Modeling and Clonal Analysis of Stem Cell-Mediated Blood Repopulation

Professor Tom Chou
Biomath, UCLA


ABSTRACT

How an individual hematopoietic stem cell (HSC) proliferates and differentiates to supply functioning blood cells in a living organism is a key biological question that is challenging to study quantitatively. To address this question, we study the polyclonal structure of differentiated blood cells in myeloablated rhesus macaques that have undergone lentivirus-marked hematopoietic stem cell transplantation (HSCT). Each transplanted HSC is distinctly marked and ultimately generates a clonal lineage of cells in the peripheral blood that is detected and quantified through sequencing of unique viral integration sites (VIS). The numbers of peripheral blood cells making up the different detected clones can vary by three orders of magnitude. Together, the sizes of all the distinct clonal lineages in each of the animals form a distribution that has a distinctive shape. After normalizing and rescaling measured clone sizes in each animal, we show that the resulting clone size-distribution becomes stationary a few months after transplantation. To better understand the observed stationarity and shape of the rescaled clone size-distributions, we develop a mathematical model describing the evolution of clone populations and show that the observations can arise simply from the intrinsic stochasticity of the hematopoietic system. By fitting measured clone size-distributions to our model, we estimate that upwards of a few thousand HSCs may be actively contributing toward blood regeneration at any time. Our model and analysis combines features consistent with notions of both clonal stability and sequential order in hematopoiesis.