drosophila ovary. , 2008, Cell stem cell.

[127]  K. Zaret.  Faculty Opinions recommendation of Beta cells can be generated from endogenous progenitors in injured adult mouse pancreas. , 2008 .

[128]  Sean J. Morrison,et al.  Stem Cells and Niches: Mechanisms That Promote Stem Cell Maintenance throughout Life , 2008, Cell.

[129]  G. Seydoux,et al.  3′ UTRs Are the Primary Regulators of Gene Expression in the C. elegans Germline , 2008, Current Biology.

[130]  R. Young,et al.  Stem Cells, the Molecular Circuitry of Pluripotency and Nuclear Reprogramming , 2008, Cell.