J Clin Pathol: first published as 10.1136/jcp.27.Suppl_7.19 on 1 January 1974. Downloaded from J. clin. Path., 27, Suppl. (Roy. Coll. Path.), 7, 19-25 The mitotic cycle and cell population control L. F. LAMERTON From the Biophysics Division, Institute of Cancer Research, Sutton, Surrey There is a danger, in the study of the mechanisms of logically, but can be studied by functional tests, the control of mitosis, of oversimplifying the problems. turnover time in the rodent is several days or more. This is particularly so in attempts to extract con- 'Turnover time' is defined here as the time required trolling substances from tissues where the procedures for the cell population to produce a number of cells used may take no account of the structural hetero- equal to the number already present. It is a measure geneity of the system. It has to be recognized that of rate of cell production, and does not necessarily in many tissues one will be dealing with a number of indicate the mean intermitotic time of the dividing subpopulations, related to each other in precursor cells, since it is a function of the proportion of the sequence or in function, but of different proliferative population which is dividing, as well as of the characteristics and potential and responding to intermitotic time of the dividing cells. different types of stimulus. In the small intestine, a tissue in which the cell It is therefore important that a study of the kinetics have been studied extensively (Fry, Lesher, structure and proliferative characteristics of cell Kisieleski, and Sacher, 1963; Cairnie, 1967), it is not populations in vivo should run parallel with funda- yet clear whether the stem-cell compartment com- mental biochemical studies if a proper under- prises all cells in the proliferative zone of the crypts standing of proliferation control is to be achieved. of Lieberkuhn or only those at the bottom. In the This paper is intended as a very brief survey of what crypt of the small intestine it has recently been copyright. might be called the dynamic histology of tissues with shown (Wright, Morley, and Appleton, 1972 and some indication of its implications for mechanisms personal communication), both for the rodent and of control of mitosis. for man, that although most of the cells in the proliferating zone are dividing rapidly, those at the Proliferative Patterns in Normal Tissues bottom have a much longer turnover time. Similarly, in the cartilage plate of the young rat, it has been There is a great variation in the rate of proliferation shown that the cells at the top of the column are of cells in different tissues of the body. In normal, turning over much more slowly than those lower unstimulated tissues of rat or mouse the mean inter- down (Kember, 1960). Thus in these tissues the http://jcp.bmj.com/ mitotic time varies from hundreds of days in stem-cell compartment, if not dividing slowly as a conditional renewal tissues such as the liver to 10 whole, at least contains a slowly dividing component. hours or so in certain cell populations, such as those Perhaps the clearest example of a stem-cell found in the small intestine or among the later population of long turnover time is found in the maturing blood cell precursors in the bone marrow. conditional renewal tissues-such as the liver, Some generalizations can, however, be made, particu- kidney, thyroid, and salivary gland-where the larly concerning the rate of division of the 'stem turnover time is normally of the order of hundreds on October 2, 2021 by guest. Protected cells', that is, the members of the progenitor com- of days, though it is reduced dramatically under the partments which have the capacity both for self- appropriate stimulus. maintenance and for providing cells for the matura- When cells leave the stem-cell compartment and tion pathways. It would appear, on the basis of enter the maturation pathway they either cease tissues so far studied, that the stem cells, in the division or continue to divide for a limited time, unstimulated state, are among the more slowly depending on the particular tissue. In the case of the dividing cell populations found in tissues or, at skin the probability of division is greatly reduced, least, contain a slowly dividing subpopulation. For possibly to zero, when a cell leaves the basal layer. instance, in the skin, the turnover time in the basal On the other hand, the bone marrow is a tissue in layer, which is composed mainly of stem cells, is which many cell divisions intervene between the of the order of several days in the rodent and con- stem cell and the mature cell. It is interesting that siderably longer in man. In the bone marrow, where the rate of cell division in the later precursors of the the stem cells cannot yet be distinguished morpho- blood cells is, in unstimulated conditions, much 19 J Clin Pathol: first published as 10.1136/jcp.27.Suppl_7.19 on 1 January 1974. Downloaded from 20 L. F. Lamerton more rapid than that of the stem cells. For and the start of DNA synthesis (Baserga, 1968; example, in rats, the recognizable red cell precursors Threfall, 1968). An explanation for this, assuming from the pronormoblast to the polychromatic stage the cells to be normally in the untriggered Go state, divide with an intermitotic time between 10 and 12 is that the interval of 20 hours represents the time hours (Hanna, Tarbutt, and Lamerton, 1969). after stimulus needed to complete preparation for Cessation of cell division, which occurs in the poly- DNA synthesis. The reason why all cells do not have chromatic stage, seems to occur without any sub- a G1 phase of 20 hours could be, as Baserga has stantial lengthening of the intermitotic time. suggested, because the enzymes necessary for the If the stem-cell compartment of the small intestine process of DNA synthesis decay with time, and that is confined to the base of the crypts, the remaining the length of the preparation period depends on the cells of the proliferation zone will represent a interval between the end of the previous division and maturation compartment in which again the rate of triggering into preparation for DNA synthesis. cell division is much higher than that of the stem With regard to the stem cells of the normal renewal cells. Also, as with the bone marrow, there appears tissues of the body, work on the skin (Block, to be a rapid 'switch off' of cell division without Seiter, and Oehlert, 1963) and on bone marrow lengthening of the cell cycle. Any broad generaliza- (Gidali and Lajtha, 1972; Lahiri and van Putten, tions about the proliferation characteristics of 1972) has indicated that a substantial increase in maturing cells must, however, await data on other labelled cells and mitotic figures can, under certain tissues. conditions, occur within a very few hours of the stimulus. This suggests that the stem cells of the Kinetic State of Unstimulated Stem Cells normal renewal tissues contain at least some cells in G1 or G2, or in both, that can quickly complete the stages to mitosis. Evidence that a variety of normal A relatively long turnover time, such as is shown by tissues contain cells arrested in the G2 phase has the stem-cell compartments of unstimulated tissues, been provided by Pederson and Gelfant (1970). could be explained in a number of ways. One However, the recent paper of Hegazy and Fowler possibility is that only a small fraction of the cells (1973) indicates that a relatively long intermitotic copyright. have division potential, though experimental data time does not necessarily indicate the presence of would argue against this. Alternatively, the cells 'resting' or 'arrest' stages. By the method of may have to wait, on the average, a relatively long percentage labelled mitoses they demonstrated, in time after mitosis (in the so-called Go state) before unstimulated mouse skin, a narrow distribution of being triggered into preparation for division, or they intermitotic time of basal layer cells around a value may be progressing slowly through some stage of the of about 110 hours. How far the duration of con- cell cycle, or temporarily arrested. With available tinued progress around the cell cycle can be extended techniques it is often difficult, and sometimes not is not known. possible, to distinguish between these various http://jcp.bmj.com/ alternatives, and particularly to distinguish between the possibilities in the pre-synthetic period, that is, Changes in Proliferative Pattern of Normal Tissues Go, slow progression through G1, or arrest in G1, under Stimulation though such information will be vital to the under- standing of proliferation control if different control An increase in the rate of cell production in tissues, mechanisms are required to operate at different under an appropriate stimulus, is characterized by stages of the cell cycle. one or both of two types of change: (1) a shortening on October 2, 2021 by guest. Protected In the liver and other conditional renewal tissues of the intermitotic time of cells, and (2) an extension the evidence points to most of the cells being a true of the zone of proliferation. The relative importance Go state, awaiting the trigger to start preparation for of these two types of change varies with the tissue DNA synthesis, but in the renewal tissues such as and, in certain cases, with the nature of the stimula- skin and bone marrow there is much doubt as to the tion. The normal response of the skin is a speeding kinetic state of stem cells, in spite of statements up of cell proliferation in the basal layer with frequently encountered in the literature that they minimal, if any, extension of the proliferative zone exist largely in the Go condition.