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The molecular repertoire of the 'almighty' stem cell

Nature Reviews Molecular Cell Biology volume 6, pages 726–737 (2005)Cite this article

Key Points

  • Stem cells are endowed with self-renewal and multi-lineage differentiation potential that enable them to generate mature functional tissues during development and to regenerate these tissues following injury or degenerative processes.

  • The regulation of stem cells is thought to be mediated by the convergence of extrinsic (microenvironmental) and intrinsic (intracellular) signals that currently are poorly understood.

  • The genetic regulation of embryonic and adult stem cells is studied using focused and global techniques for gene-expression analysis.

  • It has been shown that stem cells express many lineage-specific genes at low levels before lineage commitment, and specification to a single lineage is not only because of acquisition of lineage-specific gene-expression during differentiation, but is also associated with loss of promiscuous gene expression.

  • The many reported embryonic and adult stem-cell transcriptomes have provided a foundation for understanding the molecular mechanisms that regulate the stem-cell phenotype, but discordant results from these studies have prevented the identification of a conserved stem-cell molecular signature, if such an entity exists.

  • The ability to prospectively purify stem-cell populations to homogeneity, and to therefore eliminate the contaminating transcripts from committed cells, will advance our understanding of stem-cell gene expression, and combined with rapid high-throughput functional-genomics approaches, should reveal the molecular mechanisms that underlie the stem-cell phenotype.

  • As gene expression does not necessarily dictate which of the genes or gene pathways are functionally involved in self-renewal and pluri-/multi-potency, the next step to define the implications of an expressed gene pattern will be to design gene-targeting experiments to characterize the function of these genes and gene pathways.

Abstract

Stem cells share the defining characteristics of self-renewal, which maintains or expands the stem-cell pool, and multi-lineage differentiation, which generates and regenerates tissues. Stem-cell self-renewal and differentiation are influenced by the convergence of intrinsic cellular signals and extrinsic microenvironmental cues from the surrounding stem-cell niche, but the specific signals involved are poorly understood. Recently, several studies have sought to identify the genetic mechanisms that underlie the stem-cell phenotype. Such a molecular road map of stem-cell function should lead to an understanding of the true potential of stem cells.

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Figure 1: The stem-cell hierarchy.
Figure 2: The haematopoietic stem cell.
Figure 3: Molecular regulation of stem-cell niches.

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Acknowledgements

The authors would like to acknowledge the work of our colleagues that we have discussed, and apologize to our colleagues whose work was not discussed due to space limitations.

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  1. Craig E. Eckfeldt and Eric M. Mendenhall: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine and Stem Cell Institute, University of Minnesota, Minneapolis, Minnesota, USA

    Craig E. Eckfeldt, Eric M. Mendenhall & Catherine M. Verfaillie

Authors
  1. Craig E. Eckfeldt
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  2. Eric M. Mendenhall
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  3. Catherine M. Verfaillie
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Corresponding author

Correspondence to Catherine M. Verfaillie.

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Related links

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DATABASES

Entrez Gene

Angpt1

Bmi1

BMP4

Ccnd1

Cdkn1a

CHEK2

DNMT3B

Eras

FGF1

GDF3

GJA1

Hoxb4

Lhx2

LIN28

LMO2

Nanog

NOTCH1

Oct4

Pax6

Runx1

SHH

SOX2

TAL1

Tek

Tdgf1

TDGF1

TGIF

Uft1

Zfp42

FURTHER INFORMATION

Catherine Verfaillie's Institute

National Institutes of Health Stem Cell Information

The Stem Cell Database (SCDB)

The Stem Cell Genome Anatomy Project (SCGAP)

The Stromal Cell Database (StroCDB)

Glossary

PLURIPOTENT

The ability to give rise to all embryonic tissues, but not extra-embryonic tissues. Totipotent cells can give rise to all embryonic and extra-embryonic (trophectodermal) tissues.

INNER CELL MASS

A mass of pluripotent cells in the interior of the developing blastocyst that give rise to all embryonic tissues. The blastocyst is part of the pre-implantation-stage embryo and consists of a hollow sphere of cells with a distinct outer trophectoderm layer and an inner cell mass.

MULTIPOTENT

The ability to give rise to the diverse cell types of one or a few tissues.

GENITAL RIDGE

The bilateral structures in the developing embryo that give rise to the gonads.

TRANSCRIPTOME

The entire transcriptional repertoire of a cell or cell population.

TROPHECTODERM

The outer portion of the blastocyst that gives rise to the embryonic portion of the placenta.

HOMEODOMAIN TRANSCRIPTION FACTOR

A transcription factor that contains a homeodomain DNA-binding domain.

EST SEQUENCING

The sequencing of short segments of expressed genes (expressed sequence tags or ESTs) present in cDNA libraries that can be used for gene cloning or to show which genes are present in a cell population.

TRANS-DIFFERENTIATE

Differentiation of one cell type directly to another cell type without dedifferentiation to a more primitive intermediate.

STEM-CELL PLASTICITY

The apparent ability of a stem/progenitor cell fated to a particular tissue to acquire a differentiated phenotype of a different tissue.

cRNA

A complementary RNA molecule that hybridizes with a specific messenger RNA sequence.

IN SILICO DIFFERENTIAL DISPLAY

The use of computer algorithms to determine differential expression of transcripts from gene-expression databases.

FLUORESCENCE ACTIVATED CELL SORTING

Automated, high-speed sorting of cell populations based on the presence of intrinsic fluorescent labels such as GFP expression, or extrinsic fluorescent labels such as monoclonal antibodies conjugated to fluorochromes.

HOMEOBOX (HOX) GENE FAMILY

A family of transcriptional regulators that share a conserved homeobox DNA-binding domain, and that are involved in the regulation of embryonic and adult developmental fates.

POLYCOMB (PCG) GENE FAMILY

Genes encoding a family of proteins that form complexes that modify chromatin structure and selectively repress gene transcription.

WNT GENE FAMILY

A family of genes that mediate intercellular signalling through secreted glycoprotein Wnt ligands.

microRNA

A family of short, non-coding RNA molecules (∼22 nucleotides) that post-transcriptionally regulate target-gene expression primarily by inhibiting protein translation.

RNAi

A functional tool that use small interfering RNAs (siRNAs) to knock down gene expression through sequence-specific decay of target mRNA molecules.

MORPHOLINO ANTISENSE OLIGONUCLEOTIDES

Chemically synthesized oligonucleotide analogues used to knock down gene expression by specifically binding to target transcripts to inhibit RNA splicing or translation.

CHIP

Technique used to immunoprecipitate complexes of DNA with associated proteins.

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Eckfeldt, C., Mendenhall, E. & Verfaillie, C. The molecular repertoire of the 'almighty' stem cell. Nat Rev Mol Cell Biol 6, 726–737 (2005). https://doi.org/10.1038/nrm1713

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