EVIDENCE THAT HEMATOPOIESIS MAY BE A STOCHASTIC-PROCESS IN-VIVO

To study the behavior of hematopoietic stem cells in vivo, hematopoies is was simulated by assuming that all stem cell decisions (that is, re plication, apoptosis, initiation of a differentiation/maturation progr am) were determined by chance. Predicted outcomes from simulated exper iments were compared with data obtained in autologous marrow transplan tation studies of glucose 6-phosphate dehydrogenase (G6PD) heterozygou s female Safari cats. With this approach, we prove that stochastic dif ferentiation can result in the wide spectrum of discrete outcomes obse rved in vivo, and that clonal dominance can occur by chance. As the an alyses also suggest that the frequency of feline hematopoietic stem ce lls is only 6 per 10(7) nucleated marrow cells, and that stem cells do not replicate on average more frequently than once every three weeks, these large-animal data challenge clinical strategies for marrow tran splantation and gene therapy.