A Prospective on Stem Cell Research

ABSTRACT

Stem cell research has stimulated considerable recent interest, but the concepts are old. Nevertheless, our understanding of the basic biology of different stem cell systems is poor. Many questions remain to be answered: How can we recognize stem cells? Are the underlying control mechanisms common to different types of stem cell, the so-called stemness concept, or is the control of self-renewal and commitment distinct in different stem cell types? What is the significance of differences in stem cells from different species? Do stem cells from somatic tissues really show plasticity with an ability to generate cells from distinct lineages, or are the observed examples consequences of experimental artifact, or rare events of no physiological significance? Do genetic mutations in the genes controlling stem cell self-renewal and differentiation lie at the heart of carcinogenesis? Answers to these and related questions now offer exciting future possibilities for both basic biology and medicine.

KEYWORDS

Stem cells - embryonic - adult - self-renewal - differentiation

REFERENCES

• 1 Maximow A. Der lymphozyt als gemeinsame stammzelle der verschiedenen blutelemente in der embryonalen entwicklung und im postfetalen leben der saugetiere.  Folia Haematologica VIII. 1909;  8 125-134
• 2 Osgood E E. A unifying concept of the etiology of the leukemias, lymphomas, and cancers.  J Natl Cancer Inst. 1957;  18(2) 155-166
• 3 Osgood E E. Blood cell survival in tissue cultures.  Ann NY Acad Sci. 1959;  77 777-796
• 4 McCulloch E A, Till J E. The radiation sensitivity of normal mouse bone marrow cells, determined by quantitative marrow transplantation into irradiated mice.  Radiat Res. 1960;  13 115-125
• 5 Till J E, Mc C E. A direct measurement of the radiation sensitivity of normal mouse bone marrow cells.  Radiat Res. 1961;  14 213-222
• 6 Becker A J, Mc C E, Till J E. Cytological demonstration of the clonal nature of spleen colonies derived from transplanted mouse marrow cells.  Nature. 1963;  197 452-454
• 7 Siminovitch L, McCulloch E A, Till J E. The distribution of colony-forming cells among spleen colonies.  J Cell Physiol. 1963;  62 327-336
• 8 Till J E, McCulloch E A, Siminovitch L. A stochastic model of stem cell proliferation, based on the growth of spleen colony-forming cells.  Proc Natl Acad Sci USA. 1964;  51 29-36
• 9 Lin H, Spradling A C. Fusome asymmetry and oocyte determination in Drosophila .  Dev Genet. 1995;  16(1) 6-12
• 10 Ivanova N B, Dimos J T, Schaniel C, Hackney J A, Moore K A, Lemischka I R. A stem cell molecular signature.  Science. 2002;  298(5593) 601-604
• 11 Ramalho-Santos M, Yoon S, Matsuzaki Y, Mulligan R C, Melton D A. “Stemness”: transcriptional profiling of embryonic and adult stem cells.  Science. 2002;  298(5593) 597-600
• 12 Martin G R. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells.  Proc Natl Acad Sci USA. 1981;  78(12) 7634-7638
• 13 Evans M J, Kaufman M H. Establishment in culture of pluripotential cells from mouse embryos.  Nature. 1981;  292(5819) 154-156
• 14 Thomson J A, Itskovitz-Eldor J, Shapiro S S et al.. Embryonic stem cell lines derived from human blastocysts.  Science. 1998;  282(5391) 1145-1147
• 15 Andrews P W. From teratocarcinomas to embryonic stem cells.  Philos Trans R Soc Lond B Biol Sci. 2002;  357(1420) 405-417
• 16 Finch B W, Ephrussi B. Retention of multiple developmental potentialities by cells of a mouse testicular teratocarcinoma during prolonged culture in vitro and their extinction upon hybridization with cells of permanent lines.  Proc Natl Acad Sci USA. 1967;  57(3) 615-621
• 17 Martin G R, Evans M J. Differentiation of clonal lines of teratocarcinoma cells: formation of embryoid bodies in vitro.  Proc Natl Acad Sci USA. 1975;  72(4) 1441-1445
• 18 Jakob H, Boon T, Gaillard J, Nicolas J, Jacob F. Teratocarcinoma of the mouse: isolation, culture and properties of pluripotential cells.  Ann Microbiol (Paris). 1973;  124(3) 269-282
• 19 Evans M J. The isolation and properties of a clonal tissue culture strain of pluripotent mouse teratoma cells.  J Embryol Exp Morphol. 1972;  28(1) 163-176
• 20 Papaioannou V E, McBurney M W, Gardner R L, Evans M J. Fate of teratocarcinoma cells injected into early mouse embryos.  Nature. 1975;  258(5530) 70-73
• 21 Brinster R L. Participation of teratocarcinoma cells in mouse embryo development.  Cancer Res. 1976;  36(9 pt 2) 3412-3414
• 22 Mintz B, Illmensee K. Normal genetically mosaic mice produced from malignant teratocarcinoma cells.  Proc Natl Acad Sci USA. 1975;  72(9) 3585-3589
• 23 Amit M, Carpenter M K, Inokuma M S et al.. Clonally derived human embryonic stem cell lines maintain pluripotency and proliferative potential for prolonged periods of culture.  Dev Biol. 2000;  227(2) 271-278
• 24 Enver T, Soneji S, Joshi C et al.. Cellular differentiation hierarchies in normal and culture-adapted human embryonic stem cells.  Hum Mol Genet. 2005;  14(21) 3129-3140
• 25 Friend C, Scher W, Holland J, Sato T. Hemoglobin synthesis in murine virus-induced leukemic cells in vitro: stimulation of erythroid differentiation by dimethyl sulfoxide.  Proc Natl Acad Sci USA. 1971;  68 378-382
• 26 Orkin S H, Harosi F I, Leder P. Differentiation in erythroleukemic cells and their somatic hybrids.  Proc Natl Acad Sci USA. 1975;  72(1) 98-102
• 27 Strickland S, Mahdavi V. The induction of differentiation in teratocarcinoma stem cells by retinoic acid.  Cell. 1978;  15(2) 393-403
• 28 Andrews P W. Retinoic acid induces neuronal differentiation of a cloned human embryonal carcinoma cell line in vitro.  Dev Biol. 1984;  103(2) 285-293
• 29 Kondo M, Wagers A J, Manz M G et al.. Biology of hematopoietic stem cells and progenitors: implications for clinical application.  Annu Rev Immunol. 2003;  21 759-806
• 30 Price J, Thurlow L. Cell lineage in the rat cerebral cortex: a study using retroviral-mediated gene transfer.  Development. 1988;  104(3) 473-482
• 31 Reynolds B A, Weiss S. Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system.  Science. 1992;  255(5052) 1707-1710
• 32 Friedenstein A J, Gorskaja J F, Kulagina N N. Fibroblast precursors in normal and irradiated mouse hematopoietic organs.  Exp Hematol. 1976;  4(5) 267-274
• 33 Conget P A, Minguell J J. Phenotypical and functional properties of human bone marrow mesenchymal progenitor cells.  J Cell Physiol. 1999;  181(1) 67-73
• 34 Devine S M, Cobbs C, Jennings M, Bartholomew A, Hoffman R. Mesenchymal stem cells distribute to a wide range of tissues following systemic infusion into nonhuman primates.  Blood. 2003;  101(8) 2999-3001
• 35 Mezey E, Chandross K J, Harta G, Maki R A, McKercher S R. Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow.  Science. 2000;  290(5497) 1779-1782
• 36 Brazelton T R, Rossi F M, Keshet G I, Blau H M. From marrow to brain: expression of neuronal phenotypes in adult mice.  Science. 2000;  290(5497) 1775-1779
• 37 Lagasse E, Connors H, Al-Dhalimy M et al.. Purified hematopoietic stem cells can differentiate into hepatocytes in vivo.  Nat Med. 2000;  6(11) 1229-1234
• 38 Bjornson C R, Rietze R L, Reynolds B A, Magli M C, Vescovi A L. Turning brain into blood: a hematopoietic fate adopted by adult neural stem cells in vivo.  Science. 1999;  283(5401) 534-537
• 39 Reyes M, Lund T, Lenvik T, Aguiar D, Koodie L, Verfaillie C M. Purification and ex vivo expansion of postnatal human marrow mesodermal progenitor cells.  Blood. 2001;  98(9) 2615-2625
• 40 Jiang Y, Jahagirdar B N, Reinhardt R L et al.. Pluripotency of mesenchymal stem cells derived from adult marrow.  Nature. 2002;  418(6893) 41-49
• 41 Muguruma Y, Reyes M, Nakamura Y et al.. In vivo and in vitro differentiation of myocytes from human bone marrow-derived multipotent progenitor cells.  Exp Hematol. 2003;  31(12) 1323-1330
• 42 Kawada H, Ogawa M. Bone marrow origin of hematopoietic progenitors and stem cells in murine muscle.  Blood. 2001;  98(7) 2008-2013
• 43 McKinney-Freeman S L, Jackson K A, Camargo F D, Ferrari G, Mavilio F, Goodell M A. Muscle-derived hematopoietic stem cells are hematopoietic in origin.  Proc Natl Acad Sci USA. 2002;  99(3) 1341-1346
• 44 Harris H, Sidebottom E, Grace D M, Bramwell M E. The expression of genetic information: a study with hybrid animal cells.  J Cell Sci. 1969;  4(2) 499-525
• 45 Darlington G J, Rankin J K, Schlanger G. Expression of human hepatic genes in somatic cell hybrids.  Somatic Cell Genet. 1982;  8(3) 403-412
• 46 Rankin J K, Darlington G J. Expression of human hepatic genes in mouse hepatoma-human amniocyte hybrids.  Somatic Cell Genet. 1979;  5(1) 1-10
• 47 Malawista S E, Weiss M C. Expression of differentiated functions in hepatoma cell hybrids: high frequency of induction of mouse albumin production in rat hepatoma-mouse lymphoblast hybrids.  Proc Natl Acad Sci USA. 1974;  71(3) 927-931
• 48 Ying Q L, Nichols J, Evans E P, Smith A G. Changing potency by spontaneous fusion.  Nature. 2002;  416(6880) 545-548
• 49 Terada N, Hamazaki T, Oka M et al.. Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion.  Nature. 2002;  416(6880) 542-545
• 50 Boyse E A, Old L J. Some aspects of normal and abnormal cell surface genetics.  Annu Rev Genet. 1969;  3(1) 269-290
• 51 Morrison S J, Weissman I L. The long-term repopulating subset of hematopoietic stem cells is deterministic and isolatable by phenotype.  Immunity. 1994;  1(8) 661-673
• 52 Andrews P W, Casper J, Damjanov I et al.. Comparative analysis of cell surface antigens expressed by cell lines derived from human germ cell tumours.  Int J Cancer. 1996;  66(6) 806-816
• 53 Kannagi R, Nudelman E, Levery S B, Hakomori S. A series of human erythrocyte glycosphingolipids reacting to the monoclonal antibody directed to a developmentally regulated antigen SSEA-1.  J Biol Chem. 1982;  257(24) 14865-14874
• 54 Shevinsky L H, Knowles B B, Damjanov I, Solter D. Monoclonal antibody to murine embryos defines a stage-specific embryonic antigen expressed on mouse embryos and human teratocarcinoma cells.  Cell. 1982;  30(3) 697-705
• 55 Kannagi R, Levery S B, Ishigami F et al.. New globoseries glycosphingolipids in human teratocarcinoma reactive with the monoclonal antibody directed to a developmentally regulated antigen, stage-specific embryonic antigen 3.  J Biol Chem. 1983;  258(14) 8934-8942
• 56 Andrews P W, Banting G, Damjanov I, Arnaud D, Avner P. Three monoclonal antibodies defining distinct differentiation antigens associated with different high molecular weight polypeptides on the surface of human embryonal carcinoma cells.  Hybridoma. 1984;  3(4) 347-361
• 57 Badcock G, Pigott C, Goepel J, Andrews P W. The human embryonal carcinoma marker antigen TRA-1-60 is a sialylated keratan sulfate proteoglycan.  Cancer Res. 1999;  59(18) 4715-4719
• 58 Pera M F, Blasco-Lafita M J, Cooper S, Mason M, Mills J, Monaghan P. Analysis of cell-differentiation lineage in human teratomas using new monoclonal antibodies to cytostructural antigens of embryonal carcinoma cells.  Differentiation. 1988;  39(2) 139-149
• 59 Andrews P W, Goodfellow P N, Bronson D L. Cell-surface characteristics and other markers of differentiation of human teratocarcinoma cells in culture. In: Silver LM, Martin GR, Strickland S Teratocarcinoma Stem Cells. Vol. 10. New York; Cold Spring Harbor Laboratory 1983: 579-591
• 60 Stein H, Gerdes J, Schwab U et al.. Identification of Hodgkin and Sternberg-reed cells as a unique cell type derived from a newly-detected small-cell population.  Int J Cancer. 1982;  30(4) 445-459
• 61 Tippett P, Andrews P W, Knowles B B, Solter D, Goodfellow P N. Red cell antigens P (globoside) and Luke: identification by monoclonal antibodies defining the murine stage-specific embryonic antigens-3 and -4 (SSEA-3 and SSEA-4).  Vox Sang. 1986;  51(1) 53-56
• 62 Draper J S, Pigott C, Thomson J A, Andrews P W. Surface antigens of human embryonic stem cells: changes upon differentiation in culture.  J Anat. 2002;  200(pt 3) 249-258
• 63 Fenderson B A, Andrews P W. Carbohydrate antigens of embryonal carcinoma cells: changes upon differentiation.  APMIS. 1992;  27(suppl) 109-118
• 64 Fenderson B A, Andrews P W, Nudelman E, Clausen H, Hakomori S. Glycolipid core structure switching from globo- to lacto- and ganglio-series during retinoic acid-induced differentiation of TERA-2-derived human embryonal carcinoma cells.  Dev Biol. 1987;  122(1) 21-34
• 65 Brandenberger R, Khrebtukova I, Thies R S et al.. MPSS profiling of human embryonic stem cells.  BMC Dev Biol. 2004;  4 10
• 66 Brandenberger R, Wei H, Zhang S et al.. Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation.  Nat Biotechnol. 2004;  22(6) 707-716
• 67 Bhattacharya B, Miura T, Brandenberger R et al.. Gene expression in human embryonic stem cell lines: unique molecular signature.  Blood. 2004;  103(8) 2956-2964
• 68 Richards M, Tan S P, Tan J H, Chan W K, Bongso A. The transcriptome profile of human embryonic stem cells as defined by SAGE.  Stem Cells. 2004;  22(1) 51-64
• 69 Abeyta M J, Clark A T, Rodriguez R T, Bodnar M S, Pera R A, Firpo M T. Unique gene expression signatures of independently-derived human embryonic stem cell lines.  Hum Mol Genet. 2004;  13(6) 601-608
• 70 Sato N, Sanjuan I M, Heke M, Uchida M, Naef F, Brivanlou A H. Molecular signature of human embryonic stem cells and its comparison with the mouse.  Dev Biol. 2003;  260(2) 404-413
• 71 Avilion A A, Nicolis S K, Pevny L H, Perez L, Vivian N, Lovell-Badge R. Multipotent cell lineages in early mouse development depend on SOX2 function.  Genes Dev. 2003;  17(1) 126-140
• 72 Chambers I, Colby D, Robertson M et al.. Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells.  Cell. 2003;  113(5) 643-655
• 73 Mitsui K, Tokuzawa Y, Itoh H et al.. The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells.  Cell. 2003;  113(5) 631-642
• 74 Nichols J, Zevnik B, Anastassiadis K et al.. Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4.  Cell. 1998;  95(3) 379-391
• 75 Niwa H, Miyazaki J, Smith A G. Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells.  Nat Genet. 2000;  24(4) 372-376
• 76 Matin M M, Walsh J R, Gokhale P J et al.. Specific knockdown of Oct4 and beta2-microglobulin expression by RNA interference in human embryonic stem cells and embryonic carcinoma cells.  Stem Cells. 2004;  22(5) 659-668
• 77 Zaehres H, Lensch M W, Daheron L, Stewart S A, Itskovitz-Eldor J, Daley G Q. High-efficiency RNA interference in human embryonic stem cells.  Stem Cells. 2005;  23(3) 299-305
• 78 Hyslop L, Stojkovic M, Armstrong L et al.. Downregulation of NANOG induces differentiation of human embryonic stem cells to extraembryonic lineages.  Stem Cells. 2005;  23(8) 1035-1043
• 79 Boyer L A, Lee T I, Cole M F et al.. Core transcriptional regulatory circuitry in human embryonic stem cells.  Cell. 2005;  122(6) 947-956
• 80 Henderson J K, Draper J S, Baillie H S et al.. Preimplantation human embryos and embryonic stem cells show comparable expression of stage-specific embryonic antigens.  Stem Cells. 2002;  20(4) 329-337
• 81 Chew J L, Loh Y H, Zhang W et al.. Reciprocal transcriptional regulation of Pou5f1 and Sox2 via the Oct4/Sox2 complex in embryonic stem cells.  Mol Cell Biol. 2005;  25(14) 6031-6046
• 82 Daheron L, Opitz S L, Zaehres H et al.. LIF/STAT3 signaling fails to maintain self-renewal of human embryonic stem cells.  Stem Cells. 2004;  22(5) 770-778
• 83 Xu R H, Chen X, Li D S et al.. BMP4 initiates human embryonic stem cell differentiation to trophoblast.  Nat Biotechnol. 2002;  20(12) 1261-1264
• 84 Vallier L, Alexander M, Pedersen R A. Activin/Nodal and FGF pathways cooperate to maintain pluripotency of human embryonic stem cells.  J Cell Sci. 2005;  118(Pt 19) 4495-4509
• 85 James D, Levine A J, Besser D, Hemmati-Brivanlou A. TGFbeta/activin/nodal signaling is necessary for the maintenance of pluripotency in human embryonic stem cells.  Development. 2005;  132(6) 1273-1282
• 86 Ying Q L, Nichols J, Chambers I, Smith A. BMP induction of Id proteins suppresses differentiation and sustains embryonic stem cell self-renewal in collaboration with STAT3.  Cell. 2003;  115(3) 281-292
• 87 Kleinsmith L J, Pierce Jr G B. Multipotentiality of single embryonal carcinoma cells.  Cancer Res. 1964;  24 1544-1551
• 88 Markert C L. Neoplasia: a disease of cell differentiation.  Cancer Res. 1968;  28(9) 1908-1914
• 89 Pierce G B. Neoplasms, differentiations and mutations.  Am J Pathol. 1974;  77(1) 103-118
• 90 Cairns J. Mutation selection and the natural history of cancer.  Nature. 1975;  255 197-200
• 91 Bruce W R, Van Der Gaag H. A quantitative assay for the number of murine lymphoma cells capable of proliferation in vivo.  Nature. 1963;  199 79-80
• 92 Hamburger A W, Salmon S E. Primary bioassay of human tumor stem cells.  Science. 1977;  197(4302) 461-463
• 93 Bonnet D, Dick J E. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell.  Nat Med. 1997;  3(7) 730-737
• 94 Singh S K, Clarke I D, Terasaki M et al.. Identification of a cancer stem cell in human brain tumors.  Cancer Res. 2003;  63(18) 5821-5828
• 95 Singh S K, Hawkins C, Clarke I D et al.. Identification of human brain tumour initiating cells.  Nature. 2004;  432(7015) 396-401
• 96 Kondo T, Setoguchi T, Taga T. Persistence of a small subpopulation of cancer stem-like cells in the C6 glioma cell line.  Proc Natl Acad Sci USA. 2004;  101(3) 781-786
• 97 Galli R, Binda E, Orfanelli U et al.. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma.  Cancer Res. 2004;  64(19) 7011-7021
• 98 Al-Hajj M, Wicha M S, Benito-Hernandez A, Morrison S J, Clarke M F. Prospective identification of tumorigenic breast cancer cells.  Proc Natl Acad Sci USA. 2003;  100(7) 3983-3988
• 99 Fang D, Nguyen T K, Leishear K et al.. A tumorigenic subpopulation with stem cell properties in melanomas.  Cancer Res. 2005;  65(20) 9328-9337
• 100 Harris H. Tumour suppression: putting on the brakes.  Nature. 2004;  427(6971) 201
• 101 Liu X, Wu H, Loring J et al.. Trisomy eight in ES cells is a common potential problem in gene targeting and interferes with germ line transmission.  Dev Dyn. 1997;  209(1) 85-91
• 102 Maitra A, Arking D E, Shivapurkar N et al.. Genomic alterations in cultured human embryonic stem cells.  Nat Genet. 2005;  37(10) 1099-1103
• 103 Atkin N B, Baker M C. Specific chromosome change, i(12p), in testicular tumours?.  Lancet. 1982;  2(8311) 1349
• 104 Skotheim R I, Lind G E, Monni O et al.. Differentiation of human embryonal carcinomas in vitro and in vivo reveals expression profiles relevant to normal development.  Cancer Res. 2005;  65(13) 5588-5598
• 105 Andrews P W, Matin M M, Bahrami A R, Damjanov I, Gokhale P, Draper J S. Embryonic stem (ES) cells and embryonal carcinoma (EC) cells: opposite sides of the same coin.  Biochem Soc Trans. 2005;  33(pt 6) 1526-1530