Stem Cells for Osteochondral Regeneration

  • Raphaël F. Canadas
  • Rogério P. Pirraco
  • J. Miguel Oliveira
  • Rui L. Reis
  • Alexandra P. MarquesEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1059)


Stem cell research plays a central role in the future of medicine, which is mainly dependent on the advances on regenerative medicine (RM), specifically in the disciplines of tissue engineering (TE) and cellular therapeutics. All RM strategies depend upon the harnessing, stimulation, or guidance of endogenous developmental or repair processes in which cells have an important role. Among the most clinically challenging disorders, cartilage degeneration, which also affects subchondral bone becoming an osteochondral (OC) defect, is one of the most demanding. Although primary cells have been clinically applied, stem cells are currently seen as the promising tool of RM-related research because of its availability, in vitro proliferation ability, pluri- or multipotency, and immunosuppressive features. Being the OC unit, a transition from the bone to cartilage, mesenchymal stem cells (MSCs) are the main focus for OC regeneration. Promising alternatives, which can also be obtained from the patient or at banks and have great differentiation potential toward a wide range of specific cell types, have been reported. Still, ethical concerns and tumorigenic risk are currently under discussion and assessment. In this book chapter, we revise the existing stem cell-based approaches for engineering bone and cartilage, focusing on cell therapy and TE. Furthermore, 3D OC composites based on cell co-cultures are described. Finally, future directions and challenges still to be faced are critically discussed.


Skeletogenesis Stem cells Bone Cartilage Osteochondral constructs 



The authors would like to thank H2020-MSCA-RISE program, as this work is part of developments carried out in BAMOS project, funded from the European Union’s Horizon 2020 research and innovation program under grant agreement N° 734156. Thanks are also due to the Portuguese Foundation for Science and Technology (FCT) for the distinction attributed to J. M. Oliveira (IF/00423/2012 and IF/01285/2015) and to Rogério Pirraco (IF/00347/2015) under the Investigator FCT program. The authors also thank FCT for the Ph.D. scholarship provided to R. F. Canadas (SFRH/BD/92565/2013).


  1. 1.
    Kim YS, Park EH, Kim YC, Koh YG (2013) Clinical outcomes of mesenchymal stem cell injection with arthroscopic treatment in older patients with osteochondral lesions of the talus. Am J Sports Med 41(5):1090–1099PubMedCrossRefGoogle Scholar
  2. 2.
    Barry F, Murphy M (2013) Mesenchymal stem cells in joint disease and repair. Nat Rev Rheumatol 9(10):584–594PubMedCrossRefGoogle Scholar
  3. 3.
    Gore M, Tai K-S, Sadosky A, Leslie D, Stacey BR (2011) Clinical comorbidities, treatment patterns, and direct medical costs of patients with osteoarthritis in usual care: a retrospective claims database analysis. J Med Econ 14(4):497–507PubMedCrossRefGoogle Scholar
  4. 4.
    Michaud CM, McKenna MT, Begg S, Tomijima N, Majmudar M, Bulzacchelli MT et al (2006) The burden of disease and injury in the United States 1996. Popul Health Metr 4:11PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    McKenna MT, Michaud CM, Murray CJL, Marks JS (2005) Assessing the burden of disease in the United States using disability-adjusted life years. Am J Prev Med 28(5):415–423PubMedCrossRefGoogle Scholar
  6. 6.
    Ayral X, Pickering EH, Woodworth TG, Mackillop N, Dougados M (2005) Synovitis: a potential predictive factor of structural progression of medial tibiofemoral knee osteoarthritis – results of a 1 year longitudinal arthroscopic study in 422 patients. Osteoarthr Cartil 13(5):361–367PubMedCrossRefGoogle Scholar
  7. 7.
    Cascão R, Vidal B, Lopes IP, Paisana E, Rino J, Moita LF et al (2015) Decrease of CD68 synovial macrophages in celastrol treated arthritic rats. Ng LFP, editor. PLoS One 10(12):e0142448PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Roelofs AJ, Zupan J, Riemen AHK, Kania K, Ansboro S, White N et al (2017) Joint morphogenetic cells in the adult mammalian synovium. Nat Commun 8:15040PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Hangody L, Kish G, Módis L, Szerb I, Gáspár L, Diószegi Z et al (2001) Mosaicplasty for the treatment of osteochondritis dissecans of the talus: two to seven year results in 36 patients. Foot Ankle Int 22(7):552–558PubMedCrossRefGoogle Scholar
  10. 10.
    Kono M, Takao M, Naito K, Uchio Y, Ochi M (2006) Retrograde drilling for osteochondral lesions of the talar dome. Am J Sports Med 34(9):1450–1456PubMedCrossRefGoogle Scholar
  11. 11.
    Baltzer AWA, Arnold JP (2005) Bone-cartilage transplantation from the ipsilateral knee for chondral lesions of the talus. Arthrosc J Arthrosc Relat Surg 21(2):159–166CrossRefGoogle Scholar
  12. 12.
    Imhoff AB, Ottl GM, Burkart A, Traub S (1999) Autologous osteochondral transplantation on various joints. Orthopade 28(1):33–44PubMedPubMedCentralGoogle Scholar
  13. 13.
    Jacobi M, Villa V, Magnussen RA, Neyret P (2011) MACI - a new era? Sport Med Arthrosc Rehabil Ther Technol SMARTT 3:10PubMedCrossRefGoogle Scholar
  14. 14.
    Grässel S, Lorenz J (2014) Tissue-engineering strategies to repair chondral and osteochondral tissue in osteoarthritis: use of mesenchymal stem cells. Curr Rheumatol Rep 16(10):452PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Gupta PK, Das AK, Chullikana A, Majumdar AS (2012) Mesenchymal stem cells for cartilage repair in osteoarthritis. Stem Cell Res Ther 3(4):25PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Reyes R, Pec MK, Sanchez E, del Rosario C, Delgado A, Evora C (2013) Comparative, osteochondral defect repair: stem cells versus chondrocytes versus bone morphogenetic protein-2, solely or in combination. Eur Cell Mater 25:351–365. discussion 365PubMedCrossRefGoogle Scholar
  17. 17.
    Khan WS, Johnson DS, Hardingham TE (2010) The potential of stem cells in the treatment of knee cartilage defects. Knee 17(6):369–374PubMedCrossRefGoogle Scholar
  18. 18.
    Peterson L, Menche D, Grande D, Pitman M (1984) Chondrocyte transplantation: an experimental model in the rabbit. Trans Orthop Res Soc 9(218)Google Scholar
  19. 19.
    Brittberg M, Lindahl A, Nilsson A, Ohlsson C, Isaksson O, Peterson L (1994) Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N Engl J Med 331(14):889–895CrossRefPubMedGoogle Scholar
  20. 20.
    Bentley G, Bhamra JS, Gikas PD, Skinner JA, Carrington R, Briggs TW (2013) Repair of osteochondral defects in joints – How to achieve success. Injury 44(Supplement 1):S3–10PubMedCrossRefGoogle Scholar
  21. 21.
    Wood JJ, Malek MA, Frassica FJ, Polder JA, Mohan AK, Bloom ET et al (2006) Autologous cultured chondrocytes: adverse events reported to the United States Food and Drug Administration. J Bone Joint Surg Am 88(3):503–507PubMedPubMedCentralGoogle Scholar
  22. 22.
    Peterson L, Minas T, Brittberg M, Nilsson A, Sjogren-Jansson E, Lindahl A (2000) Two- to 9-year outcome after autologous chondrocyte transplantation of the knee. Clin Orthop Relat Res 374:212–234CrossRefGoogle Scholar
  23. 23.
    Benya PD, Shaffer JD (1982) Dedifferentiated chondrocytes reexpress the differentiated collagen phenotype when cultured in agarose gels. Cell 30(1):215–224PubMedCrossRefGoogle Scholar
  24. 24.
    Takata N, Furumatsu T, Ozaki T, Abe N, Naruse K (2011) Comparison between loose fragment chondrocytes and condyle fibrochondrocytes in cellular proliferation and redifferentiation. J Orthop Sci 16(5):589–597PubMedCrossRefGoogle Scholar
  25. 25.
    Goldberg A, Mitchell K, Soans J, Kim L, Zaidi R (2017) The use of mesenchymal stem cells for cartilage repair and regeneration: a systematic review. J Orthop Surg Res 12:39PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Makris EA, Gomoll AH, Malizos KN, Hu JC, Athanasiou KA (2015) Repair and tissue engineering techniques for articular cartilage. Nat Rev Rheumatol 11(1):21–34PubMedCrossRefGoogle Scholar
  27. 27.
    Keramaris NC, Kanakaris NK, Tzioupis C, Kontakis G, Giannoudis PV (2008) Translational research: from benchside to bedside. Injury 39(6):643–650PubMedCrossRefGoogle Scholar
  28. 28.
    Woolf SH (2008) The meaning of translational research and why it matters. JAMA 299(2):211–213PubMedCrossRefGoogle Scholar
  29. 29.
    Lefebvre V, Bhattaram P (2010) Vertebrate skeletogenesis. Curr Top Dev Biol 90:291–317PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Yang Y (2013) Skeletal morphogenesis and embryonic development. In: Primer on the metabolic bone diseases and disorders of mineral metabolism. John Wiley & Sons, Inc., Ames, pp 1–14Google Scholar
  31. 31.
    Su N (2008) FGF signaling: its role in bone development and human skeleton diseases. Front Biosci 13(13):2842PubMedCrossRefGoogle Scholar
  32. 32.
    Rosen V (2009) BMP2 signaling in bone development and repair. Cytokine Growth Factor Rev 20(5–6):475–480PubMedCrossRefGoogle Scholar
  33. 33.
    Kim HJ, Rice DP, Kettunen PJ, Thesleff I (1998) FGF-, BMP- and Shh-mediated signalling pathways in the regulation of cranial suture morphogenesis and calvarial bone development. Development 125(7):1241–1251PubMedPubMedCentralGoogle Scholar
  34. 34.
    Zanotti S, Canalis E (2012) Notch regulation of bone development and remodeling and related skeletal disorders. Calcif Tissue Int 90(2):69–75PubMedCrossRefGoogle Scholar
  35. 35.
    Day TF, Yang Y (2008) Wnt and hedgehog signaling pathways in bone development. J Bone Joint Surg Am 90(Suppl 1):19–24PubMedCrossRefGoogle Scholar
  36. 36.
    Akiyama H (2002) The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6. Genes Dev 16(21):2813–2828PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Komori T (2010) Regulation of bone development and extracellular matrix protein genes by RUNX2. Cell Tissue Res 339(1):189–195PubMedCrossRefGoogle Scholar
  38. 38.
    Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD et al (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284(5411):143–147PubMedCrossRefGoogle Scholar
  39. 39.
    da Silva Meirelles L (2006) Mesenchymal stem cells reside in virtually all post-natal organs and tissues. J Cell Sci 119(11):2204–2213PubMedCrossRefGoogle Scholar
  40. 40.
    Bielby R, Jones E, McGonagle D (2007) The role of mesenchymal stem cells in maintenance and repair of bone. Injury 38(1):S26–S32PubMedCrossRefGoogle Scholar
  41. 41.
    Devescovi V, Leonardi E, Ciapetti G, Cenni E (2008) Growth factors in bone repair. Chir Organi Mov 92(3):161–168PubMedCrossRefGoogle Scholar
  42. 42.
    Maes C, Carmeliet G, Schipani E (2012) Hypoxia-driven pathways in bone development, regeneration and disease. Nat Rev Rheumatol 8(6):358–366PubMedCrossRefGoogle Scholar
  43. 43.
    Caplan AI (1991) Mesenchymal stem cells. J Orthop Res 9(5):641–650PubMedCrossRefGoogle Scholar
  44. 44.
    Le Blanc K (2003) Immunomodulatory effects of fetal and adult mesenchymal stem cells. Cytotherapy 5(6):485–489PubMedCrossRefGoogle Scholar
  45. 45.
    Hass R, Kasper C, Böhm S, Jacobs R (2011) Different populations and sources of human mesenchymal stem cells (MSC): a comparison of adult and neonatal tissue-derived MSC. Cell Commun Signal [Internet] 9(1):12. Available from: CrossRefGoogle Scholar
  46. 46.
    Polymeri A, Giannobile W, Kaigler D (2016) Bone marrow stromal stem cells in tissue engineering and regenerative medicine. Horm Metab Res 48(11):700–713PubMedCrossRefGoogle Scholar
  47. 47.
    Romanov YA (2003) Searching for alternative sources of postnatal human mesenchymal stem cells: candidate MSC-like cells from umbilical cord. Stem Cells 21(1):105–110PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Pierdomenico L, Bonsi L, Calvitti M, Rondelli D, Arpinati M, Chirumbolo G et al (2005) Multipotent mesenchymal stem cells with immunosuppressive activity can be easily isolated from dental pulp. Transplantation 80(6):836–842PubMedCrossRefGoogle Scholar
  49. 49.
    Zuk P, Zhu M, Ashjian P, De Ugarte DA, Huang JI, Mizuno H et al (2002) Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell [Internet] 13:4279–4295. Available from: CrossRefGoogle Scholar
  50. 50.
    Mesimäki K, Lindroos B, Törnwall J, Mauno J, Lindqvist C, Kontio R et al (2009) Novel maxillary reconstruction with ectopic bone formation by GMP adipose stem cells. Int J Oral Maxillofac Surg 38(3):201–209PubMedCrossRefGoogle Scholar
  51. 51.
    Dragoo JL, Carlson G, McCormick F, Khan-Farooqi H, Zhu M, Zuk PA et al (2007) Healing full-thickness cartilage defects using adipose-derived stem cells. Tissue Eng 13(7):1615–1621PubMedCrossRefGoogle Scholar
  52. 52.
    Crisan M, Yap S, Casteilla L, Chen C-W, Corselli M, Park TS et al (2008) A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell 3(3):301–313PubMedCrossRefGoogle Scholar
  53. 53.
    Caplan AI, Correa D (2011) The MSC: an injury drugstore. Cell Stem Cell 9(1):11–15PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Marolt D, Campos IM, Bhumiratana S, Koren A, Petridis P, Zhang G et al (2012) Engineering bone tissue from human embryonic stem cells. Proc Natl Acad Sci 109(22):8705–8709PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126(4):663–676CrossRefGoogle Scholar
  56. 56.
    Yamanaka S (2010) Patient-specific pluripotent stem cells become even more accessible. Cell Stem Cell 7(1):1–2PubMedCrossRefGoogle Scholar
  57. 57.
    Bianco P, Riminucci M, Gronthos S, Robey PG (2001) Bone marrow stromal stem cells: nature, biology, and potential applications. Stem Cells 19(3):180–192PubMedCrossRefGoogle Scholar
  58. 58.
    Papadimitropoulos A, Piccinini E, Brachat S, Braccini A, Wendt D, Barbero A et al (2014) Expansion of human mesenchymal stromal cells from fresh bone marrow in a 3D scaffold-based system under direct perfusion. Ivanovic Z, editor. PLoS One 9(7):e102359PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Di Maggio N, Piccinini E, Jaworski M, Trumpp A, Wendt DJ, Martin I (2011) Toward modeling the bone marrow niche using scaffold-based 3D culture systems. Biomaterials 32(2):321–329PubMedCrossRefGoogle Scholar
  60. 60.
    Pirraco RP, Obokata H, Iwata T, Marques AP, Tsuneda S, Yamato M et al (2011) Development of osteogenic cell sheets for bone tissue engineering applications. Tissue Eng Part A 17(11–12):1507–1515PubMedCrossRefGoogle Scholar
  61. 61.
    Juneja SC, Viswanathan S, Ganguly M, Veillette C (2016) A simplified method for the aspiration of bone marrow from patients undergoing hip and knee joint replacement for isolating mesenchymal stem cells and in vitro chondrogenesis. Bone Marrow Res 2016:1–18CrossRefGoogle Scholar
  62. 62.
    Agata H, Asahina I, Watanabe N, Ishii Y, Kubo N, Ohshima S et al (2010) Characteristic change and loss of in vivo osteogenic abilities of human bone marrow stromal cells during passage. Tissue Eng Part A 16(2):663–673PubMedCrossRefGoogle Scholar
  63. 63.
    Galipeau J (2013) The mesenchymal stromal cells dilemma—does a negative phase III trial of random donor mesenchymal stromal cells in steroid-resistant graft-versus-host disease represent a death knell or a bump in the road? Cytotherapy 15(1):2–8PubMedCrossRefGoogle Scholar
  64. 64.
    Caplan AI (2007) Adult mesenchymal stem cells for tissue engineering versus regenerative medicine. J Cell Physiol [Internet] 213(2):341–347. Available from: CrossRefGoogle Scholar
  65. 65.
    Mahmoud EE, Tanaka Y, Kamei N, Harada Y, Ohdan H, Adachi N et al (2017) Monitoring immune response after allogeneic transplantation of mesenchymal stem cells for osteochondral repair. J Tissue Eng Regen Med 12(1):e275-e286PubMedCrossRefGoogle Scholar
  66. 66.
    Zuk PA, Zhu M, Mizuno H, Huang J, Futrell JW, Katz AJ et al (2001) Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng 7(2):211–228PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Aust L, Devlin B, Foster SJ, Halvorsen YDC, Hicok K, du Laney T et al (2004) Yield of human adipose-derived adult stem cells from liposuction aspirates. Cytotherapy 6(1):7–14PubMedCrossRefGoogle Scholar
  68. 68.
    Zhu M, Kohan E, Bradley J, Hedrick M, Benhaim P, Zuk P (2009) The effect of age on osteogenic, adipogenic and proliferative potential of female adipose-derived stem cells. J Tissue Eng Regen Med 3(4):290–301PubMedCrossRefGoogle Scholar
  69. 69.
    Zanetti AS, Sabliov C, Gimble JM, Hayes DJ (2013) Human adipose-derived stem cells and three-dimensional scaffold constructs: a review of the biomaterials and models currently used for bone regeneration. J Biomed Mater Res Part B Appl Biomater 101B(1):187–199CrossRefGoogle Scholar
  70. 70.
    Ko E, Yang K, Shin J, Cho S-W (2013) Polydopamine-assisted osteoinductive peptide immobilization of polymer scaffolds for enhanced bone regeneration by human adipose-derived stem cells. Biomacromolecules 14(9):3202–3213PubMedCrossRefGoogle Scholar
  71. 71.
    Kakudo N, Shimotsuma A, Miyake S, Kushida S, Kusumoto K (2008) Bone tissue engineering using human adipose-derived stem cells and honeycomb collagen scaffold. J Biomed Mater Res Part A 84A(1):191–197CrossRefGoogle Scholar
  72. 72.
    Koh YJ, Koh BI, Kim H, Joo HJ, Jin HK, Jeon J et al (2011) Stromal vascular fraction from adipose tissue forms profound vascular network through the dynamic reassembly of blood endothelial cells. Arterioscler Thromb Vasc Biol 31(5):1141–1150PubMedCrossRefGoogle Scholar
  73. 73.
    Costa M, Cerqueira MT, Santos TC, Sampaio-Marques B, Ludovico P, Marques AP et al (2017) Cell sheet engineering using the stromal vascular fraction of adipose tissue as a vascularization strategy. Acta Biomater 55:131–143PubMedCrossRefGoogle Scholar
  74. 74.
    Costa M, Pirraco RP, Cerqueira MT, Reis RL, Marques AP (2016) Growth factor-free pre-vascularization of cell sheets for tissue engineering. Methods Mol Biol:219–226Google Scholar
  75. 75.
    Gronthos S, Mankani M, Brahim J, Robey PG, Shi S (2000) Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo. Proc Natl Acad Sci U S A 97(25):13625–13630PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Kawashima N (2012) Characterisation of dental pulp stem cells: a new horizon for tissue regeneration? Arch Oral Biol 57(11):1439–1458PubMedCrossRefGoogle Scholar
  77. 77.
    d’Aquino R, De Rosa A, Lanza V, Tirino V, Laino L, Graziano A et al (2009) Human mandible bone defect repair by the grafting of dental pulp stem/progenitor cells and collagen sponge biocomplexes. Eur Cell Mater 18:75–83PubMedCrossRefGoogle Scholar
  78. 78.
    Ito K, Yamada Y, Nakamura S, Ueda M (2011) Osteogenic potential of effective bone engineering using dental pulp stem cells, bone marrow stem cells, and periosteal cells for osseointegration of dental implants. Int J Oral Maxillofac Implants 26(5):947–954PubMedPubMedCentralGoogle Scholar
  79. 79.
    Yamada Y, Ito K, Nakamura S, Ueda M, Nagasaka T (2011) Promising cell-based therapy for bone regeneration using stem cells from deciduous teeth, dental pulp, and bone marrow. Cell Transplant 20(7):1003–1013PubMedCrossRefGoogle Scholar
  80. 80.
    Tatullo M, Marrelli M, Shakesheff KM, White LJ (2015) Dental pulp stem cells: function, isolation and applications in regenerative medicine. J Tissue Eng Regen Med 9(11):1205–1216PubMedCrossRefGoogle Scholar
  81. 81.
    Degistirici Ö, Jäger M, Knipper A (2008) Applicability of cord blood-derived unrestricted somatic stem cells in tissue engineering concepts. Cell Prolif 41(3):421–440PubMedCrossRefGoogle Scholar
  82. 82.
    Atala A, Murphy SV (eds) (2014) Perinatal stem cells, vol 9781493911. Springer New York, New York, pp 1–373Google Scholar
  83. 83.
    Perin L, Sedrakyan S, Da Sacco S, De Filippo R (2008) Characterization of human amniotic fluid stem cells and their pluripotential capability. Methods Cell Biol:85–99Google Scholar
  84. 84.
    Deuse T, Stubbendorff M, Tang-Quan K, Phillips N, Kay MA, Eiermann T et al (2011) Immunogenicity and immunomodulatory properties of umbilical cord lining mesenchymal stem cells. Cell Transplant 20(5):655–667PubMedCrossRefGoogle Scholar
  85. 85.
    Baba K, Yamazaki Y, Takeda A, Uchinuma E (2014) Bone regeneration using Wharton’s jelly mesenchymal stem cells. In: Atala A, Murphy SV (eds) Perinatal stem cells. Springer New York, New York, pp 299–311Google Scholar
  86. 86.
    Kim J, Ryu S, Ju YM, Yoo JJ, Atala A (2014) Amniotic fluid-derived stem cells for bone tissue engineering. In: Atala A, Murphy SV (eds) Perinatal stem cells. Springer New York, New York, pp 107–114Google Scholar
  87. 87.
    Handschel J, Naujoks C, Depprich R, Lammers L, Kübler N, Meyer U et al (2011) Embryonic stem cells in scaffold-free three-dimensional cell culture: osteogenic differentiation and bone generation. Head Face Med 7(1):12PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Jukes JM, Both SK, Leusink A, Sterk LMT, C a v B, de Boer J (2008) Endochondral bone tissue engineering using embryonic stem cells. Proc Natl Acad Sci 105(19):6840–6845PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Marcos-Campos I, Marolt D, Petridis P, Bhumiratana S, Schmidt D, Vunjak-Novakovic G (2012) Bone scaffold architecture modulates the development of mineralized bone matrix by human embryonic stem cells. Biomaterials 33(33):8329–8342PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Kang H, Wen C, Hwang Y, Shih Y-RV, Kar M, Seo SW et al (2014) Biomineralized matrix-assisted osteogenic differentiation of human embryonic stem cells. J Mater Chem B Mater Biol Med 2(34):5676–5688PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Blum B, Benvenisty N et al (2008) Adv Cancer Res 100:133–158PubMedCrossRefGoogle Scholar
  92. 92.
    Hou P, Li Y, Zhang X, Liu C, Guan J, Li H et al (2013) Pluripotent stem cells induced from mouse somatic cells by small-molecule compounds. Science (80- ) 341(6146):651–654CrossRefGoogle Scholar
  93. 93.
    Wang P, Liu X, Zhao L, Weir MD, Sun J, Chen W et al (2015) Bone tissue engineering via human induced pluripotent, umbilical cord and bone marrow mesenchymal stem cells in rat cranium. Acta Biomater 18:236–248PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Jeon OH, Panicker LM, Lu Q, Chae JJ, Feldman RA, Elisseeff JH (2016) Human iPSC-derived osteoblasts and osteoclasts together promote bone regeneration in 3D biomaterials. Sci Rep 6(1):26761PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    TheinHan W, Liu J, Tang M, Chen W, Cheng L, Xu HHK (2013) Induced pluripotent stem cell-derived mesenchymal stem cell seeding on biofunctionalized calcium phosphate cements. Bone Res 1(4):371–384PubMedCentralCrossRefGoogle Scholar
  96. 96.
    de Peppo GM, Marcos-Campos I, Kahler DJ, Alsalman D, Shang L, Vunjak-Novakovic G et al (2013) Engineering bone tissue substitutes from human induced pluripotent stem cells. Proc Natl Acad Sci 110(21):8680–8685PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Yan H, Yu C (2007) Repair of full-thickness cartilage defects with cells of different origin in a rabbit model. Arthrosc J Arthrosc Relat Surg 23(2):178–187CrossRefGoogle Scholar
  98. 98.
    Dashtdar H, Rothan HA, Tay T, Ahmad RE, Ali R, Tay LX et al (2011) A preliminary study comparing the use of allogenic chondrogenic pre-differentiated and undifferentiated mesenchymal stem cells for the repair of full thickness articular cartilage defects in rabbits. J Orthop Res 29(9):1336–1342PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Beris AE, Lykissas MG, Papageorgiou CD, Georgoulis AD (2005) Advances in articular cartilage repair. Injury 36(4, Supplement):S14–S23PubMedCrossRefGoogle Scholar
  100. 100.
    Galois L, Freyria A-M, Herbage D, Mainard D (2005) Ingénierie tissulaire du cartilage: état des lieux et perspectives. Pathol Biol 53(10):590–598PubMedCrossRefGoogle Scholar
  101. 101.
    Oreffo ROC, Cooper C, Mason C, Clements M (2005) Mesenchymal stem cells. Stem Cell Rev 1(2):169–178PubMedCrossRefGoogle Scholar
  102. 102.
    Potian JA, Aviv H, Ponzio NM, Harrison JS, Rameshwar P (2003) Veto-like activity of mesenchymal stem cells: functional discrimination between cellular responses to alloantigens and recall antigens. J Immunol 171(7):3426 LP–3423434CrossRefGoogle Scholar
  103. 103.
    Glennie S, Soeiro I, Dyson PJ, Lam EW-F, Dazzi F (2005) Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. Blood 105(7):2821 LP–2822827CrossRefGoogle Scholar
  104. 104.
    Corcione A, Benvenuto F, Ferretti E, Giunti D, Cappiello V, Cazzanti F et al (2005) Human mesenchymal stem cells modulate B-cell functions. Blood 107(1):367 LP–367372CrossRefGoogle Scholar
  105. 105.
    Aggarwal S, Pittenger MF (2005) Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 105(4):1815 LP–1811822CrossRefGoogle Scholar
  106. 106.
    Kang S-H, Chung Y-G, Oh I-H, Kim Y-S, Min K-O, Chung J-Y (2014) Bone regeneration potential of allogeneic or autogeneic mesenchymal stem cells loaded onto cancellous bone granules in a rabbit radial defect model. Cell Tissue Res 355(1):81–88PubMedCrossRefGoogle Scholar
  107. 107.
    Arinzeh TL, Peter SJ, Archambault MP, van den Bos C, Gordon S, Kraus K et al (2003) Allogeneic mesenchymal stem cells regenerate bone in a critical-sized canine segmental defect. J Bone Joint Surg Am 85–A(10):1927–1935PubMedCrossRefGoogle Scholar
  108. 108.
    Mei L, Shen B, Ling P, Liu S, Xue J, Liu F et al (2017) Culture-expanded allogenic adipose tissue-derived stem cells attenuate cartilage degeneration in an experimental rat osteoarthritis model. Lammi MJ, editor. PLoS One 12(4):e0176107PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Zhou S, Greenberger JS, Epperly MW, Goff JP, Adler C, LeBoff MS et al (2008) Age-related intrinsic changes in human bone marrow-derived mesenchymal stem cells and their differentiation to osteoblasts. Aging Cell 7(3):335–343PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Danisovic L, Varga I, Polak S, Ulicna M, Hlavackova L, Bohmer D et al (2009) Comparison of in vitro chondrogenic potential of human mesenchymal stem cells derived from bone marrow and adipose tissue. Gen Physiol Biophys 28(1):56–62PubMedCrossRefGoogle Scholar
  111. 111.
    Saddik D, McNally EG, Richardson M (2004) MRI of Hoffa’s fat pad. Skelet Radiol 33(8):433–444CrossRefGoogle Scholar
  112. 112.
    Staeubli HU, Bollmann C, Kreutz R, Becker W, Rauschning W (1999) Quantification of intact quadriceps tendon, quadriceps tendon insertion, and suprapatellar fat pad: MR arthrography, anatomy, and cryosections in the sagittal plane. Am J Roentgenol 173(3):691–698CrossRefGoogle Scholar
  113. 113.
    Pires de Carvalho P, Hamel KM, Duarte R, King AGS, Haque M, Dietrich MA et al (2014) Comparison of infrapatellar and subcutaneous adipose tissue stromal vascular fraction and stromal/stem cells in osteoarthritic subjects. J Tissue Eng Regen Med 8(10):757–762PubMedCrossRefGoogle Scholar
  114. 114.
    Koh Y-G, Choi Y-J (2012) Infrapatellar fat pad-derived mesenchymal stem cell therapy for knee osteoarthritis. Knee 19(6):902–907PubMedCrossRefGoogle Scholar
  115. 115.
    Jurgens WJFM, van Dijk A, Doulabi BZ, Niessen FB, Ritt MJPF, van Milligen FJ et al (2009) Freshly isolated stromal cells from the infrapatellar fat pad are suitable for a one-step surgical procedure to regenerate cartilage tissue. Cytotherapy 11(8):1052–1064PubMedCrossRefGoogle Scholar
  116. 116.
    Saw K-Y, Anz A, Siew-Yoke Jee C, Merican S, Ching-Soong Ng R, Roohi SA et al (2013) Articular cartilage regeneration with autologous peripheral blood stem cells versus hyaluronic acid: a randomized controlled trial. Arthrosc J Arthrosc Relat Surg [Internet] 29(4):684–694. Available from: CrossRefGoogle Scholar
  117. 117.
    Fukumoto T, Sperling JW, Sanyal A, Fitzsimmons JS, Reinholz GG, Conover CA et al (2003) Combined effects of insulin-like growth factor-1 and transforming growth factor-β1 on periosteal mesenchymal cells during chondrogenesis in vitro. Osteoarthr Cartil 11(1):55–64PubMedCrossRefGoogle Scholar
  118. 118.
    De Bari C, Dell’Accio F, Tylzanowski P, Luyten FP (2001) Multipotent mesenchymal stem cells from adult human synovial membrane. Arthritis Rheum 44(8):1928–1942PubMedCrossRefGoogle Scholar
  119. 119.
    Baksh D, Yao R, Tuan RS (2007) Comparison of proliferative and multilineage differentiation potential of human mesenchymal stem cells derived from umbilical cord and bone marrow. Stem Cells [Internet] 25(6):1384–92. Available from: PubMedCrossRefGoogle Scholar
  120. 120.
    Chen M-Y, Lie P-C, Li Z-L, Wei X (2009) Endothelial differentiation of Wharton’s jelly–derived mesenchymal stem cells in comparison with bone marrow–derived mesenchymal stem cells. Exp Hematol [Internet] 37(5):629–640. Available from: CrossRefGoogle Scholar
  121. 121.
    Fong C-Y, Chak L-L, Biswas A, Tan J-H, Gauthaman K, Chan W-K et al (2011) Human Wharton’s jelly stem cells have unique transcriptome profiles compared to human embryonic stem cells and other mesenchymal stem cells. Stem Cell Rev Reports [Internet] 7(1):1–16. Available from: CrossRefGoogle Scholar
  122. 122.
    Ahmed TAE, Hincke MT (2014) Mesenchymal stem cell-based tissue engineering strategies for repair of articular cartilage. Histol Histopathol 29(6):669–689PubMedPubMedCentralGoogle Scholar
  123. 123.
    Berg LC, Koch TG, Heerkens T, Bessonov K, Thomsen PD, Betts DH (2009) Chondrogenic potential of mesenchymal stromal cells derived from equine bone marrow and umbilical cord blood. Vet Comp Orthop Traumatol 22(5):363–370PubMedCrossRefGoogle Scholar
  124. 124.
    Adachi N, Sato K, Usas A, Fu FH, Ochi M, Han C-W et al (2002) Muscle derived, cell based ex vivo gene therapy for treatment of full thickness articular cartilage defects. J Rheumatol 29(9):1920 LP–1921930Google Scholar
  125. 125.
    Wei Y, Zeng W, Wan R, Wang J, Zhou Q, Qiu S et al (2012) Chondrogenic differentiation of induced pluripotent stem cells from osteoarthritic chondrocytes in alginate matrix. Eur Cell Mater 23:1–12PubMedCrossRefGoogle Scholar
  126. 126.
    Medvedev SP, Grigor’eva EV, Shevchenko AI, Malakhova AA, Dementyeva EV, Shilov AA et al (2010) Human induced pluripotent stem cells derived from fetal neural stem cells successfully undergo directed differentiation into cartilage. Stem Cells Dev 20(6):1099–1112PubMedCrossRefGoogle Scholar
  127. 127.
    Nguyen D, Hägg DA, Forsman A, Ekholm J, Nimkingratana P, Brantsing C et al (2017) Cartilage tissue engineering by the 3D bioprinting of iPS cells in a Nanocellulose/alginate bioink. Sci Rep 7:658PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Menendez L, Kulik MJ, Page AT, Park SS, Lauderdale JD, Cunningham ML et al (2013) Directed differentiation of human pluripotent cells to neural crest stem cells. Nat Protoc 8(1):203–212PubMedCrossRefGoogle Scholar
  129. 129.
    Ishii M, Arias AC, Liu L, Chen Y-B, Bronner ME, Maxson RE (2012) A stable cranial neural crest cell line from mouse. Stem Cells Dev 21(17):3069–3080PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Nagoshi N, Shibata S, Kubota Y, Nakamura M, Nagai Y, Satoh E et al (2017) Ontogeny and multipotency of neural crest-derived stem cells in mouse bone marrow, dorsal root ganglia, and whisker pad. Cell Stem Cell 2(4):392–403CrossRefGoogle Scholar
  131. 131.
    Chijimatsu R, Ikeya M, Yasui Y, Ikeda Y, Ebina K, Moriguchi Y et al (2017) Characterization of mesenchymal stem cell-like cells derived from human iPSCs via neural crest development and their application for osteochondral repair. Stem Cells Int 2017:1960965PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Zhang S, Chu WC, Lai RC, Lim SK, Hui JHP, Toh WS (2017) Exosomes derived from human embryonic mesenchymal stem cells promote osteochondral regeneration. Osteoarthr Cartil 24(12):2135–2140CrossRefGoogle Scholar
  133. 133.
    Solchaga LA, Gao J, Dennis JE, Awadallah A, Lundberg M, Caplan AI et al (2002) Treatment of osteochondral defects with autologous bone marrow in a hyaluronan-based delivery vehicle. Tissue Eng 8(2):333–347PubMedCrossRefGoogle Scholar
  134. 134.
    Betsch M, Schneppendahl J, Thuns S, Herten M, Sager M, Jungbluth P et al (2013) Bone marrow aspiration concentrate and platelet rich plasma for osteochondral repair in a porcine osteochondral defect model. PLoS One 8(8):e71602PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Oshima Y, Watanabe N, Matsuda K, Takai S, Kawata M, Kubo T (2017) Fate of transplanted bone-marrow-derived mesenchymal cells during osteochondral repair using transgenic rats to simulate autologous transplantation. Osteoarthr Cartil 12(10):811–817CrossRefGoogle Scholar
  136. 136.
    Saw K-Y, Hussin P, Loke S-C, Azam M, Chen H-C, Tay Y-G et al (2017) Articular cartilage regeneration with autologous marrow aspirate and hyaluronic acid: an experimental study in a goat model. Arthroscopy 25(12):1391–1400CrossRefGoogle Scholar
  137. 137.
    Oliveira JM, Rodrigues MT, Silva SS, Malafaya PB, Gomes ME, Viegas CA et al (2006) Novel hydroxyapatite/chitosan bilayered scaffold for osteochondral tissue-engineering applications: Scaffold design and its performance when seeded with goat bone marrow stromal cells. Biomaterials [Internet] 27(36):6123–6137. Available from: CrossRefGoogle Scholar
  138. 138.
    Wang X, Wenk E, Zhang X, Meinel L, Vunjak-Novakovic G, Kaplan DL (2009) Growth factor gradients via microsphere delivery in biopolymer scaffolds for osteochondral tissue engineering. J Control Release 134(2):81–90PubMedCrossRefGoogle Scholar
  139. 139.
    Lee Y-H, Wu H-C, Yeh C-W, Kuan C-H, Liao H-T, Hsu H-C et al (2017) Enzyme-crosslinked gene-activated matrix for the induction of mesenchymal stem cells in osteochondral tissue regeneration. Acta Biomater 63(Supplement C):210–226PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Kuiper NJ, Wang QG, Cartmell SH (2014) A perfusion co-culture bioreactor for osteochondral tissue engineered plugs. J Biomater Tissue Eng 4(2):162–171CrossRefGoogle Scholar
  141. 141.
    Goldman SM, Barabino GA (2016) Spatial engineering of osteochondral tissue constructs through microfluidically directed differentiation of mesenchymal stem cells. Biores Open Access 5(1):109–117PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Jiang J, Nicoll SB, Lu HH (2005) Co-culture of osteoblasts and chondrocytes modulates cellular differentiation in vitro. Biochem Biophys Res Commun 338(2):762–770PubMedCrossRefGoogle Scholar
  143. 143.
    Sheehy EJ, Vinardell T, Buckley CT, Kelly DJ (2013) Engineering osteochondral constructs through spatial regulation of endochondral ossification. Acta Biomater 9(3):5484–5492PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Lee W, Park J (2016) 3D patterned stem cell differentiation using thermo-responsive methylcellulose hydrogel molds. Sci Rep 6:29408PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Lam J, Lu S, Meretoja VV, Tabata Y, Mikos AG, Kasper FK (2014) Generation of osteochondral tissue constructs with chondrogenically and osteogenically predifferentiated mesenchymal stem cells encapsulated in bilayered hydrogels. Acta Biomater 10(3):1112–1123PubMedCrossRefGoogle Scholar
  146. 146.
    Mellor LF, Mohiti-Asli M, Williams J, Kannan A, Dent MR, Guilak F et al (2015) Extracellular calcium modulates Chondrogenic and osteogenic differentiation of human adipose-derived stem cells: a novel approach for osteochondral tissue engineering using a single stem cell source. Tissue Eng Part A 21(17–18):2323–2333PubMedPubMedCentralCrossRefGoogle Scholar
  147. 147.
    Song K, Li W, Wang H, Zhang Y, Li L, Wang Y, Wang H, Wang L, Liu T (2016) Development and fabrication of a two-layer tissue engineered osteochondral composite using hybrid hydrogel-cancellous bone scaffolds in a spinner flask. Biomed Mater 11(6):65002CrossRefGoogle Scholar
  148. 148.
    Cakmak S, Cakmak AS, Kaplan DL, Gumusderelioglu M (2016) A silk fibroin and peptide amphiphile-based co-culture model for osteochondral tissue engineering. Macromol Biosci 16(8):1212–1226PubMedCrossRefGoogle Scholar
  149. 149.
    Amadori S, Torricelli P, Panzavolta S, Parrilli A, Fini M, Bigi A (2015) Multi-layered scaffolds for osteochondral tissue engineering: in vitro response of co-cultured human mesenchymal stem cells. Macromol Biosci 15(11):1535–1545PubMedCrossRefGoogle Scholar
  150. 150.
    Galperin A, Oldinski RA, Florczyk SJ, Bryers JD, Zhang M, Ratner BD (2013) Integrated bi-layered scaffold for osteochondral tissue engineering. Adv Healthc Mater 2(6):872–883PubMedCrossRefGoogle Scholar
  151. 151.
    Gao J, Dennis JE, Solchaga LA, Awadallah AS, Goldberg VM, Caplan AI (2001) Tissue-engineered fabrication of an osteochondral composite graft using rat bone marrow-derived mesenchymal stem cells. Tissue Eng 7(4):363–371PubMedCrossRefGoogle Scholar
  152. 152.
    Brunger JM, Huynh NPT, Guenther CM, Perez-Pinera P, Moutos FT, Sanchez-Adams J et al (2014) Scaffold-mediated lentiviral transduction for functional tissue engineering of cartilage. Proc Natl Acad Sci U S A 111(9):E798–E806PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Brunger JM, Huynh NPT, Moutos FT, Guilak F, Gersbach CA (2017) 407. Biomaterial-mediated lentiviral gene delivery for osteochondral tissue engineering. Mol Ther 22:S155Google Scholar
  154. 154.
    Zhao Q, Wang S, Tian J, Wang L, Dong S, Xia T et al (2013) Combination of bone marrow concentrate and PGA scaffolds enhance bone marrow stimulation in rabbit articular cartilage repair. J Mater Sci Mater Med 24(3):793–801PubMedCrossRefGoogle Scholar
  155. 155.
    Agung M, Ochi M, Yanada S, Adachi N, Izuta Y, Yamasaki T et al (2006) Mobilization of bone marrow-derived mesenchymal stem cells into the injured tissues after intraarticular injection and their contribution to tissue regeneration. Knee Surg Sport Traumatol Arthrosc 14(12):1307–1314CrossRefGoogle Scholar
  156. 156.
    Food and Drug Administration (FDA) (2004). Innovation or stagnation: challenge and opportunity on the critical path to New Medical Products [Internet]. Available from:

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Raphaël F. Canadas
    • 1
    • 2
  • Rogério P. Pirraco
    • 1
    • 2
  • J. Miguel Oliveira
    • 1
    • 2
    • 3
  • Rui L. Reis
    • 1
    • 2
    • 3
  • Alexandra P. Marques
    • 1
    • 2
    • 3
    Email author
  1. 1.3B’s Research Group – Biomaterials, Biodegradables, and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative MedicineBarco, GuimarãesPortugal
  2. 2.ICVS/3B’s - PT Government Associate LaboratoryBraga/GuimarãesPortugal
  3. 3.The Discoveries Centre for Regenerative and Precision Medicine, Headquarters at the University of MinhoBarco, GuimarãesPortugal

Personalised recommendations