Unraveling the molecular components and genetic blueprints of stem cells.

Remarkable progress in stem cell biology research over the past few years has provoked a promise for the future of tissue regeneration and gene therapies; so much so, that the use of stem cells in clinical therapy seemed to be just around the corner. However, we now realize there is still a huge task before us to improve our understanding of the nature of stem cells before utilizing them to benefit human health. Stem cell behavior is determined by specific gene products; thus, unraveling the molecular components and genetic blueprints of stem cells will provide important insight into understanding stem cell properties. Here we summarize the research of various groups using microarray technology and other approaches to determine the gene expression profiles in stem cells, particularly in hematopoietic stem cells (HSCs). These works have, to a certain degree, helped to narrow down the candidate genes predominantly expressed in HSCs, revealed a list of stemness genes, and indirectly demonstrated the wide-open chromatin state of stem cells and, with it, the molecular basis of the multipotentiality of stem cells.

[1]  Christoph Schaniel,et al.  Response to Comments on " 'Stemness': Transcriptional Profiling of Embryonic and Adult Stem Cells" and "A Stem Cell Molecular Signature" , 2003, Science.

[2]  M. Murakami,et al.  The Homeoprotein Nanog Is Required for Maintenance of Pluripotency in Mouse Epiblast and ES Cells , 2003, Cell.

[3]  J. Nichols,et al.  Functional Expression Cloning of Nanog, a Pluripotency Sustaining Factor in Embryonic Stem Cells , 2003, Cell.

[4]  I. Weissman,et al.  A role for Wnt signalling in self-renewal of haematopoietic stem cells , 2003, Nature.

[5]  G. Sauvageau,et al.  Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells , 2003, Nature.

[6]  Irving L. Weissman,et al.  Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells , 2003, Nature.

[7]  G. Vassilopoulos,et al.  Transplanted bone marrow regenerates liver by cell fusion , 2003, Nature.

[8]  M. Grompe,et al.  Cell fusion is the principal source of bone-marrow-derived hepatocytes , 2003, Nature.

[9]  Xi C. He,et al.  Transcriptional accessibility for genes of multiple tissues and hematopoietic lineages is hierarchically controlled during early hematopoiesis. , 2003, Blood.

[10]  Leonard I Zon,et al.  Portrait of a stem cell. , 2002, Developmental cell.

[11]  D. Melton,et al.  "Stemness": Transcriptional Profiling of Embryonic and Adult Stem Cells , 2002, Science.

[12]  John T. Dimos,et al.  A Stem Cell Molecular Signature , 2002, Science.

[13]  I. Weissman,et al.  Little Evidence for Developmental Plasticity of Adult Hematopoietic Stem Cells , 2002, Science.

[14]  Min Ye,et al.  Myeloid or lymphoid promiscuity as a critical step in hematopoietic lineage commitment. , 2002, Developmental cell.

[15]  C. Westbrook,et al.  Novel transcription factors in human CD34 antigen-positive hematopoietic cells. , 2002, Blood.

[16]  K. Calvo,et al.  Nup98-HoxA9 immortalizes myeloid progenitors, enforces expression of Hoxa9, Hoxa7 and Meis1, and alters cytokine-specific responses in a manner similar to that induced by retroviral co-expression of Hoxa9 and Meis1 , 2002, Oncogene.

[17]  G. Sauvageau,et al.  HOXB4-Induced Expansion of Adult Hematopoietic Stem Cells Ex Vivo , 2002, Cell.

[18]  E. Scott,et al.  Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion , 2002, Nature.

[19]  H. Bojar,et al.  Gene expression profiling identifies significant differences between the molecular phenotypes of bone marrow-derived and circulating human CD34+ hematopoietic stem cells. , 2002, Blood.

[20]  Roger E Bumgarner,et al.  Differential gene expression profiling of adult murine hematopoietic stem cells. , 2002, Blood.

[21]  M. Frotscher,et al.  Targeting gene-modified hematopoietic cells to the central nervous system: Use of green fluorescent protein uncovers microglial engraftment , 2001, Nature Medicine.

[22]  J. Rowley,et al.  The pattern of gene expression in human CD34+ stem/progenitor cells , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[23]  K. Calvo,et al.  Meis1a suppresses differentiation by G-CSF and promotes proliferation by SCF: Potential mechanisms of cooperativity with Hoxa9 in myeloid leukemia , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[24]  S. Heimfeld,et al.  Comparison of gene expression in CD34+ cells from bone marrow and G-CSF-mobilized peripheral blood by high-density oligonucleotide array analysis. , 2001, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[25]  D. Geschwind,et al.  From hematopoiesis to neuropoiesis: Evidence of overlapping genetic programs , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[26]  D. Bodine,et al.  Transplanted Adult Bone Marrow Cells Repair Myocardial Infarcts in Mice , 2001, Annals of the New York Academy of Sciences.

[27]  Neil D. Theise,et al.  Multi-Organ, Multi-Lineage Engraftment by a Single Bone Marrow-Derived Stem Cell , 2001, Cell.

[28]  S. Berger,et al.  The Histone Modification Circus , 2001, Science.

[29]  D. Kalderon,et al.  Hedgehog acts as a somatic stem cell factor in the Drosophila ovary , 2001, Nature.

[30]  D. Baker,et al.  Sonic hedgehog induces the proliferation of primitive human hematopoietic cells via BMP regulation , 2001, Nature Immunology.

[31]  Xin Wang,et al.  Purified hematopoietic stem cells can differentiate into hepatocytes in vivo , 2000, Nature Medicine.

[32]  I. Bernstein,et al.  Pluripotent, cytokine-dependent, hematopoietic stem cells are immortalized by constitutive Notch1 signaling , 2000, Nature Medicine.

[33]  A. Riggs,et al.  Chromatin fine structure profiles for a developmentally regulated gene: reorganization of the lysozyme locus before trans-activator binding and gene expression. , 2000, Genes & development.

[34]  E. Winzeler,et al.  Genomics, gene expression and DNA arrays , 2000, Nature.

[35]  G C Overton,et al.  The genetic program of hematopoietic stem cells. , 2000, Science.

[36]  F. Alt,et al.  Defective embryonic neurogenesis in Ku-deficient but not DNA-dependent protein kinase catalytic subunit-deficient mice. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[37]  I. Weissman,et al.  Stem Cells Units of Development, Units of Regeneration, and Units in Evolution , 2000, Cell.

[38]  L. Kömüves,et al.  Frequent co-expression of the HOXA9 and MEIS1 homeobox genes in human myeloid leukemias , 1999, Leukemia.

[39]  A. Bigas,et al.  Notch as a mediator of cell fate determination in hematopoiesis: evidence and speculation. , 1999, Blood.

[40]  J. Thomson,et al.  Embryonic stem cell lines derived from human blastocysts. , 1998, Science.

[41]  R. Nusse,et al.  Wnt signaling: a common theme in animal development. , 1997, Genes & development.

[42]  T. Enver,et al.  The lineage commitment of haemopoietic progenitor cells. , 1997, Current opinion in genetics & development.

[43]  I. Weissman,et al.  Identification of a lineage of multipotent hematopoietic progenitors. , 1997, Development.

[44]  M. Greaves,et al.  Multilineage gene expression precedes commitment in the hemopoietic system. , 1997, Genes & development.

[45]  G. Felsenfeld,et al.  Chromatin structure and gene expression. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[46]  C. Auffray,et al.  Novel gene transcripts preferentially expressed in human muscles revealed by quantitative hybridization of a high density cDNA array. , 1996, Genome research.

[47]  G. Stamatoyannopoulos,et al.  Human CD34+ cell EST database: single-pass sequencing of 402 clones from a directional cDNA library. , 1996, Experimental hematology.

[48]  Ronald W. Davis,et al.  Quantitative Monitoring of Gene Expression Patterns with a Complementary DNA Microarray , 1995, Science.

[49]  K. Kinzler,et al.  Serial Analysis of Gene Expression , 1995, Science.

[50]  R. Willemze,et al.  Modification of rhodamine staining allows identification of hematopoietic stem cells with preferential short-term or long-term bone marrow-repopulating ability. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[51]  B. Torok-Storb,et al.  Identification of a novel DNA sequence differentially expressed between normal human CD34+CD38hi and CD34+CD38lo marrow cells. , 1995, Blood.

[52]  J. Craig Venter,et al.  Rapid cDNA sequencing (expressed sequence tags) from a directionally cloned human infant brain cDNA library , 1993, Nature Genetics.

[53]  M. Wigler,et al.  Cloning the differences between two complex genomes , 1993, Science.

[54]  A. Pardee,et al.  Differential display of eukaryotic messenger RNA by means of the polymerase chain reaction. , 1992, Science.

[55]  J. Sklar,et al.  TAN-1, the human homolog of the Drosophila Notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms , 1991, Cell.

[56]  G. Spangrude,et al.  Resting and activated subsets of mouse multipotent hematopoietic stem cells. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[57]  B. Seed,et al.  Isolation of cDNAs of scrapie-modulated RNAs by subtractive hybridization of a cDNA library. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[58]  I. Weissman,et al.  Purification and characterization of mouse hematopoietic stem cells. , 1988, Science.

[59]  H. Weintraub.  Assembly and propagation of repressed and derepressed chromosomal states , 1985, Cell.

[60]  S. Berger.  Molecular biology. The histone modification circus. , 2001, Science.

[61]  I. Weissman,et al.  Stem and progenitor cells: origins, phenotypes, lineage commitments, and transdifferentiations. , 2001, Annual review of cell and developmental biology.

[62]  C. Niu,et al.  Gene expression in CD34(+) cells from normal bone marrow and leukemic origins. , 2000, The hematology journal : the official journal of the European Haematology Association.

[63]  W Gaffield,et al.  Essential role for Sonic hedgehog during hair follicle morphogenesis. , 1999, Developmental biology.

[64]  B. Trask,et al.  The human homolog of rat Jagged1 expressed by marrow stroma inhibits differentiation of 32D cells through interaction with Notch1. , 1998, Immunity.

[65]  Kenji Matsuno,et al.  Notch signaling. , 1995, Science.