Mathematical modelling of interacting mechanisms for hypoxia mediated cell cycle commitment for mesenchymal stromal cells

Abstract

BackgroundExisting experimental data have shown hypoxia to be an important factor affecting the proliferation of mesenchymal stromal cells (MSCs), but the contrasting observations made at various hypoxic levels raise the questions of whether hypoxia accelerates proliferation, and how. On the other hand, in order to meet the increasing demand of MSCs, an optimised bioreactor control strategy is needed to enhance in vitro production.ResultsA comprehensive, single-cell mathematical model has been constructed in this work, which combines cellular oxygen sensing with hypoxia-mediated cell cycle progression to predict cell cycle commitment as a proxy to proliferation rate. With oxygen levels defined for in vitro cell culture, the model predicts enhanced proliferation under intermediate (2–8%) and mild (8–15%) hypoxia and cell quiescence under severe (< 2%) hypoxia. Global sensitivity analysis and quasi-Monte Carlo simulation revealed that within a certain range (+/− 100%), model parameters affect (with varying significance) the minimum commitment time, but the existence of a range of optimal oxygen tension could be preserved with the hypothesized effects of Hif2α and reactive oxygen species (ROS). It appears that Hif2α counteracts Hif1α and ROS-mediated protein deactivation under intermediate hypoxia and normoxia (20%), respectively, to regulate the response of cell cycle commitment to oxygen tension.ConclusionOverall, this modelling study offered an integrative framework to capture several interacting mechanisms and allowed in silico analysis of their individual and collective roles in shaping the hypoxia-mediated commitment to cell cycle. The model offers a starting point to the establishment of a suitable mechanism that can satisfactorily explain the different existing experimental observations from different studies, and warrants future extension and dedicated experimental validation to eventually support bioreactor optimisation.Electronic supplementary materialThe online version of this article (10.1186/s12918-018-0560-3) contains supplementary material, which is available to authorized users.

Interleukin-15 Signaling in HIF-1α Regulation in Natural Killer Cells, Insights Through Mathematical Models

“…We hypothesize that the proposed regulatory network is appropriate for describing HIF-1α regulation not only in NK cells but also in other types of immune cells. Moreover, the model (2)–(11) can be applied to refine and extend mathematical models in which HIF-1α dynamics is involved, e.g., models of cell cycle regulation (75) or cell proliferation (76). When studying the effects of biochemical signaling at the cellular level, it might be convenient to adopt simpler regulatory networks than those proposed here [see for example (77) for a model for proliferation of IL-15 stimulated NK cells].…”

Differential Oxygen Exposure Modulates Mesenchymal Stem Cell Metabolism and Proliferation through mTOR Signaling

“…Moderate hypoxia (3–5% O 2 ) has been consistently shown to stimulate MSC proliferation [ 7 , 9 ]. However, different O 2 levels can lead to distinct results in terms of MSC proliferation, differentiation capacity, and viability [ 11 ].…”

“…In recent years, hypoxia preconditioning has been acknowledged as an adequate priming technique to both enhance and preserve MSC bioactivity and biological identity, respectively [ 8 ]. Nevertheless, studies on hypoxia preconditioning predominantly show the effects of moderate hypoxia on MSC differentiation and expansion—with several authors reporting an increase in proliferation following hypoxic treatment [ 9 , 10 , 11 ]. However, severe hypoxia may have underlying advantages and might be key to promoting a hypo-proliferative state that safeguards the cell and guarantees its longevity.…”