Circadian variation in cell proliferation and maturation. A hypothesis for the growth regulation of the rat corneal epithelium.

The rat corneal epithelium has been chosen as a model for studying growth regulation. In this epithelium a large single cohort of cells enters the S phase during a fairly short time period once a day. The factor responsible for this wave of cell proliferation is unknown, but it may be a chemical signal from the central nervous system (the suprachiasmatic nucleus or the corpus pineale). The mature cell compartment of the corneal epithelium is assumed to produce a negative feedback factor (chalone), counteracting the effect of the circadian proliferative factor on the local cell proliferation. When no circadian factor is being produced, during most of the 24 h, the chalone seems to enhance the maturation process. During diminished chalone production (e.g. after cell injury and subsequent regeneration), we will get a more or less unrestricted cell proliferation in the tissue with a delayed maturation process prolonging the chalone depletion. This interaction between the circadian proliferative factor and the negative feedback factor for regulation of proliferation with its accompanying stimulatory effect on maturation, may represent a general mechanism in the regulation of cell proliferation in any tissue. Since in at least some organs virtually all cells entering the S phase do this as a single wave once a day, this mechanism may be enough to explain the regulation of cell proliferation during both normal and regenerative conditions.