ON THE DOUBLING DISTRIBUTIONS OF DAY 7-MEGAKARYOCYTE (MKC) PROGENITORS

It has often been assumed that hemopoietic progenitors undergo a rather uniform, deterministic number of proliferative cycles before they generate the elements which are recognizable by pano-ptiG and cytochemical methods. We now confirm and extend previous data on the distribution of the number of doublings undergone before polyploi'dization by day 7-MKC progenitors. Cultures of mouse bone marrow were stimulated by erythropoietin, WEHI conditioned medium (CM) and/or pokeweed CM. In all cases, cumulative doubling distributions of pure MKC colonies could be precisely fitted by exponential lines, whose slope and length depended on the stimulus or combination of stimuli used. The frequency of single MKC could be fitted by the same line as that plotting the number of doublings in MKC colonies, suggesting that single MKC and MKC colonies can be generated by the same class of progenitors. Exponential shape implies that the coefficient of variation (SD/mean) of doubling numbers is one, indicating significant variability in proliferative behavior among day 7-MKC progenitors. Such exponential distributions are best explained in the framework of Renewal Theory (Cox, Methuen, 1962). Whatever the distribution of the number of progenitor renewals in fixed time, the distribution of renewals will be geometric (i.e discontinuous exponential) if the total time spent by individual colonies in the proliferation phase (1) is distributed exponentially, and (2) is independent from the renewal process itself. These results suggest that the wave of MKC progenitor mitoses is randomly arrested by a differentia-tive event which strikes progenitor clones independently from their proliferative past.