Abstract
Current in vivo models for investigating human primary bone tumors and cancer metastasis to the bone rely on the injection of human cancer cells into the mouse skeleton. This approach does not mimic species-specific mechanisms occurring in human diseases and may preclude successful clinical translation. We have developed a protocol to engineer humanized bone within immunodeficient hosts, which can be adapted to study the interactions between human cancer cells and a humanized bone microenvironment in vivo. A researcher trained in the principles of tissue engineering will be able to execute the protocol and yield study results within 4–6 months. Additive biomanufactured scaffolds seeded and cultured with human bone-forming cells are implanted ectopically in combination with osteogenic factors into mice to generate a physiological bone 'organ', which is partially humanized. The model comprises human bone cells and secreted extracellular matrix (ECM); however, other components of the engineered tissue, such as the vasculature, are of murine origin. The model can be further humanized through the engraftment of human hematopoietic stem cells (HSCs) that can lead to human hematopoiesis within the murine host. The humanized organ bone model has been well characterized and validated and allows dissection of some of the mechanisms of the bone metastatic processes in prostate and breast cancer.
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Acknowledgements
This work was supported by the Australian Research Council (Future Fellowship awarded to D.W.H.), the National Health and Medical Research Council (NHMRC Research Fellowship 1044091 to J.-P.L.; NHMRC Project Grant 1082313 to B.M.H., J.-P.L. and D.W.H.), the German Research Foundation (DFG HO 5068/1-1 to B.M.H., B.M.H. and DFG WA 3606/1-1 to F.W.), the National Breast Cancer Foundation (NBCF IN-15-047 to B.M.H. and D.W.H.) and a grant from Worldwide Cancer Research (WWCR 15-11563 to D.W.H.). We thank O. Ramuz, C. Theodoropoulos and J. Baldwin for their help and scientific input. Fibrin glue (TISSEEL Fibrin Sealant) was kindly provided by Baxter Healthcare International. The fibronectin (HFN 7.1) and osteonectin (AON-1) antibodies, developed by R.J. Klebe and J.D. Termine, respectively, were obtained from the Developmental Studies Hybridoma Bank, created by the National Institute of Child Health and Human Development of the National Institutes of Health, and were maintained at the University of Iowa Department of Biology.
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L.C.M., B.M.H., A.V.T., J.-P.L., P.Z., R.M. and D.W.H. conceived and designed the experiments. L.C.M., B.M.H., F.W., D.M., D.J.W., C.O.H., T.O., E.P., J.A.M. and B.N. performed the experiments and analyzed the data. L.C.M. wrote the manuscript with the assistance of B.M.H., C.V., E.M.D.-J.-P., F.M.W., J.-P.L., J.A.M. and R.M. C.V. established the CaP coating procedure. T.D.B., P.D.D. and D.W.H. designed and built the custom-made melt electrospinning machine. E.M.D.-J.-P., D.W.H. and F.M.W. developed the scaffold design and fabrication. V.M.Q., P.H. and A.V.T. conducted the first studies to establish the hTEBC model. D.W.H., A.V.T., B.M.H. and L.C.M. supervised the project. All authors read and critiqued the manuscript extensively.
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Supplementary Figure 1 Long term engraftment and multi-lineage reconstitution in mouse PB.
Flow cytometry gating strategy for hCD45+, hCD34+, CD19+, CD3+ and CD33+ cells. Cells were gated on living cells before cell doublets were excluded. Data was gated on all hCD45+ and mCD45+ cells were to account for hematopoietic lineages before sub-lineage populations were determined. Mouse peripheral blood (PB) and fluorescence minus one (FMO) controls from mice injected with 10,000 CD34+ cord blood cells (16 weeks) and implanted with hTEBC were used as examples of the flow cytometry gating strategy.
Supplementary Figure 2 Long term engraftment and multi-lineage reconstitution in mouse spleen.
Flow cytometry gating strategy for hCD45+, hCD34+, CD19+, CD3+ and CD33+ cells. Cells were gated on living cells before cell doublets were excluded. Data was gated on all hCD45+ and mCD45+ cells were to account for hematopoietic lineages before sub-lineage populations were determined. Cells isolated from mouse spleens and fluorescence minus one (FMO) controls from mice injected with 10,000 hCD34+ cord blood cells (16 weeks) and implanted with hTEBC were used as examples of the flow cytometry gating strategy.
Supplementary Figure 3 Long term engraftment and multi-lineage reconstitution in mouse femur.
Flow cytometry gating strategy for hCD45+, hCD34+, CD19+, CD3+ and CD33+ cells. Cells were gated on living cells before cell doublets were excluded. Data was gated on all hCD45+ and mCD45+ cells were to account for hematopoietic lineages before sub-lineage populations were determined. Analysis of bone marrow from mouse femurs (mBone) and fluorescence minus one (FMO) controls from mice injected with 10,000 hCD34+ cord blood cells (16 weeks) and implanted with hTEBC were used as examples of the flow cytometry gating strategy.
Supplementary Figure 4 Long term engraftment and multi-lineage reconstitution in hTEBC
Flow cytometry gating strategy for hCD45+, hCD34+, CD19+, CD3+ and CD33+ cells. Cells were gated on living cells before cell doublets were excluded. Data was gated on all hCD45+ and mCD45+ cells were to account for hematopoietic lineages before sub-lineage populations were determined. Analysis of bone marrow from the hTEBC and fluorescence minus one (FMO) controls from mice injected with 10,000 hCD34+ cord blood cells (16 weeks) and implanted with hTEBC were used as examples of the flow cytometry gating strategy. Note that the FMO controls are the same as used in Supplementary Figure 3.
Supplementary Figure 5 Multi-lineage reconstitution in mice peripheral blood and organs following hCD34+ cell engraftment
Mice were engrafted with either (a, c) 10,000 or (b, d) 50,000 hCD34+ cord blood cells. Flow cytometry analysis was performed and gated on the total population of mCD45+ and hCD45+ cells to detect (a, b) the time course of the relative hCD19+, hCD3+ and hCD33+ cell engraftment in mouse PB. (c, d) The organ distribution and engraftment of hCD19+, hCD3+ and hCD33+ cells within the total population of mCD45+ and hCD45+ cells at the experimental endpoint (16-24 weeks). Data is represented as mean ± s.e.m, n=3 for mice without a hTEBC and n=4 for mice with a hTEBC.
Supplementary Figure 6 Engraftment and multi-lineage reconstitution of mouse femur and hTEBC.
Flow cytometry gating strategy for hCD45+, hCD34+, hCD38+, hCD3+, hCD19+ and CD11b+ following engraftment with adult bone-derived hCD34+ cells. Analysis of bone marrow isolated from (a) mouse femur and (b) hTEBC from mice 5 weeks after injection with 2 × 105 hCD34+ cells.
Supplementary Figure 7 Controls for species-specificity of antibodies used for immunohistochemical analysis.
Human and mouse tissues were used to serve respectively as positive and negative controls to test the human-specificity of antibodies against human NuMA, lamin A/C, mitochondria, collagen type I, osteocalcin, CD146, CD45 and CD34. Details of antigen retrieval methods, antibody suppliers and antibody dilutions can be found in Supplementary Table 1.
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Martine, L., Holzapfel, B., McGovern, J. et al. Engineering a humanized bone organ model in mice to study bone metastases. Nat Protoc 12, 639–663 (2017). https://doi.org/10.1038/nprot.2017.002
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DOI: https://doi.org/10.1038/nprot.2017.002
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