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Stromal cells and stem cells in clinical bone regeneration

Nature Reviews Endocrinology volume 11, pages 140–150 (2015)Cite this article

Subjects

Key Points

  • Stromal cells and/or stem cells can be isolated from different tissues on the basis of plastic adherence and surface-antigen profiles, thereby providing opportunities for bone regeneration

  • The regenerative potential of therapies that are based on adipose-tissue-derived and bone-marrow-derived mesenchymal stromal or stem cells is being tested clinically for the treatment of craniofacial bone defects, tibial non-unions and osteonecrosis of the femoral head

  • Although most approaches in this area use autologous cells, allogeneic sources that include commercially available allograft cell-based products are being investigated

  • Widespread use of cell-based products requires the development and standardization of guidelines and protocols for the shipment and storage of cell therapeutics

  • Despite strong clinical data, which indicates enhanced regenerative outcomes following stromal-cell or stem-cell transplantation, further insight is needed into the mechanisms of action of these strategies

  • Opportunities exist to develop technologies that improve cell survival, morphogenesis and functionality to advance cell therapy as standard care for the treatment of bone defects

Abstract

Stem-cell-mediated bone repair has been used in clinical trials for the regeneration of large craniomaxillofacial defects, to slow the process of bone degeneration in patients with osteonecrosis of the femoral head and for prophylactic treatment of distal tibial fractures. Successful regenerative outcomes in these investigations have provided a solid foundation for wider use of stromal cells in skeletal repair therapy. However, employing stromal cells to facilitate or enhance bone repair is far from being adopted into clinical practice. Scientific, technical, practical and regulatory obstacles prevent the widespread therapeutic use of stromal cells. Ironically, one of the major challenges lies in the limited understanding of the mechanisms via which transplanted cells mediate regeneration. Animal models have been used to provide insight, but these models largely fail to reproduce the nuances of human diseases and bone defects. Consequently, the development of targeted approaches to optimize cell-mediated outcomes is difficult. In this Review, we highlight the successes and challenges reported in several clinical trials that involved the use of bone-marrow-derived mesenchymal or adipose-tissue-derived stromal cells. We identify several obstacles blocking the mainstream use of stromal cells to enhance skeletal repair and highlight technological innovations or areas in which novel techniques might be particularly fruitful in continuing to advance the field of skeletal regenerative medicine.

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Figure 1: Generalized clinical approach for stem-cell-based regeneration of large craniofacial bone defects.

References

  1. Raggatt, L. J. et al. Fracture healing via periosteal callus formation requires macrophages for both initiation and progression of early endochondral ossification. Am. J. Pathol. 184, 3192–3204 (2014).

    Article  CAS  PubMed  Google Scholar 

  2. Das, A., Segar, C. E., Hughley, B. B., Bowers, D. T. & Botchwey, E. A. The promotion of mandibular defect healing by the targeting of S1P receptors and the recruitment of alternatively activated macrophages. Biomaterials 34, 9853–9862 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Kuroda, R. et al. Clinical impact of circulating CD34-positive cells on bone regeneration and healing. Tissue Eng. Part B Rev. 20, 190–199 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Hutton, D. L. & Grayson, W. L. Stem cell-based approaches to engineering vascularized bone. Curr. Opin. Chem. Eng. 3, 75–82 (2014).

    Article  Google Scholar 

  5. Neovius, E. & Engstrand, T. Craniofacial reconstruction with bone and biomaterials: review over the last 11 years. J. Plast. Reconstr. Aesthet. Surg. 63, 1615–1623 (2010).

    Article  PubMed  Google Scholar 

  6. Casserbette, M., Murray, A. B., Closs, E. I., Erfle, V. & Schmidt, J. Bone-formation by osteoblast-like cells in a 3-dimensional cell-culture. Calcif. Tissue Int. 46, 46–56 (1990).

    Article  CAS  Google Scholar 

  7. Dupont, K. M. et al. Human stem cell delivery for treatment of large segmental bone defects. Proc. Natl Acad. Sci. USA 107, 3305–3310 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Friedenstein, A. J. Precursor cells of mechanocytes. Int. Rev. Cytol. 47, 327–359 (1976).

    Article  CAS  PubMed  Google Scholar 

  9. Friedenstein, A. J. & Lalykina, K. S. Thymus cells are inducible to osteogenesis. Eur. J. Immunol. 2, 602–603 (1972).

    Article  CAS  PubMed  Google Scholar 

  10. Friedenstein, A. J., Petrakova, K. V., Kurolesova, A. I. & Frolova, G. P. Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation 6, 230–247 (1968).

    Article  CAS  PubMed  Google Scholar 

  11. Owen, M. & Friedenstein, A. J. Stromal stem cells: marrow-derived osteogenic precursors. Ciba Found. Symp. 136, 42–60 (1988).

    CAS  PubMed  Google Scholar 

  12. Ashton, B. A. et al. Formation of bone and cartilage by marrow stromal cells in diffusion chambers in vivo. Clin. Orthop. Relat. Res. 151, 294–307 (1980).

    Google Scholar 

  13. Allen, T. D. & Dexter, T. M. Cellular interrelationships during in vitro granulopoiesis. Differentiation 6, 191–194 (1976).

    Article  CAS  PubMed  Google Scholar 

  14. Dexter, T. M., Allen, T. D. & Lajtha, L. G. Conditions controlling the proliferation of haemopoietic stem cells in vitro. J. Cell. Physiol. 91, 335–344 (1977).

    Article  CAS  PubMed  Google Scholar 

  15. Lanotte, M., Scott, D., Dexter, T. M. & Allen, T. D. Clonal preadipocyte cell lines with different phenotypes derived from murine marrow stroma: factors influencing growth and adipogenesis in vitro. J. Cell. Physiol. 111, 177–186 (1982).

    Article  CAS  PubMed  Google Scholar 

  16. Hunt, P. et al. A single bone marrow-derived stromal cell type supports the in vitro growth of early lymphoid and myeloid cells. Cell 48, 997–1007 (1987).

    Article  CAS  PubMed  Google Scholar 

  17. Pietrangeli, C. E., Hayashi, S. & Kincade, P. W. Stromal cell lines which support lymphocyte growth: characterization, sensitivity to radiation and responsiveness to growth factors. Eur. J. Immunol. 18, 863–872 (1988).

    Article  CAS  PubMed  Google Scholar 

  18. Whitlock, C. A., Tidmarsh, G. F., Muller-Sieburg, C. & Weissman, I. L. Bone marrow stromal cell lines with lymphopoietic activity express high levels of a pre-B neoplasia-associated molecule. Cell 48, 1009–1021 (1987).

    Article  CAS  PubMed  Google Scholar 

  19. Namen, A. E. et al. Stimulation of B-cell progenitors by cloned murine interleukin-7. Nature 333, 571–573 (1988).

    Article  CAS  PubMed  Google Scholar 

  20. Lee, G., Namen, A. E., Gillis, S. & Kincade, P. W. Recombinant interleukin-7 supports the growth of normal B lymphocyte precursors. Curr. Top. Microbiol. Immunol. 141, 16–18 (1988).

    CAS  PubMed  Google Scholar 

  21. Paul, S. R. et al. Molecular cloning of a cDNA encoding interleukin 11, a stromal cell-derived lymphopoietic and hematopoietic cytokine. Proc. Natl Acad. Sci. USA 87, 7512–7516 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Caplan, A. I. Mesenchymal stem cells. J. Orthop. Res. 9, 641–650 (1991).

    Article  CAS  PubMed  Google Scholar 

  23. Wakitani, S., Saito, T. & Caplan, A. I. Myogenic cells derived from rat bone marrow mesenchymal stem cells exposed to 5-azacytidine. Muscle Nerve 18, 1417–1426 (1995).

    Article  CAS  PubMed  Google Scholar 

  24. Haynesworth, S. E., Baber, M. A. & Caplan, A. I. Cell surface antigens on human marrow-derived mesenchymal cells are detected by monoclonal antibodies. Bone 13, 69–80 (1992).

    Article  CAS  PubMed  Google Scholar 

  25. Simmons, P. J. & Torok-Storb, B. Identification of stromal cell precursors in human bone marrow by a novel monoclonal antibody, STRO-1. Blood 78, 55–62 (1991).

    CAS  PubMed  Google Scholar 

  26. Dominici, M. et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8, 315–317 (2006).

    Article  CAS  PubMed  Google Scholar 

  27. Mendicino, M., Bailey, A. M., Wonnacott, K., Puri, R. K. & Bauer, S. R. MSC-based product characterization for clinical trials: an FDA perspective. Cell Stem Cell 14, 141–145 (2014).

    Article  CAS  PubMed  Google Scholar 

  28. Lo Surdo, J. & Bauer, S. R. Quantitative approaches to detect donor and passage differences in adipogenic potential and clonogenicity in human bone marrow-derived mesenchymal stem cells. Tissue Eng. Part C Methods 18, 877–889 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Lo Surdo, J. L., Millis, B. A. & Bauer, S. R. Automated microscopy as a quantitative method to measure differences in adipogenic differentiation in preparations of human mesenchymal stromal cells. Cytotherapy 15, 1527–1540 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Mindaye, S. T., Ra, M., Lo Surdo, J., Bauer, S. R. & Alterman, M. A. Improved proteomic profiling of the cell surface of culture-expanded human bone marrow multipotent stromal cells. J. Proteomics 78, 1–14 (2013).

    Article  CAS  PubMed  Google Scholar 

  31. Mindaye, S. T., Ra, M., Lo Surdo, J. L., Bauer, S. R. & Alterman, M. A. Global proteomic signature of undifferentiated human bone marrow stromal cells: evidence for donor-to-donor proteome heterogeneity. Stem Cell Res. 11, 793–805 (2013).

    Article  CAS  PubMed  Google Scholar 

  32. Bianco, P. et al. The meaning, the sense and the significance: translating the science of mesenchymal stem cells into medicine. Nat. Med. 19, 35–42 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Robey, P. G., Kuznetsov, S. A., Riminucci, M. & Bianco, P. Bone marrow stromal cell assays: in vitro and in vivo. Methods Mol. Biol. 1130, 279–293 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Zuk, P. A. et al. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng. 7, 211–228 (2001).

    Article  CAS  PubMed  Google Scholar 

  35. De Coppi, P. et al. Isolation of amniotic stem cell lines with potential for therapy. Nat. Biotechnol. 25, 100–106 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Mitchell, K. E. et al. Matrix cells from Wharton's jelly form neurons and glia. Stem Cells 21, 50–60 (2003).

    Article  CAS  PubMed  Google Scholar 

  37. Troyer, D. L. & Weiss, M. L. Wharton's jelly-derived cells are a primitive stromal cell population. Stem Cells 26, 591–599 (2008).

    Article  PubMed  Google Scholar 

  38. Gronthos, S., Mankani, M., Brahim, J., Robey, P. G. & Shi, S. Postnatal human dental pulp stem cells (DPSCS) in vitro and in vivo. Proc. Natl Acad. Sci. USA 97, 13625–13630 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Usas, A. & Huard, J. Muscle-derived stem cells for tissue engineering and regenerative therapy. Biomaterials 28, 5401–5406 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Feisst, V., Brooks, A. E., Chen, C. J. & Dunbar, P. R. Characterization of mesenchymal progenitor cell populations directly derived from human dermis. Stem Cells Dev. 23, 631–642 (2014).

    Article  CAS  PubMed  Google Scholar 

  41. Erices, A., Conget, P. & Minguell, J. J. Mesenchymal progenitor cells in human umbilical cord blood. Br. J. Haematol. 109, 235–242 (2000).

    Article  CAS  PubMed  Google Scholar 

  42. Kern, S., Eichler, H., Stoeve, J., Kluter, H. & Bieback, K. Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells 24, 1294–1301 (2006).

    Article  CAS  PubMed  Google Scholar 

  43. Qu-Petersen, Z. et al. Identification of a novel population of muscle stem cells in mice: potential for muscle regeneration. J. Cell Biol. 157, 851–864 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Zuk, P. A. et al. Human adipose tissue is a source of multipotent stem cells. Mol. Biol. Cell 13, 4279–4295 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Gronthos, S. et al. Surface protein characterization of human adipose tissue-derived stromal cells. J. Cell. Physiol. 189, 54–63 (2001).

    Article  CAS  PubMed  Google Scholar 

  46. Crisan, M. et al. A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell 3, 301–313 (2008).

    Article  CAS  PubMed  Google Scholar 

  47. Pachon-Pena, G. et al. Stromal stem cells from adipose tissue and bone marrow of age-matched female donors display distinct immunophenotypic profiles. J. Cell. Physiol. 226, 843–851 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Bourin, P. et al. Stromal cells from the adipose tissue-derived stromal vascular fraction and culture expanded adipose tissue-derived stromal/stem cells: a joint statement of the International Federation for Adipose Therapeutics and Science (IFATS) and the International Society for Cellular Therapy (ISCT). Cytotherapy 15, 641–648 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Halvorsen, Y. D. et al. Extracellular matrix mineralization and osteoblast gene expression by human adipose tissue-derived stromal cells. Tissue Eng. 7, 729–741 (2001).

    Article  CAS  PubMed  Google Scholar 

  50. Hicok, K. C. et al. Human adipose-derived adult stem cells produce osteoid in vivo. Tissue Eng. 10, 371–380 (2004).

    Article  CAS  PubMed  Google Scholar 

  51. Justesen, J., Pedersen, S. B., Stenderup, K. & Kassem, M. Subcutaneous adipocytes can differentiate into bone-forming cells in vitro and in vivo. Tissue Eng. 10, 381–391 (2004).

    Article  CAS  PubMed  Google Scholar 

  52. Mesimaki, K. et al. Novel maxillary reconstruction with ectopic bone formation by GMP adipose stem cells. Int. J. Oral Maxillofac. Surg. 38, 201–209 (2009).

    Article  CAS  PubMed  Google Scholar 

  53. Levi, B. et al. Human adipose derived stromal cells heal critical size mouse calvarial defects. PLoS ONE 5, e11177 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Sandor, G. K. et al. Adipose stem cells used to reconstruct 13 cases with cranio-maxillofacial hard-tissue defects. Stem Cells Transl Med. 3, 530–540 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Levi, B. et al. Differences in osteogenic differentiation of adipose-derived stromal cells from murine, canine, and human sources in vitro and in vivo. Plast. Reconstr. Surg. 128, 373–386 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. de Girolamo, L., Sartori, M. F., Albisetti, W. & Brini, A. T. Osteogenic differentiation of human adipose-derived stem cells: comparison of two different inductive media. J. Tissue Eng. Regen. Med. 1, 154–157 (2007).

    Article  CAS  PubMed  Google Scholar 

  57. Im, G. I., Shin, Y. W. & Lee, K. B. Do adipose tissue-derived mesenchymal stem cells have the same osteogenic and chondrogenic potential as bone marrow-derived cells? Osteoarthritis Cartilage 13, 845–853 (2005).

    Article  PubMed  Google Scholar 

  58. Hayashi, O., Katsube, Y., Hirose, M., Ohgushi, H. & Ito, H. Comparison of osteogenic ability of rat mesenchymal stem cells from bone marrow, periosteum, and adipose tissue. Calcif. Tissue Int. 82, 238–247 (2008).

    Article  CAS  PubMed  Google Scholar 

  59. Wolff, J. et al. GMP-level adipose stem cells combined with computer-aided manufacturing to reconstruct mandibular ameloblastoma resection defects: experience with three cases. Ann. Maxillofac. Surg. 3, 114–125 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Eilertsen, K. J., Floyd, Z. & Gimble, J. M. The epigenetics of adult (somatic) stem cells. Crit. Rev. Eukaryot. Gene Expr. 18, 189–206 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Li, H. et al. Sustained release of bone morphogenetic protein 2 via coacervate improves the osteogenic potential of muscle-derived stem cells. Stem Cells Transl Med. 2, 667–677 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Usas, A. et al. Skeletal muscle-derived stem cells: implications for cell-mediated therapies. Medicina 47, 469–479 (2011).

    Article  PubMed  Google Scholar 

  63. Gao, X. et al. Role of donor and host cells in muscle-derived stem cell-mediated bone repair: differentiation vs. paracrine effects. FASEB J. 28, 3792–3809 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Studeny, M. et al. Mesenchymal stem cells: potential precursors for tumor stroma and targeted-delivery vehicles for anticancer agents. J. Natl Cancer Inst. 96, 1593–1603 (2004).

    Article  CAS  PubMed  Google Scholar 

  65. Katakowski, M. et al. Exosomes from marrow stromal cells expressing miR-146b inhibit glioma growth. Cancer Lett. 335, 201–204 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Xin, H. et al. Targeted delivery of CX3CL1 to multiple lung tumors by mesenchymal stem cells. Stem Cells 25, 1618–1626 (2007).

    Article  CAS  PubMed  Google Scholar 

  67. Loebinger, M. R., Eddaoudi, A., Davies, D. & Janes, S. M. Mesenchymal stem cell delivery of trail can eliminate metastatic cancer. Cancer Res. 69, 4134–4142 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Belmar-Lopez, C. et al. Tissue-derived mesenchymal stromal cells used as vehicles for anti-tumor therapy exert different in vivo effects on migration capacity and tumor growth. BMC Med. 11, 139 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Dwyer, R. M. et al. Mesenchymal stem cell-mediated delivery of the sodium iodide symporter supports radionuclide imaging and treatment of breast cancer. Stem Cells 29, 1149–1157 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Shah, K. Mesenchymal stem cells engineered for cancer therapy. Adv. Drug Deliv. Rev. 64, 739–748 (2012).

    Article  CAS  PubMed  Google Scholar 

  71. Zhao, J. et al. Stem cell-mediated delivery of SPIO-loaded gold nanoparticles for the theranosis of liver injury and hepatocellular carcinoma. Nanotechnology 25, 5101–5101 (2014).

    Google Scholar 

  72. Zhang, T. et al. Bone marrow-derived mesenchymal stem cells promote growth and angiogenesis of breast and prostate tumors. Stem Cell Res. Ther. 4, 70 (2014).

    Article  CAS  Google Scholar 

  73. Luo, J. et al. Infiltrating bone marrow mesenchymal stem cells increase prostate cancer stem cell population and metastatic ability via secreting cytokines to suppress androgen receptor signaling. Oncogene 33, 2768–2778 (2013).

    Article  CAS  PubMed  Google Scholar 

  74. Warnke, P. H. et al. Growth and transplantation of a custom vascularised bone graft in a man. Lancet 364, 766–770 (2004).

    Article  CAS  PubMed  Google Scholar 

  75. Mesimaki, K. et al. Novel maxillary reconstruction with ectopic bone formation by GMP adipose stem cells. Int. J. Oral Maxillofac. Surg. 38, 201–209 (2009).

    Article  CAS  PubMed  Google Scholar 

  76. Sandor, G. K. et al. Adipose stem cell tissue-engineered construct used to treat large anterior mandibular defect: a case report and review of the clinical application of good manufacturing practice-level adipose stem cells for bone regeneration. J. Oral Maxillofac. Surg. 71, 938–950 (2013).

    Article  PubMed  Google Scholar 

  77. Lendeckel, S. et al. Autologous stem cells (adipose) and fibrin glue used to treat widespread traumatic calvarial defects: case report. J. Craniomaxillofac. Surg. 32, 370–373 (2004).

    Article  PubMed  Google Scholar 

  78. Bose, S., Roy, M. & Bandyopadhyay, A. Recent advances in bone tissue engineering scaffolds. Trends Biotechnol. 30, 546–554 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Shrivats, A. R., McDermott, M. C. & Hollinger, J. O. Bone tissue engineering: state of the union. Drug Discov. Today 19, 781–786 (2014).

    Article  CAS  PubMed  Google Scholar 

  80. Bhumiratana, S. & Vunjak-Novakovic, G. Personalized human bone grafts for reconstructing head and face. Stem Cells Transl Med. 1, 64–69 (2012).

    Article  CAS  PubMed  Google Scholar 

  81. Tevlin, R. et al. Biomaterials for craniofacial bone engineering. J. Dent. Res. 93, 1187–1195 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Liebergall, M. et al. Stem cell-based therapy for prevention of delayed fracture union: a randomized and prospective preliminary study. Mol. Ther. 21, 1631–1638 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Gangji, V., De Maertelaer, V. & Hauzeur, J.-P. Autologous bone marrow cell implantation in the treatment of non-traumatic osteonecrosis of the femoral head: five year follow-up of a prospective controlled study. Bone 49, 1005–1009 (2011).

    Article  PubMed  Google Scholar 

  84. Gangji, V. et al. Treatment of osteonecrosis of the femoral head with implantation of autologous bone-marrow cells—a pilot study. J. Bone Joint Surg. Am. 86–A, 1153–1160 (2004).

    Article  Google Scholar 

  85. Mao, Q. et al. The efficacy of targeted intraarterial delivery of concentrated autologous bone marrow containing mononuclear cells in the treatment of osteonecrosis of the femoral head: a five year follow-up study. Bone 57, 509–516 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Zhao, D. et al. Treatment of early stage osteonecrosis of the femoral head with autologous implantation of bone marrow-derived and cultured mesenchymal stem cells. Bone 50, 325–330 (2012).

    Article  PubMed  Google Scholar 

  87. Levi, B. et al. Human adipose derived stromal cells heal critical size mouse calvarial defects. PLoS ONE 5, e11177 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Levi, B. et al. Dura mater stimulates human adipose-derived stromal cells to undergo bone formation in mouse calvarial defects. Stem Cells 29, 1241–1255 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Cowan, C. M. et al. Adipose-derived adult stromal cells heal critical-size mouse calvarial defects. Nat. Biotechnol. 22, 560–567 (2004).

    Article  CAS  PubMed  Google Scholar 

  90. Boerckel, J. D., Uhrig, B. A., Willett, N. J., Huebsch, N. & Guldberg, R. E. Mechanical regulation of vascular growth and tissue regeneration in vivo. Proc. Natl Acad. Sci. USA 108, E674–E680 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  91. Caplan, A. I. & Dennis, J. E. Mesenchymal stem cells as trophic mediators. J. Cell. Biochem. 98, 1076–1084 (2006).

    Article  CAS  PubMed  Google Scholar 

  92. Dong, F. & Caplan, A. I. Cell transplantation as an initiator of endogenous stem cell-based tissue repair. Curr. Opin. Organ Transplant. 17, 670–674 (2012).

    Article  CAS  PubMed  Google Scholar 

  93. Eshkar-Oren, I. et al. The forming limb skeleton serves as a signaling center for limb vasculature patterning via regulation of Vegf. Development 136, 1263–1272 (2009).

    Article  CAS  PubMed  Google Scholar 

  94. Okuyama, H. et al. Expression of vascular endothelial growth factor receptor 1 in bone marrow-derived mesenchymal cells is dependent on hypoxia-inducible factor 1. J. Biol. Chem. 281, 15554–15563 (2006).

    Article  CAS  PubMed  Google Scholar 

  95. Kubo, S. et al. Blocking vascular endothelial growth factor with soluble Flt-1 improves the chondrogenic potential of mouse skeletal muscle-derived stem cells. Arthritis Rheum. 60, 155–165 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Reichert, J. C. et al. A tissue engineering solution for segmental defect regeneration in load-bearing long bones. Sci. Transl Med. 4, 141ra93 (2012).

    Article  CAS  PubMed  Google Scholar 

  97. Springer, I. N. et al. Bone graft versus BMP-7 in a critical size defect—cranioplasty in a growing infant model. Bone 37, 563–569 (2005).

    Article  CAS  PubMed  Google Scholar 

  98. Wilson, S. M. et al. Adipose-derived mesenchymal stem cells enhance healing of mandibular defects in the ramus of swine. J. Oral Maxillofac. Surg. 70, E193–E203 (2012).

    Article  PubMed  Google Scholar 

  99. Au, P., Tam, J., Fukumura, D. & Jain, R. K. Bone marrow-derived mesenchymal stem cells facilitate engineering of long-lasting functional vasculature. Blood 111, 4551–4558 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Correia, C. et al. In vitro model of vascularized bone: synergizing vasculogenesis and osteogenesis. PLoS ONE 6, e28352 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Correia, C. et al. Human adipose-derived cells can serve as a single-cell source for the in vitro cultivation of vascularized bone grafts. J. Tissue Eng. Regen. Med. 8, 629–639 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Tsigkou, O. et al. Engineered vascularized bone grafts. Proc. Natl Acad. Sci. USA 107, 3311–3316 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  103. Rivron, N. C. et al. Sonic hedgehog-activated engineered blood vessels enhance bone tissue formation. Proc. Natl Acad. Sci. USA 109, 4413–4418 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Fuchs, S., Hofmann, A. & Kirkpatrick, C. J. Microvessel-like structures from outgrowth endothelial cells from human peripheral blood in 2-dimensional and 3-dimensional co-cultures with osteoblastic lineage cells. Tissue Eng. 13, 2577–2588 (2007).

    Article  CAS  PubMed  Google Scholar 

  105. Martineau, L. & Doillon, C. J. Angiogenic response of endothelial cells seeded dispersed versus on beads in fibrin gels. Angiogenesis 10, 269–277 (2007).

    Article  PubMed  Google Scholar 

  106. Laib, A. M. et al. Spheroid-based human endothelial cell microvessel formation in vivo. Nat. Protoc. 4, 1202–1215 (2009).

    Article  CAS  PubMed  Google Scholar 

  107. Alajati, A. et al. Spheroid-based engineering of a human vasculature in mice. Nat. Methods 5, 439–445 (2008).

    Article  CAS  PubMed  Google Scholar 

  108. Hutton, D. L., Moore, E. M., Gimble, J. & Grayson, W. L. Platelet-derived growth factor and spatiotemporal cues induce development of vascularized bone tissue by adipose-derived stem cells. Tissue Eng. Part A 19, 2076–2086 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Mehta, M., Schmidt-Bleek, K., Duda, G. N. & Mooney, D. J. Biomaterial delivery of morphogens to mimic the natural healing cascade in bone. Adv. Drug Deliv. Rev. 64, 1257–1276 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Kaigler, D., Silva, E. A. & Mooney, D. J. Guided bone regeneration using injectable vascular endothelial growth factor delivery gel. J. Periodontol. 84, 230–238 (2013).

    Article  PubMed  Google Scholar 

  111. Martino, M. M. et al. Engineering the growth factor microenvironment with fibronectin domains to promote wound and bone tissue healing. Sci. Transl Med. 3, 100ra89 (2011).

    Article  CAS  PubMed  Google Scholar 

  112. Shah, N. J. et al. Tunable dual growth factor delivery from polyelectrolyte multilayer films. Biomaterials 32, 6183–6193 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Shah, N. J. et al. Surface-mediated bone tissue morphogenesis from tunable nanolayered implant coatings. Sci. Transl Med. 5, 191ra183 (2013).

    Article  CAS  Google Scholar 

  114. Spiess, B. D. Perfluorocarbon emulsions as a promising technology: a review of tissue and vascular gas dynamics. J. Appl. Physiol. 106, 1444–1452 (2009).

    Article  CAS  PubMed  Google Scholar 

  115. Kimelman-Bleich, N. et al. The use of a synthetic oxygen carrier-enriched hydrogel to enhance mesenchymal stem cell-based bone formation in vivo. Biomaterials 30, 4639–4648 (2009).

    Article  CAS  PubMed  Google Scholar 

  116. Kelly, B. D. et al. Cell type-specific regulation of angiogenic growth factor gene expression and induction of angiogenesis in nonischemic tissue by a constitutively active form of hypoxia-inducible factor 1. Circ. Res. 93, 1074–1081 (2003).

    Article  CAS  PubMed  Google Scholar 

  117. Bosch-Marce, M. et al. Effects of aging and hypoxia-inducible factor-1 activity on angiogenic cell mobilization and recovery of perfusion after limb ischemia. Circ. Res. 101, 1310–1318 (2007).

    Article  CAS  PubMed  Google Scholar 

  118. Wang, Y. et al. The hypoxia-inducible factor a pathway couples angiogenesis to osteogenesis during skeletal development. J. Clin. Invest. 117, 1616–1626 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Wang, Y., Wan, C., Gilbert, S. R. & Clemens, T. L. Oxygen sensing and osteogenesis. Ann. NY Acad. Sci. 1117, 1–11 (2007).

    Article  CAS  PubMed  Google Scholar 

  120. Schipani, E., Maes, C., Carmeliet, G. & Semenza, G. L. Regulation of osteogenesis-angiogenesis coupling by HIFs and VEGF. J. Bone Miner. Res. 24, 1347–1353 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Hu, X. et al. Leptin signaling is required for augmented therapeutic properties of mesenchymal stem cells conferred by hypoxia preconditioning. Stem Cells 32, 2702–2713 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Jiang, Q. et al. Remote ischemic postconditioning enhances cell retention in the myocardium after intravenous administration of bone marrow mesenchymal stromal cells. J. Mol. Cell. Cardiol. 56, 1–7 (2013).

    Article  CAS  PubMed  Google Scholar 

  123. Carlier, A. et al. Mosaic: a multiscale model of osteogenesis and sprouting angiogenesis with lateral inhibition of endothelial cells. PLoS Comput. Biol. 8, e10022724 (2012).

    Article  CAS  Google Scholar 

  124. Xie, C. et al. Structural bone allograft combined with genetically engineered mesenchymal stem cells as a novel platform for bone tissue engineering. Tissue Eng. 13, 435–445 (2007).

    Article  CAS  PubMed  Google Scholar 

  125. Huang, C., Tang, M., Yehling, E. & Zhang, X. Overexpressing sonic hedgehog peptide restores periosteal bone formation in a murine bone allograft transplantation model. Mol. Ther. 22, 430–439 (2014).

    Article  CAS  PubMed  Google Scholar 

  126. Rosen, V. Harnessing the parathyroid hormone, Wnt, and bone morphogenetic protein signaling cascades for successful bone tissue engineering. Tissue Eng. Part B Rev. 17, 475–479 (2011).

    Article  CAS  PubMed  Google Scholar 

  127. Bleich, N. K. et al. Gene therapy approaches to regenerating bone. Adv. Drug Deliv. Rev. 64, 1320–1330 (2012).

    Article  CAS  PubMed Central  Google Scholar 

  128. Hung, B. P., Babalola, O. M. & Bonassar, L. J. Quantitative characterization of mesenchymal stem cell adhesion to the articular cartilage surface. J. Biomed. Mater. Res. A. 101, 3592–3598 (2013).

    Article  CAS  PubMed  Google Scholar 

  129. Vangsness, C. T. et al. Adult human mesenchymal stem cells delivered via intra-articular injection to the knee following partial medial meniscectomy. J. Bone Joint Surg. Am. 96, 90–98 (2014).

    Article  PubMed  Google Scholar 

  130. Sart, S., Tsai, A. C., Li, Y. & Ma, T. Three-dimensional aggregates of mesenchymal stem cells: cellular mechanisms, biological properties, and applications. Tissue Eng. Part B 20, 365–380 (2014).

    Article  Google Scholar 

  131. Sart, S., Ma, T. & Li, Y. Preconditioning stem cells for in vivo delivery. Biores. Open Access 3, 137–149 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Harrison, B. S., Eberli, D., Lee, S. J., Atala, A. & Yoo, J. J. Oxygen producing biomaterials for tissue regeneration. Biomaterials 28, 4628–4634 (2007).

    Article  CAS  PubMed  Google Scholar 

  133. Oh, S. H., Ward, C. L., Atala, A., Yoo, J. J. & Harrison, B. S. Oxygen generating scaffolds for enhancing engineered tissue survival. Biomaterials 30, 757–762 (2009).

    Article  CAS  PubMed  Google Scholar 

  134. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  135. US National Library of Medicine. ClinicalTrials.gov[online], (2011).

  136. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  137. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  138. US National Library of Medicine. ClinicalTrials.gov[online], (2011).

  139. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  140. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  141. US National Library of Medicine. ClinicalTrials.gov[online], (2012).

  142. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  143. US National Library of Medicine. ClinicalTrials.gov[online], (2012).

  144. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  145. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  146. US National Library of Medicine. ClinicalTrials.gov[online], (2012).

  147. US National Library of Medicine. ClinicalTrials.gov[online], (2012).

  148. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  149. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  150. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  151. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  152. US National Library of Medicine. ClinicalTrials.gov[online], (2012).

  153. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  154. US National Library of Medicine. ClinicalTrials.gov[online], (2008).

  155. US National Library of Medicine. ClinicalTrials.gov[online], (2010).

  156. US National Library of Medicine. ClinicalTrials.gov[online], (2011).

  157. US National Library of Medicine. ClinicalTrials.gov[online], (2009).

  158. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  159. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  160. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  161. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

  162. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  163. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  164. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  165. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  166. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  167. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  168. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  169. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  170. US National Library of Medicine. ClinicalTrials.gov[online], (2014).

  171. US National Library of Medicine. ClinicalTrials.gov[online], (2013).

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Acknowledgements

The authors acknowledge funding from the Maryland Stem Cell Research Fund (2014-MSCRFI-0699), NSF CAREER award (CBET 1350554), Johns Hopkins University Centre for Musculoskeletal Research, and the American Society for Bone and Mineral Research (2013CEA13). The authors also thank D. Hutton for assistance with the artwork.

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Authors and Affiliations

  1. Department of Biomedical Engineering, Johns Hopkins University, 400 North Broadway, Baltimore, 21205, MD, USA

    Warren L. Grayson & Ben P. Hung

  2. Centre for Stem Cell Research and Regenerative Medicine, 1430 Tulane Avenue, SL-99, New Orleans, 70112, LA, USA

    Bruce A. Bunnell, Elizabeth Martin, Trivia Frazier & Jeffrey M. Gimble

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  1. Warren L. Grayson
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  2. Bruce A. Bunnell
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Contributions

W.L.G., B.P.H. and J.M.G. researched data for the article and wrote the article. W.L.G., B.A.B., E.M., T.F. and J.M.G. made substantial contributions to discussions of the content. All authors reviewed and/or edited the manuscript before submission.

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Correspondence to Warren L. Grayson.

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Competing interests

J.M.G. is co-founder, co-owner and Chief Scientific Officer of LaCell, a biotechnology company focusing on the clinical translation of stromal-cell and stem-cell science. The other authors declare no competing interests.

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Grayson, W., Bunnell, B., Martin, E. et al. Stromal cells and stem cells in clinical bone regeneration. Nat Rev Endocrinol 11, 140–150 (2015). https://doi.org/10.1038/nrendo.2014.234

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