Biomaterials Research (생체재료학회지)

Korean Society for Biomaterials (한국생체재료학회)
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Multiple genetically engineered humanized microenvironments in a single mouse

  • Lee, Jungwoo (Department of Surgery, Center for Engineering in Medicine, Massachusetts General Hospital & Harvard Medical School and Shriners Hospital for Children) ;
  • Heckl, Dirk (Department of Medicine, Brigham and Women's Hospital) ;
  • Parekkadan, Biju (Department of Surgery, Center for Engineering in Medicine, Massachusetts General Hospital & Harvard Medical School and Shriners Hospital for Children)
  • Received : 2016.02.10
  • Accepted : 2016.06.13
  • Published : 2016.09.01
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Abstract

Background: Immunodeficient mouse models that accept human cell and tissue grafts can contribute greater knowledge to human stem cell research. In this technical report, we used biomaterial implants seeded with genetically engineered stromal cells to create several unique microenvironments in a single mouse. The scope of study was focused on human CD34 hematopoietic stem/progenitor cell (HSPC) engraftment and differentiation within the engineered microenvironment. Results: A mouse model system was created using subdermal implant sites that overexpressed a specific human cytokines (Vascular Endothelial Growth Factor A (hVEGFa), Stromal Derived Factor 1 Alpha (hSDF1a), or Tumor Necrosis Factor Alpha (hTNFa)) by stromal cells in a three-dimensional biomaterial matrix. The systemic exposure of locally overexpressed cytokines was minimized by controlling the growth of stromal cells, which led to autonomous local, concentrated sites in a single mouse for study. This biomaterial implant approach allowed for the local analysis of each cytokine on hematopoietic stem cell recruitment, engraftment and differentiation in four different tissue microenvironments in the same host. The engineered factors were validated to have bioactive effects on human CD34+ hematopoietic progenitor cell differentiation. Conclusions: This model system can serve as a new platform for the study of multiple human proteins and their local effects on hematopoietic cell biology for in vivo validation studies.

Keywords

Acknowledgement

Supported by : NIH

References

  1. Bosma GC, Custer RP, Bosma MJ. A severe combined immunodeficiency mutation in the mouse. Nature. 1983;301(5900):527-30. https://doi.org/10.1038/301527a0
  2. Shultz LD, Ishikawa F, Greiner DL. Humanized mice in translational biomedical research. Nat Rev Immunol. 2007;7(2):118-30. https://doi.org/10.1038/nri2017
  3. Ito M et al. NOD/SCID/gamma(c)(null) mouse: an excellent recipient mouse model for engraftment of human cells. Blood. 2002;100(9):3175-82. https://doi.org/10.1182/blood-2001-12-0207
  4. Legrand N et al. Humanized mice for modeling human infectious disease: challenges, progress, and outlook. Cell Host Microbe. 2009;6(1):5-9. https://doi.org/10.1016/j.chom.2009.06.006
  5. Morton CL, Houghton PJ. Establishment of human tumor xenografts in immunodeficient mice. Nat Protoc. 2007;2(2):247-50. https://doi.org/10.1038/nprot.2007.25
  6. Quintana E et al. Efficient tumour formation by single human melanoma cells. Nature. 2008;456(7222):593-8. https://doi.org/10.1038/nature07567
  7. McCune JM et al. The SCID-hu mouse: murine model for the analysis of human hematolymphoid differentiation and function. Science. 1988;241(4873):1632-9. https://doi.org/10.1126/science.2971269
  8. Traggiai E et al. Development of a human adaptive immune system in cord blood cell-transplanted mice. Science. 2004;304(5667):104-7. https://doi.org/10.1126/science.1093933
  9. Doulatov S et al. Hematopoiesis: a human perspective. Cell Stem Cell. 2012;10(2):120-36. https://doi.org/10.1016/j.stem.2012.01.006
  10. Shultz LD et al. Humanized mice for immune system investigation: progress, promise and challenges. Nat Rev Immunol. 2012;12(11):786-98. https://doi.org/10.1038/nri3311
  11. Dao MA, Pepper KA, Nolta JA. Long-term cytokine production from engineered primary human stromal cells influences human hematopoiesis in an in vivo xenograft model. Stem Cells. 1997;15(6):443-54. https://doi.org/10.1002/stem.150443
  12. Lapidot T et al. Cytokine stimulation of multilineage hematopoiesis from immature human cells engrafted in SCID mice. Science. 1992;255(5048):1137-41. https://doi.org/10.1126/science.1372131
  13. O'Connell RM et al. Lentiviral vector delivery of human interleukin-7 (hIL-7) to human immune system (HIS) mice expands T lymphocyte populations. PLoS One. 2010;5(8):e12009. https://doi.org/10.1371/journal.pone.0012009
  14. Chen Q, Khoury M, Chen J. Expression of human cytokines dramatically improves reconstitution of specific human-blood lineage cells in humanized mice. Proc Natl Acad Sci U S A. 2009;106(51):21783-8. https://doi.org/10.1073/pnas.0912274106
  15. Covassin L et al. Human peripheral blood CD4 T cell-engrafted non-obese diabetic-scid IL2rgamma(null) H2-Ab1 (tm1Gru) Tg (human leucocyte antigen D-related 4) mice: a mouse model of human allogeneic graft-versus-host disease. Clin Exp Immunol. 2011;166(2):269-80. https://doi.org/10.1111/j.1365-2249.2011.04462.x
  16. Billerbeck E et al. Development of human CD4+FoxP3+ regulatory T cells in human stem cell factor-, granulocyte-macrophage colony-stimulating factor-, and interleukin-3-expressing NOD-SCID IL2Rgamma(null) humanized mice. Blood. 2011;117(11):3076-86. https://doi.org/10.1182/blood-2010-08-301507
  17. Muguruma Y et al. Reconstitution of the functional human hematopoietic microenvironment derived from human mesenchymal stem cells in the murine bone marrow compartment. Blood. 2006;107(5):1878-87. https://doi.org/10.1182/blood-2005-06-2211
  18. Melkus MW et al. Humanized mice mount specific adaptive and innate immune responses to EBV and TSST-1. Nat Med. 2006;12(11):1316-22. https://doi.org/10.1038/nm1431
  19. Parekkadan B et al. Mesenchymal stem cell-derived molecules reverse fulminant hepatic failure. PLoS One. 2007;2(9):e941. https://doi.org/10.1371/journal.pone.0000941
  20. Lee J et al. Implantable microenvironments to attract hematopoietic stem/cancer cells. Proc Natl Acad Sci U S A. 2012;109(48):19638-43. https://doi.org/10.1073/pnas.1208384109
  21. Bersani F et al. Bioengineered implantable scaffolds as a tool to study stromalderived factors in metastatic cancer models. Cancer Res. 2014;74(24):7229-38. https://doi.org/10.1158/0008-5472.CAN-14-1809
  22. Adams GB, Scadden DT. The hematopoietic stem cell in its place. Nat Immunol. 2006;7(4):333-7. https://doi.org/10.1038/ni1331
  23. Wilson A, Trumpp A. Bone-marrow haematopoietic-stem-cell niches. Nat Rev Immunol. 2006;6(2):93-106. https://doi.org/10.1038/nri1779
  24. Zhang CC, Lodish HF. Cytokines regulating hematopoietic stem cell function. Curr Opin Hematol. 2008;15(4):307-11. https://doi.org/10.1097/MOH.0b013e3283007db5
  25. Lapidot T, Kollet O. The essential roles of the chemokine SDF-1 and its receptor CXCR4 in human stem cell homing and repopulation of transplanted immunedeficient NOD/SCID and NOD/SCID/B2m(null) mice. Leukemia. 2002;16(10):1992-2003. https://doi.org/10.1038/sj.leu.2402684
  26. Lataillade JJ et al. Stromal cell-derived factor 1 regulates primitive hematopoiesis by suppressing apoptosis and by promoting G(0)/G(1) transition in CD34(+) cells: evidence for an autocrine/paracrine mechanism. Blood. 2002;99(4):1117-29. https://doi.org/10.1182/blood.V99.4.1117
  27. Peled A et al. Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4. Science. 1999;283(5403):845-8. https://doi.org/10.1126/science.283.5403.845
  28. Stellos K et al. Platelet-derived stromal cell-derived factor-1 regulates adhesion and promotes differentiation of human CD34+ cells to endothelial progenitor cells. Circulation. 2008;117(2):206-15. https://doi.org/10.1161/CIRCULATIONAHA.107.714691
  29. Ricks DM et al. Optimized lentiviral transduction of mouse bone marrowderived mesenchymal stem cells. Stem Cells Dev. 2008;17(3):441-50. https://doi.org/10.1089/scd.2007.0194
  30. Zhang YS et al. Optical-resolution photoacoustic microscopy for volumetric and spectral analysis of histological and immunochemical samples. Angew Chem. 2014;53(31):8099-103. https://doi.org/10.1002/anie.201403812
  31. Gerber HP et al. VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism. Nature. 2002;417(6892):954-8. https://doi.org/10.1038/nature00821
  32. Ziegler BL et al. KDR receptor: a key marker defining hematopoietic stem cells. Science. 1999;285(5433):1553-8. https://doi.org/10.1126/science.285.5433.1553
  33. Dar A, Kollet O, Lapidot T. Mutual, reciprocal SDF-1/CXCR4 interactions between hematopoietic and bone marrow stromal cells regulate human stem cell migration and development in NOD/SCID chimeric mice. Exp Hematol. 2006;34(8):967-75. https://doi.org/10.1016/j.exphem.2006.04.002
  34. Hattori K, Heissig B, Rafii S. The regulation of hematopoietic stem cell and progenitor mobilization by chemokine SDF-1. Leuk Lymphoma. 2003;44(4):575-82. https://doi.org/10.1080/1042819021000037985
  35. Greenbaum A et al. CXCL12 in early mesenchymal progenitors is required for haematopoietic stem-cell maintenance. Nature. 2013;495(7440):227-30. https://doi.org/10.1038/nature11926
  36. Lu L et al. Effects of recombinant human tumor necrosis factor alpha, recombinant human gamma-interferon, and prostaglandin E on colony formation of human hematopoietic progenitor cells stimulated by natural human pluripotent colony-stimulating factor, pluripoietin alpha, and recombinant erythropoietin in serum-free cultures. Cancer Res. 1986;46(9):4357-61.
  37. Pronk CJ et al. Tumor necrosis factor restricts hematopoietic stem cell activity in mice: involvement of two distinct receptors. J Exp Med. 2011;208(8):1563-70. https://doi.org/10.1084/jem.20110752

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