February 3, 2016

Speaker: Siddhartha Goyal, Department of Physics, University of Toronto
Title: Understanding clonal composition of repopulating blood
Abstract: How hematopoietic stem cells (HSCs) proliferate and differentiate to supply more than 10^11 mature blood cells every day in humans is a key biological question. While significant cell-to-cell variation is observed among different HSCs both in healthy and diseased individuals, what controls these variations remain an open question. To address this question, we quantitatively study the structure of mature blood in monkeys (rhesus macaques) over a period of 4-10 years, which is a significant fraction of their life span. Mature blood cell production from a large population of individual HSCs were tracked by sequencing lentiviral integration site (VIS) unique to each HSC. Deep sequencing allowed us to observe hundreds of distinct clonal lineages starting from individual HSC exhibiting a wide variation (~ 3 orders of magnitude) in their clone sizes. Surprisingly, the sizes of the distinct clonal lineages form a distribution that has a distinctive shape which remained stationary for years. Using a quantitative model we show that the distinctive shape of the clone size distribution and the wide variation may result from a combination of slow HSC differentiation followed by a burst of progenitor growth, both of which are generic features of HSC biology across different organisms. By fitting the measured clone size-distributions to our model, we estimate that only a few thousand HSCs may be actively contributing toward blood regeneration at any time. Our model combines features consistent with notions of both clonal stability and sequential order in hematopoiesis and may shed light on hematopoietic homeostasis more generally.