Modelling of the SDF-1/CXCR4 regulated homing of therapeutic mesenchymal stem/stromal cells in mice.
Wang Jin, Xiaowen Liang, Anastasia Brooks, Kathryn Futrega, Xin Liu, Michael R Doran, Matthew J Simpson, Michael S Roberts, Haolu Wang
Author Information
Wang Jin: School of Mathematical Sciences, Queensland University of Technology, Brisbane, Australia.
Xiaowen Liang: Therapeutics Research Centre, The University of Queensland Diamantina Institute, University of Queensland, Translational Research Institute, Brisbane, Australia.
Anastasia Brooks: Therapeutics Research Centre, The University of Queensland Diamantina Institute, University of Queensland, Translational Research Institute, Brisbane, Australia.
Kathryn Futrega: Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Brisbane, Australia.
Xin Liu: Therapeutics Research Centre, The University of Queensland Diamantina Institute, University of Queensland, Translational Research Institute, Brisbane, Australia.
Michael R Doran: Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Brisbane, Australia.
Matthew J Simpson: School of Mathematical Sciences, Queensland University of Technology, Brisbane, Australia.
Michael S Roberts: Therapeutics Research Centre, The University of Queensland Diamantina Institute, University of Queensland, Translational Research Institute, Brisbane, Australia.
Haolu Wang: Therapeutics Research Centre, The University of Queensland Diamantina Institute, University of Queensland, Translational Research Institute, Brisbane, Australia.
BACKGROUND: Mesenchymal stem/stromal cells (MSCs) are a promising tool for cell-based therapies in the treatment of tissue injury. The stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) axis plays a significant role in directing MSC homing to sites of injury. However MSC distribution following intravenous transplantation remains poorly understood, potentially hampering the precise prediction and evaluation of therapeutic efficacy. METHODS: A murine model of partial ischemia/reperfusion (I/R) is used to induce liver injury, increase the hepatic levels of SDF-1, and study MSC distribution. Hypoxia-preconditioning increases the expression of CXCR4 in human bone marrow-derived MSCs. Quantitative assays for human DNA using droplet digital PCR (ddPCR) allow us to examine the kinetics of intravenously infused human MSCs in mouse blood and liver. A mathematical model-based system is developed to characterize homing of human MSCs in mouse models with SDF-1 levels in liver and CXCR4 expression on the transfused MSCs. The model is calibrated to experimental data to provide novel estimates of relevant parameter values. RESULTS: Images of immunohistochemistry for SDF-1 in the mouse liver with I/R injury show a significantly higher SDF-1 level in the I/R injured liver than that in the control. Correspondingly, the ddPCR results illustrate a higher MSC concentration in the I/R injured liver than the normal liver. CXCR4 is overexpressed in hypoxia-preconditioned MSCs. An increased number of hypoxia-preconditioned MSCs in the I/R injured liver is observed from the ddPCR results. The model simulations align with the experimental data of control and hypoxia-preconditioned human MSC distribution in normal and injured mouse livers, and accurately predict the experimental outcomes with different MSC doses. DISCUSSION: The modelling results suggest that SDF-1 in organs is an effective attractant for MSCs through the SDF-1/CXCR4 axis and reveal the significance of the SDF-1/CXCR4 chemotaxis on homing of MSCs. This modelling approach allows qualitative characterization and prediction of the MSC homing to normal and injured organs on the basis of clinically accessible variables, such as the MSC dose and SDF-1 concentration in blood. This model could also be adapted to abnormal conditions and/or other types of circulating cells to predict homing patterns.
