Cellular differentiation

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"Cell differentiation" redirects here. For the journal, see Cell Differentiation (journal).



Mammalian cell types[edit]




Pluripotent stem cells undergo further specialization into multipotent progenitor cells that then give rise to functional cells. Examples of stem and progenitor cells include:[citation needed]

A pathway that is guided by the cell adhesion molecules consisting of four amino acids, arginine, glycine, asparagine, and serine, is created as the cellular blastomere differentiates from the single-layered blastula to the three primary layers of germ cells in mammals, namely the ectoderm, mesoderm and endoderm (listed from most distal (exterior) to proximal (interior)). The ectoderm ends up forming the skin and the nervous system, the mesoderm forms the bones and muscular tissue, and the endoderm forms the internal organ tissues.



Dedifferentiation is a cellular process often seen in more basal life forms such as worms and amphibians in which a partially or terminally differentiated cell reverts to an earlier developmental stage, usually as part of a regenerative process.[3][4] Dedifferentiation also occurs in plants.[5] Cells in cell culture can lose properties they originally had, such as protein expression, or change shape. This process is also termed dedifferentiation.[6]

Some believe dedifferentiation is an aberration of the normal development cycle that results in cancer,[7] whereas others believe it to be a natural part of the immune response lost by humans at some point as a result of evolution.

A small molecule dubbed reversine, a purine analog, has been discovered that has proven to induce dedifferentiation in myotubes. These dedifferentiated cells could then redifferentiate into osteoblasts and adipocytes.[8]



Mechanisms of cellular differentiation



Signal induction refers to cascades of signaling events, during which a cell or tissue signals to another cell or tissue to influence its developmental fate.[11] Yamamoto and Jeffery[12] investigated the role of the lens in eye formation in cave- and surface-dwelling fish, a striking example of induction.[11] Through reciprocal transplants, Yamamoto and Jeffery[12] found that the lens vesicle of surface fish can induce other parts of the eye to develop in cave- and surface-dwelling fish, while the lens vesicle of the cave-dwelling fish cannot.[11]

Other important mechanisms fall under the category of asymmetric cell divisions, divisions that give rise to daughter cells with distinct developmental fates. Asymmetric cell divisions can occur because of asymmetrically expressed maternal cytoplasmic determinants or because of signaling.[11] In the former mechanism, distinct daughter cells are created during cytokinesis because of an uneven distribution of regulatory molecules in the parent cell; the distinct cytoplasm that each daughter cell inherits results in a distinct pattern of differentiation for each daughter cell. A well-studied example of pattern formation by asymmetric divisions is body axis patterning in Drosophila. RNA molecules are an important type of intracellular differentiation control signal. The molecular and genetic basis of asymmetric cell divisions has also been studied in green algae of the genus Volvox, a model system for studying how unicellular organisms can evolve into multicellular organisms.[11] In Volvox carteri, the 16 cells in the anterior hemisphere of a 32-cell embryo divide asymmetrically, each producing one large and one small daughter cell. The size of the cell at the end of all cell divisions determines whether it becomes a specialized germ or somatic cell.[11][13]

Epigenetic control of cellular differentiation[edit]


Importance of epigenetic control[edit]





Mechanisms of epigenetic regulation[edit]

Pioneering factors (Oct4, Sox2, Nanog)[edit]

Three transcription factors, OCT4, SOX2, and NANOG – the first two of which are used in iPSC reprogramming – are highly expressed in undifferentiated embryonic stem cells and are necessary for the maintenance of their pluripotency.[15] It is thought that they achieve this through alterations in chromatin structure, such as histone modification and DNA methylation, to restrict or permit the transcription of target genes.

Polycomb repressive complex (PRC2)[edit]

In the realm of gene silencing, Polycomb repressive complex 2, one of two classes of the Polycomb group (PcG) family of proteins, catalyzes the di- and tri-methylation of histone H3 lysine 27 (H3K27me2/me3).[16][15][17] By binding to the H3K27me2/3-tagged nucleosome, PRC1 (also a complex of PcG family proteins) catalyzes the mono-ubiquitinylation of histone H2A at lysine 119 (H2AK119Ub1), blocking RNA polymerase II activity and resulting in transcriptional suppression.[15] PcG knockout ES cells do not differentiate efficiently into the three germ layers, and deletion of the PRC1 and PRC2 genes leads to increased expression of lineage-affiliated genes and unscheduled differentiation.[15] Presumably, PcG complexes are responsible for transcriptionally repressing differentiation and development-promoting genes.

Trithorax group proteins (TrxG)[edit]

Alternately, upon receiving differentiation signals, PcG proteins are recruited to promoters of pluripotency transcription factors. PcG-deficient ES cells can begin differentiation but cannot maintain the differentiated phenotype.[15] Simultaneously, differentiation and development-promoting genes are activated by Trithorax group (TrxG) chromatin regulators and lose their repression.[15][17] TrxG proteins are recruited at regions of high transcriptional activity, where they catalyze the trimethylation of histone H3 lysine 4 (H3K4me3) and promote gene activation through histone acetylation.[17] PcG and TrxG complexes engage in direct competition and are thought to be functionally antagonistic, creating at differentiation and development-promoting loci what is termed a “bivalent domain” and rendering these genes sensitive to rapid induction or repression.[18]

DNA methylation[edit]

Regulation of gene expression is further achieved through DNA methylation, in which the DNA methyltransferase-mediated methylation of cytosine residues in CpG dinucleotides maintains heritable repression by controlling DNA accessibility.[18] The majority of CpG sites in embryonic stem cells are unmethylated and appear to be associated with H3K4me3-carrying nucleosomes.[15] Upon differentiation, a small number of genes, including OCT4 and NANOG,[18] are methylated and their promoters repressed to prevent their further expression. Consistently, DNA methylation-deficient embryonic stem cells rapidly enter apoptosis upon in vitro differentiation.[15]

Nucleosome positioning[edit]

While the DNA sequence of almost all cells of an organism is the same, the binding patterns of transcription factors and the corresponding gene expression patterns are different. To a large extent, differences in transcription factor binding are determined by the chromatin accessibility of their binding sites through histone modification and/or pioneer factors. In particular, it is important to know whether a nucleosome is covering a given genomic binding site or not. Recent studies have elucidated the role of nucleosome positioning during stem cell development.[19]

Role of signaling in epigenetic control[edit]


The first major candidate is Wnt signaling pathway. The Wnt pathway is involved in all stages of differentiation, and the ligand Wnt3a can substitute for the overexpression of c-Myc in the generation of induced pluripotent stem cells.[20] On the other hand, disruption of ß-catenin, a component of the Wnt signaling pathway, leads to decreased proliferation of neural progenitors.


Several other signaling pathways are also considered to be primary candidates. Cytokine leukemia inhibitory factors are associated with the maintenance of mouse ESCs in an undifferentiated state. This is achieved through its activation of the Jak-STAT3 pathway, which has been shown to be necessary and sufficient towards maintaining mouse ESC pluripotency.[21] Retinoic acid can induce differentiation of human and mouse ESCs,[20] and Notch signaling is involved in the proliferation and self-renewal of stem cells. Finally, Sonic hedgehog, in addition to its role as a morphogen, promotes embryonic stem cell differentiation and the self-renewal of somatic stem cells.[20]


Expression of Shh (Sonic hedgehog) upregulates the production of Bmi1, a component of the PcG complex that recognizes H3K27me3. This occurs in a Gli-dependent manner, as Gli1 and Gli2 are downstream effectors of the Hedgehog signaling pathway. In culture, Bmi1 mediates the Hedgehog pathway’s ability to promote human mammary stem cell self-renewal.[22] In both humans and mice, researchers showed Bmi1 to be highly expressed in proliferating immature cerebellar granule cell precursors. When Bmi1 was knocked out in mice, impaired cerebellar development resulted, leading to significant reductions in postnatal brain mass along with abnormalities in motor control and behavior.[23] A separate study showed a significant decrease in neural stem cell proliferation along with increased astrocyte proliferation in Bmi null mice.[24]


See also[edit]


  1. ^ "NCI Dictionary of Cancer Terms". National Cancer Institute. Retrieved 1 November 2013. 
  2. ^ Kumar, Rani (2008). Textbook of Human Embryology. I.K. International Publishing House. p. 22. ISBN 9788190675710. 
  3. ^ Stocum DL (2004). "Amphibian regeneration and stem cells". Curr. Top. Microbiol. Immunol. Current Topics in Microbiology and Immunology 280: 1–70. doi:10.1007/978-3-642-18846-6_1. ISBN 978-3-540-02238-1. PMID 14594207. 
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  9. ^ Ben-Tabou de-Leon S, Davidson EH. (2007). "Gene regulation: gene control network in development.". Annu Rev Biophys Biomol Struct. 36 (191). PMID 17291181. 
  11. ^ a b c d e f g Rudel and Sommer; The evolution of developmental mechanisms. Developmental Biology 264, 15-37, 2003 Rudel, D.; Sommer, R. J. (2003). "The evolution of developmental mechanisms". Developmental Biology 264 (1): 15–37. doi:10.1016/S0012-1606(03)00353-1. PMID 14623229.  edit
  12. ^ a b Yamamoto Y and WR Jeffery; Central role for the lens in cave fish eye degeneration. Science 289 (5479), 631-633, 2000 Yamamoto, Y.; Jeffery, W. R. (2000). "Central Role for the Lens in Cave Fish Eye Degeneration". Science 289 (5479): 631–633. Bibcode:2000Sci...289..631Y. doi:10.1126/science.289.5479.631. PMID 10915628.  edit
  14. ^ a b Lister R, et al (2011). "Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells". Nature 471 (7336): 68–73. Bibcode:2011Natur.471...68L. doi:10.1038/nature09798. PMC 3100360. PMID 21289626. 
  16. ^ Zhu, J., et al.. (2013). "Genome-wide chromatin state transitions associated with developmental and environmental cues". Cell 152 (3): 642–654. PMID 23333102. 
  17. ^ a b c Guenther MG, Young RA (2010). "Repressive Transcription". Science 329 (5988): 150–1. Bibcode:2010Sci...329..150G. doi:10.1126/science.1193995. PMC 3006433. PMID 20616255. 
  19. ^ Teif VB, Vainshtein Y, Caudron-Herger M, Mallm JP, Marth C, Höfer T, Rippe K. (2012). "Genome-wide nucleosome positioning during embryonic stem cell development". Nat Struct Mol Biol. 19 (11): 1185–92. doi:10.1038/nsmb.2419. PMID 23085715. 
  23. ^ Leung C, et al (2004). "Bmi1 is essential for cerebellar development and is overexpressed in human medulloblastomas". Nature 428 (6980): 337–41. Bibcode:2004Natur.428..337L. doi:10.1038/nature02385. PMID 15029199. 