Mathematical and experimental approaches to identify and predict the effects of chemotherapy on neuroglial precursors
Ollivier Hyrien1, Jörg Dietrich, Mark Noble
1Department of Biostatistics and Computational Biology, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA. Ollivier_Hyrien@urmc.rochester.edu
Unlabelled:
The adverse effects of chemotherapy on normal cells of the body create substantial clinical problems for many cancer patients. However, relatively little is known about the effects, other than promotion of cell death, of such agents on the function of normal precursor cells critical in tissue homeostasis and repair. We have combined mathematical and experimental analyses to identify the effects of sublethal doses of chemotherapy on glial precursor cells of the central nervous system. We modeled the temporal development of a population of precursor and terminally differentiated cells exposed to sublethal doses of carmustine (BCNU), a classic alkylating chemotherapeutic agent used in treatment of gliomas and non-Hodgkin's lymphomas, as a multitype age-dependent branching process. We fitted our model to data from in vitro clonal experiments using the method of pseudo-likelihood. This approach identifies several novel drug effects, including modification of the cell cycle length, the time between division and differentiation, and alteration in the probability of undergoing self-renewal division in precursor cells. These changes of precursor cell function in the chemotherapy-exposed brain may have profound clinic implications.
Major Findings:
We applied our computational approach to analyze the effects of BCNU on clonal cultures of oligodendrocyte progenitor cells-one of the best-characterized neural progenitor cells in the mammalian brain. Our analysis reveals that transient exposures to BCNU increased the cell cycle length of progenitor cells and decreased their time to differentiation, while also decreasing the likelihood that they will undergo self-renewing divisions. By investigating the behavior of our mathematical model, we demonstrate that precursor cell populations should recover spontaneously from transient modifications of the timing of division and of differentiation, but such recovery will not happen after alteration of cell fate. These studies identify means by which precursor cell function can be critically compromised by transient exposure to chemotherapy with long-term consequences on the progenitor cell pool even in the absence of drug-induced apoptosis. These analyses also provide novel tools that apply broadly to identify effects of chemotherapeutic agents and other physiological stressors.
Insights
Sublethal chemotherapy doses alter brain precursor cell function, affecting cell cycle and differentiation. These changes compromise tissue repair and may have long-term clinical implications, even without cell death.
Area of Science:
- Neuroscience
- Cancer Biology
- Computational Biology
Background:
- Chemotherapy's adverse effects on normal cells pose clinical challenges.
- Limited understanding exists regarding chemotherapy's impact on normal precursor cell function beyond cell death.
- Precursor cells are crucial for tissue homeostasis and repair.
Purpose of the Study:
- To investigate the effects of sublethal chemotherapy doses on central nervous system glial precursor cells.
- To identify novel drug effects on precursor cell function using mathematical and experimental analyses.
Main Methods:
- Developed a multitype age-dependent branching process model for precursor and differentiated cells.
- Exposed oligodendrocyte progenitor cells to sublethal doses of carmustine (BCNU).
- Fitted the model to in vitro clonal experimental data using pseudo-likelihood estimation.
Main Results:
- Transient carmustine (BCNU) exposure increased progenitor cell cycle length and decreased differentiation time.
- BCNU decreased the probability of self-renewing divisions in precursor cells.
- Mathematical modeling indicated spontaneous recovery from timing modifications but not from cell fate alterations.
Conclusions:
- Sublethal chemotherapy can compromise precursor cell function, impacting the progenitor cell pool long-term, independent of apoptosis.
- Altered cell cycle, differentiation timing, and self-renewal probability are key drug effects.
- The developed computational tools can broadly identify effects of chemotherapeutic agents and other stressors.
