Further assessment of stochastic proliferation and its potential application to hematopoietic scaling across species.

Spleen colony-forming unit (CFU-s) growth in spleen colonies is a stochastic process in which CFU-s, with each cell division, can either self-renew or differentiate, but not both. The fundamental parameter governing this process is p, or the probability of CFU-s self-renewing. Previously, when CFU-s growth was modeled by Monte Carlo simulations, p was kept constant during the 20 cell cycles required for the modeling. However, it is known that CFU-s self-renewal undergoes decline with proliferation. In the present study, this was taken into consideration, such that p was forced to undergo a small decline with each cell division. These new Monte Carlo calculations give an improved fit to CFU-s cumulative growth curves as compared with those calculations using fixed p. This new model, referred to as the variable p model, offers an explanation as to how large mammals can amplify marrow output from stem cell compartments that are no larger than those found in small mammals. It is a model in which small changes in active stem cell aging generate disproportionally large increases in the size of active stem cell clones.

Marrow frequency of rat long-term repopulating cells: evidence that marrow hematopoietic stem cell concentration may be inversely proportional to species body weight.

As measured by the long-term repopulating cell (LTRC) assay, only a few hematopoietic stem cells (HSCs) or perhaps a single HSC are required to totally repopulate the lymphohematopoietic tissues of lethally irradiated mice, cats, and humans, raising the question as to why large mammals require more marrow cells to either rescue them from lethal irradiation or establish a long-term hematopoietic graft than do small mammals. An explanation might be that HSC marrow frequency across species is not constant, but decreases as species body weight increases. This hypothesis was tested by comparing the LTRC marrow concentration of mice to that of rats. Specifically, histocompatible AKR/J Thy 1.1 marrow was transferred to 7-Gy irradiated C3H/HeN, Thy 1.2 mice, and histocompatible Norway Black marrow (NBr), RT 7.2 marrow was transferred to 7-Gy irradiated RT 7.1 Lewis rats. The recipients were scored for successful grafts 6 to 20 weeks later. By limiting dilution analysis, a value of 1 LTRC/47 700 marrow cells was calculated for mice, but only 1 LTRC/502,000 marrow cells was calculated for rats. Viewed in the context of marrow grafting in larger mammals, these results suggest that species with greater body mass have lower marrow HSC frequency.