Nongenetic origins of cell-to-cell variability in B lymphocyte proliferation

Mitchell, Simon, Roy, Koushik, Zangle, Thomas A and Hoffmann, Alexander (2018) Nongenetic origins of cell-to-cell variability in B lymphocyte proliferation. Proceedings of the National Academy of Sciences, 115 (12). E2888-E2897. ISSN 0027-8424

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Abstract

Rapid antibody production in response to invading pathogens requires the dramatic expansion of pathogen-derived antigen-specific B-lymphocyte populations. Whether B-cell population dynamics are based on stochastic competition between competing cell fates, as in the development of competence by the bacterium Bacillus subtilis, or on deterministic cell fate decisions that execute a predictable program, as during the development of the worm Caenorhabditis elegans, remains unclear. Here, we developed long term live-cell microscopy of B-cell population expansion and multi-scale mechanistic computational modeling in order to characterize the role of molecular noise in determining phenotype heterogeneity. We show that the cell lineage trees underlying B-cell population dynamics are mediated by a largely predictable decision-making process where the heterogeneity of cell fates at any given timepoint largely derives from non-genetic heterogeneity in the founder cells. This means that contrary to previous models only a minority of genetically identical founder cells contribute the majority to the population response. We computationally predict and experimentally confirm non- genetic molecular determinants that are predictive of founder cells’ proliferative capacity. While founder cell heterogeneity may arise from different exposure histories, we show that it may also be due to the gradual accumulation of small amounts of intrinsic noise during the lineage differentiation process of hematopoietic stem cells to mature B cells. Our finding of the largely deterministic nature of B-lymphocyte responses may provide opportunities for diagnostic and therapeutic development.

Item Type: Article
Keywords: B Cells, Variability, Heterogeneity, Systems Biology, Proliferation, Lymphocytes
Schools and Departments: Brighton and Sussex Medical School > Clinical and Experimental Medicine
Subjects: R Medicine
Depositing User: Gemma Hamilton
Date Deposited: 17 Jun 2019 09:56
Last Modified: 02 Oct 2019 17:36
URI: http://sro.sussex.ac.uk/id/eprint/84322

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