Mechanisms of blood homeostasis: lineage tracking and a neutral model of cell populations in rhesus macaques.
BACKGROUND
How a potentially diverse population of hematopoietic stem cells (HSCs) differentiates and proliferates to supply more than 10(11) mature blood cells every day in humans remains a key biological question. We investigated this process by quantitatively analyzing the clonal structure of peripheral blood that is generated by a population of transplanted lentivirus-marked HSCs in myeloablated rhesus macaques. Each transplanted HSC generates a clonal lineage of cells in the peripheral blood that is then detected and quantified through deep sequencing of the viral vector integration sites (VIS) common within each lineage. This approach allowed us to observe, over a period of 4-12 years, hundreds of distinct clonal lineages.


RESULTS
While the distinct clone sizes varied by three orders of magnitude, we found that collectively, they form a steady-state clone size-distribution with a distinctive shape. Steady-state solutions of our model show that the predicted clone size-distribution is sensitive to only two combinations of parameters. By fitting the measured clone size-distributions to our mechanistic model, we estimate both the effective HSC differentiation rate and the number of active HSCs.


CONCLUSIONS
Our concise mathematical model shows how slow HSC differentiation followed by fast progenitor growth can be responsible for the observed broad clone size-distribution. Although all cells are assumed to be statistically identical, analogous to a neutral theory for the different clone lineages, our mathematical approach captures the intrinsic variability in the times to HSC differentiation after transplantation.
Department of Physics, University of Toronto, St George Campus, Toronto, Canada.
Sidhartha
S
Goyal
Department of Microbiology, Immunology, and Molecular Genetics, UCLA, Los Angeles, USA.
Sanggu
S
Kim
Department of Microbiology, Immunology, and Molecular Genetics, UCLA, Los Angeles, USA.|UCLA AIDS Institute and Department of Medicine, UCLA, Los Angeles, USA.
Irvin S Y
IS
Chen
Departments of Biomathematics and Mathematics, UCLA, Los Angeles, USA. tomchou@ucla.edu.
Tom
T
Chou
D000818:Animals; D001773:Blood Cells / Q000166:cytology / Q000502:physiology*; D002454:Cell Differentiation; D019070:Cell Lineage; D002999:Clone Cells / Q000166:cytology / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology*; D006706:Homeostasis; D008253:Macaca mulatta / Q000097:blood*; D008954:Models, Biological