Modelling of the SDF-1/CXCR4 regulated in vivo 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

doi:10.7287/peerj.preprints.27144v1

Modelling of the SDF-1/CXCR4 regulated in vivo homing of therapeutic mesenchymal stem/stromal cells in mice

Wang Jin¹, Xiaowen Liang², Anastasia Brooks², Kathryn Futrega³, Xin Liu², Michael R. Doran^3,4,5, Matthew J. Simpson¹, Michael S. Roberts ^2,6, Haolu Wang ²

1 School of Mathematical Sciences, Queensland University of Technology, Brisbane, Australia

2 Therapeutics Research Centre, The University of Queensland Diamantina Institute, University of Queensland, Translational Research Institute, Brisbane, Australia

3 Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Brisbane, Australia

4 Mater Research Institute, University of Queensland, Translational Research Institute, Brisbane, Australia

5 Australian National Centre for the Public Awareness of Science, Australian National University, Canberra, Australia

6 School of Pharmacy and Medical Science, University of South Australia, Adelaide, Australia

DOI: 10.7287/peerj.preprints.27144v1

Published: 2018-08-27
Accepted: 2018-08-27

Subject Areas: Cell Biology, Mathematical Biology, Drugs and Devices
Keywords: Mesenchymal stem cells, Stem cell transplantation, Chemotaxis, Mathematical modelling, In vivo homing

Copyright: © 2018 Jin et al.
Licence: This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ Preprints) and either DOI or URL of the article must be cited.

Cite this article: Jin W, Liang X, Brooks A, Futrega K, Liu X, Doran MR, Simpson MJ, Roberts MS, Wang H. 2018. Modelling of the SDF-1/CXCR4 regulated in vivo homing of therapeutic mesenchymal stem/stromal cells in mice. PeerJ Preprints 6:e27144v1 https://doi.org/10.7287/peerj.preprints.27144v1

Abstract

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 in vivo 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 in vivo MSC distribution. Hypoxia-preconditioning increases the expression of CXCR4 in human bone marrow-derived MSCs. Quantitative assays for human DNA allow us to examine the in vivo kinetics of intravenously infused human MSCs in mouse blood and liver. A mathematical model-based system is developed to characterize in vivo 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-1level in the I/R injured liver than that in the control. Correspondingly, the ELISA results illustrate a higher MSC dose 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 ELISA 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 in vivo attractant for MSCs through the SDF-1/CXCR4 axis and reveals the significance of the SDF-1/CXCR4 chemotaxis on in vivo homing of MSCs, especially under hypoxic preconditioning. The impact of the liver and MSC conditions on passive homing is small. This in vivo 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 in vivo homing patterns.