An age-dependent branching process model for the analysis of CFSE-labeling experiments.
BACKGROUND
Over the past decade, flow cytometric CFSE-labeling experiments have gained considerable popularity among experimentalists, especially immunologists and hematologists, for studying the processes of cell proliferation and cell death. Several mathematical models have been presented in the literature to describe cell kinetics during these experiments.


RESULTS
We propose a multi-type age-dependent branching process to model the temporal development of populations of cells subject to division and death during CFSE-labeling experiments. We discuss practical implementation of the proposed model; we investigate a competing risk version of the process; and we identify the classes of cellular dependencies that may influence the expectation of the process and those that do not. An application is presented where we study the proliferation of human CD8+ T lymphocytes using our model and a competing risk branching process.


CONCLUSIONS
The proposed model offers a widely applicable approach to the analysis of CFSE-labeling experiments. The model fitted very well our experimental data. It provided reasonable estimates of cell kinetics parameters as well as meaningful insights into the processes of cell division and cell death. In contrast, the competing risk branching process could not describe the kinetics of CD8+ T cells. This suggested that the decision of cell division or cell death may be made early in the cell cycle if not in preceding generations. Also, we show that analyses based on the proposed model are robust with respect to cross-sectional dependencies and to dependencies between fates of linearly filiated cells.


METHODS
This article was reviewed by Marek Kimmel, Wai-Yuan Tan and Peter Olofsson.
Hyrien
Ollivier
O
Department of Biostatistics & Computational Biology, University of Rochester Medical Center, Rochester, NY 14642, USA. Ollivier_Hyrien@urmc.rochester.edu
Chen
Rui
R
Zand
Martin S
MS
D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D049109:Cell Proliferation; D005434:Flow Cytometry / Q000379:methods*; D005452:Fluoresceins / Q000737:chemistry*; D006801:Humans; D008962:Models, Theoretical; D013388:Succinimides / Q000737:chemistry*
C087165:5-(6)-carboxyfluorescein diacetate succinimidyl ester; D005452:Fluoresceins; D013388:Succinimides