Effects of Quiescence and Senescence on Hematopoietic Stem Cell Population Dynamics and Extinction

• Activity Number: 123
• Type: Contributed
• Date/Time: Monday, August 4, 2014 : 8:30 AM to 10:20 AM
• Sponsor: Section on Statistics in Epidemiology
• Author(s): Mary Sehl*+ and Hua Zhou and Han Su Myat and Trevor R. Shaddox and Sanggu Kim and Irvin S.Y. Chen and Janet S.Y. Sinsheimer and Kenneth L. Lange
• Companies: and North Carolina State University and University of California, Los Angeles and University of California, Los Angeles and University of California, Los Angeles and University of California, Los Angeles and University of California, Los Angeles and University of California, Los Angeles
• Keywords: branching process ; stem cell dynamics ; senescence ; quiescence ; extinction model

Abstract

Quantitative understanding of hematopoietic recovery after hematopoietic stem cell (HSC) transplantation is vital to predict clinical outcomes such as hematopoietic insufficiency and stem cell exhaustion. We explore the effects of quiescence and senescence on HSC population dynamics following transplantation. We study a multi-type branching process model in which an HSC freely interconverts between a primitive proliferative state and a quiescent state, and once transformed to a replicative state undergoes telomere shortening until reaching a final senescent state. We calculate extinction probabilities of a population of primitive HSCs as a function of birth and death rates, quiescence and activation rates, and the rate of transformation to a replicative state. We find that unless the birth rate of the most primitive HSC exceeds the sum of its death rate and the rate of transformation to a replicative state, the population of HSCs and its progeny are sure to go extinct. Using matrix exponentiation, we further compute mean counts of each cell type after transplantation and explore scenarios in which engraftment is successful depending on the initial distribution of HSC types.