Mapping clone extinction and resurrection to intermittent hematopoietic stem cell differentiation: Analysis of a decade-long clone tracking study in rhesus macaque*

Recently, virally tagged hematopoietic stem cells (HSCs) were autologously transplanted into rhesus macaques and peripheral blood cells were sampled and sequenced over 14 years to quantify the proliferation of each viral tag. Through mathematical modeling and statistical analysis of the data, we develop a simple mechanistic picture of hematopoiesis of tagged cells. We show that HSC self-renewal in the bone marrow leads to heterogeneity in clone sizes, which can ultimately lead to the heterogeneity seen in clone sizes observed in the peripheral blood. The magnitude of the temporal variations of clone abundances in the sampled blood is controlled by intermittent HSC differentiation, described by a Poisson process. Experimental data are analyzed using a new statistic that is insensitive to the unknown underlying HSC clone heterogeneity, from which least-squares estimates of key parameters in our model were inferred.