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CELL DIFFERENTIATION

As the embryo develops, its cells pass through a series of changes in gene expression, reflected in alterations of cell structure and behaviour. They begin to diversify, separating first into two main tissue arrangements, epithelium and embryonic mesenchyme, then into more restricted subtypes of tissue, until finally they mature into cells of their particular adult lineage. In this process, and in the maturation of functioning cells of the different lineages from their stem cells, there is a sequential pattern of gene expression that changes and limits the cell to a particular specialized range of activities. Such changes involve alterations in cell structure and biochemical characteristics, particularly in the types of proteins that are synthesized. At the genetic level, differentiation is based on a change in the pattern of repression and activation of the DNA sequences encoding proteins specific to that stage of development.

A cell may be committed to a particular differentiated fate without manifesting its commitment until later. Once switched in this way, cells are not usually able to revert to an earlier stage of commitment to a differentiation pathway, so that an irreversible repression of some gene sequences must have occurred. Differentiation signals include interactions between cells that are mediated by diffusible signalling molecules elaborated by one cell and detected by another, and by contactmediated signalling (such as Delta–Notch signalling). The latter is particularly important in establishing boundaries between different cell populations in development.

Differentiation may also depend in some instances on a temporal sequence, but probably not the number of previous cell divisions. In mature tissues in which cell turnover occurs, similar mechanisms appear to ensure the final differentiation to a functional end cell. This may be linked to the presence of a physiological stimulus, e.g. B lymphocytes respond to exposure to an antigen by differentiating into plasma cells that secrete a neutralizing antibody. In other cases, particularly where a cell is part of a highly organized tissue system, more subtle mechanisms exist to ensure a balance between cell proliferation, differentiation and programmed cell death (apoptosis). This balance is disturbed when tissue is damaged and different cell types respond differently to repair the damage. Liver hepatocytes are able to revert to a functionally less well-differentiated phenotype and re-enter the cell cycle, in order to restore cell numbers and tissue mass. Other cell types (such as skeletal muscle fibres) are unable to do so and depend on the proliferation of precursor cells (stem cells) for repair. In many tissues such as skin, where normal cell turnover is continuous, wound repair includes up-regulation of proliferation in the stem cell and transit amplifying cell compartments.

There are few instances of the transdifferentiation of one differentiated cell type into another (metaplasia, see Ch. 2), but there is evidence that stem cells in the developing embryo and in certain mature tissues (e.g. bone marrow) may have the potential to differentiate into more diverse phenotypes than was once believed. This plasticity depends on environmental cues and offers the prospect of engineering tissues for clinical therapy. For further reading, see Alberts et al (2002).

CELL FUSION

A small number of cell types undergo a process of fusion, the regulation of which is not well understood, as part of their normal programme of differentiation. A variable number of precursor cells fuse their plasma membranes and form syncytia, with their nuclei occupying a common cytoplasm. The best known examples are: skeletal muscle, where many hundreds of mononucleated myoblasts fuse to form a myotube which differentiates further to form the mature skeletal muscle fibre; osteoclasts (bone resorbing cells) form from the fusion of up to 30 precursor haemopoietic cells of the monocytic lineage. Such multinucleated cells do not divide. Oocyte and spermatocyte fusion initiates embryonic development, and because the gametes are haploid, mitotic division of the diploid zygote follows.

Some normal polyploid cells, which may also have more than one nucleus, arise however by a different mechanism. Cells replicate their DNA (endoreduplication) to produce a tetraploid or octaploid nucleus, or may proceed to nuclear division and become binucleate, but fail to complete cytokinesis. Liver hepatocytes, some cardiac myocytes and the superficial cells of the urinary bladder are examples.

Other examples of cell fusion are pathological and usually result from viral infection. Measles, mumps and human immunodeficiency virus (HIV) are all fusogenic. Most cells fused as a result of viral infection do not divide and die without causing adverse effects.

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