CELL DIFFERENTIATION

Cell differentiation Adult organisms are composed of a number of distinct types of cell; in humans they number about 200. Cells are organized into tissues, each of which typically contains a small number of cell types and is devoted to a specific physiological function. For example, the epithelial tissue lining the stomach consists of three principal cell types: mucus-secreting columnar cells, acid-secreting parietal cells, and pepsin-secreting chief cells, together with smaller numbers of enteroendocrine cells secreting specific peptide hormones. The skeletal tissue of a long bone contains osteoblasts in the outer sheath; within the matrix are osteocytes, or mature bone cells, and osteoclasts, multinucleate cells involved in bone remodeling. Invertebrate animals are also composed of differentiated cell types, many of which are similar to the cells of mammals; but, in general, the simpler the overall organization of the animal, the fewer the number of distinct cell types that they possess. Plants are also composed of differentiated cells, but they are quite different from the cells of animals. For example, a leaf in a higher plant is covered with a cuticle layer of epidermal cells. Among these are pores composed of two specialized cells, which regulate gaseous exchange across the epidermis. Within the leaf is the mesophyll, a spongy tissue responsible for photosynthetic activity. There are also veins composed of xylem elements, which transport water up from the soil, and phloem elements, which transport products of photosynthesis to the storage organs. The various cell types have traditionally been recognized and classified according to their appearance in the light microscope following the process of fixing, processing, sectioning, and staining tissues that is known as histology. Classical histology has been augmented since the 1940s by electron microscopy, by histochemistry (methods of staining particular enzymes and other substances), and, since the 1960s, by immunohistochemistry (the use of specific antibodies to stain particular molecular species in situ). Immunohistochemistry has allowed the identification of many more cell types than could be visualized by classical histology, particularly in the immune system and among the scattered hormone-secreting cells of the endocrine system. The differentiated state The biochemical basis of cell differentiation is the synthesis by the cell of a particular set of proteins, carbohydrates, and lipids. These syntheses are catalyzed by enzymes, all of them proteins, and each enzyme in turn is synthesized in accordance with a particular gene, or sequence of nucleotides in the DNA of the cell nucleus. A particular state of differentiation, then, corresponds to the set of genes that is expressed and the level to which it is expressed. It is generally believed that all of an organism's genes are present in each cell nucleus, no matter what the cell type, and that differences between tissues are due not to the presence or absence of certain genes but to the expression of some and the repression of others. In animals the best evidence for retention of the entire set of genes comes from experiments in which the nucleus of a differentiated cell is substituted for the nucleus of a fertilized ovum, resulting in a small number of cases in the growth of a normal embryo. Such experiments show that any nucleus has the genetic information required for the growth of a developing organism, and they strongly suggest that, for most tissues, cell differentiation arises from the regulation of genetic activity rather than the removal or destruction of unwanted genes. The only known exception to this rule comes from the immune system, where segments of DNA in developing white blood cells are slightly rearranged, producing a wide variety of antibody and receptor molecules. (See above The nucleus: Rearrangement and modification of DNA.) At the molecular level there are many ways in which the expression of a gene can be differentially regulated in different cell types. There may be differences in the copying, or transcription, of the gene into RNA, in the processing of the initial RNA transcript into messenger RNA (mRNA), in the control of mRNA movement to the cytoplasm, in the translation of mRNA to protein, or in the stability of mRNA. One of the best-understood cases is the differentiation of the red blood cell, of which hemoglobin is the major protein. In other tissues the globin genes are present but not transcribed at a high level, while, in the DNA of the developing red blood cell, nucleotide sequences called enhancers have been identified in and around the regions encoding hemoglobin. These enhancers, presumably upon interaction with regulatory proteins specific to red blood cells, allow the transcription of hemoglobin genes only in those cells. Cells are normally sharply different from one another when they reach a state of terminal, or final, differentiation; intermediate forms found in an adult organism are in a process of maturation from a precursor cell type. States of terminal differentiation are stable and persistent, both in the lifetime of the cell and, in the case of differentiated types capable of continued cell division, through successive cell generations. The inherent stability of the differentiated state may be the result of a feedback mechanism, in which the products of active genes act on those genes to maintain their activity and on other genes to maintain their inactivity.