Chondrocytes, Mesenchymal Stem Cells, and Their Combination in Articular Cartilage Regenerative Medicine

Abstract

Articular cartilage (AC) is a highly organized connective tissue lining, covering the ends of bones within articulating joints. Its highly ordered structure is essential for stable motion and provides a frictionless surface easing load transfer. AC is vulnerable to lesions and, because it is aneural and avascular, it has limited self-repair potential which often leads to osteoarthritis. To date, no fully successful treatment for osteoarthritis has been reported. Thus, the development of innovative therapeutic approaches is desperately needed. Autologous chondrocyte implantation, the only cell-based surgical intervention approved in the United States for treating cartilage defects, has limitations because of de-differentiation of articular chondrocytes (AChs) upon in vitro expansion. De-differentiation can be abated if initial populations of AChs are co-cultured with mesenchymal stem cells (MSCs), which not only undergo chondrogenesis themselves but also support chondrocyte vitality. In this review we summarize studies utilizing AChs, non-AChs, and MSCs and compare associated outcomes. Moreover, a comprehensive set of recent human studies using chondrocytes to direct MSC differentiation, MSCs to support chondrocyte re-differentiation and proliferation in co-culture environments, and exploratory animal intra- and inter-species studies are systematically reviewed and discussed in an innovative manner allowing side-by-side comparisons of protocols and outcomes. Finally, a comprehensive set of recommendations are made for future studies.

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Figure 1

Abbreviations

ABMSCT:

Autologous bone marrow derived mesenchymal stem cell transplantation

AC:

Articular cartilage

ACAN:

Aggrecan

ACh:

Articular chondrocyte

ACI:

Autologous chondrocyte implantation

ACTE:

Articular cartilage tissue engineering

ALP:

Alkaline phosphatase

AMSC:

Adipose derived mesenchymal stem cell

AMSCT:

Adipose mesenchymal stem cell transplantation

b:

Bovine

BMP:

Bone morphogenic protein

BMSC:

Bone marrow derived mesenchymal stem cell

C-ACI:

Col I/III-covered ACI

Ch:

Chondrocyte

CM:

Conditioned medium

Col:

Collagen

COMP:

Cartilage oligomeric matrix protein

Dex:

Dexamethasone

ECM:

Extracellular matrix

FGF:

Fibroblast growth factor

GAG:

Glycosaminoglycans

GF:

Growth factor

GFP:

Green fluorescent protein

h:

Human

IGF:

Insulin like growth factor

IHC:

Immunohistochemistry

iMSC:

Induced MSC w/specified GFs

M-ACI:

Matrix-induced ACI

MMP:

Matrix metallopeptidase

MSC:

Mesenchymal stem cell

OA:

Osteoarthritis

oaACh:

Osteoarthritic ACh

P#:

Passage number

P-ACI:

Periosteum-covered ACI

PD:

Population doubling

PTHrP:

Parathyroid hormone related peptide

Q-PCR:

Quantitative polymerase chain reaction

qRT-PCR:

Quantitative reverse transcription polymerase chain reaction

RT-PCR:

Real time polymerase chain reaction

SC:

Stem cell

SCID:

Severe combined immunodeficiency

TE:

Tissue engineering

TGF-β:

Transforming growth factor

TIMP:

Tissue inhibitor metallopeptidase

USDA:

United State Food & Drug Administration

References

  1. 1.

    Acharya, C., A. Adesida, P. Zajac, M. Mumme, J. Riesle, I. Martin, and A. Barbero. Enhanced chondrocyte proliferation and mesenchymal stromal cells chondrogenesis in coculture pellets mediate improved cartilage formation. J. Cell. Physiol. 227:88–97, 2012.

    CAS  PubMed  Article  Google Scholar 

  2. 2.

    Adesida, A. B., A. Mulet-Sierra, and N. M. Jomha. Hypoxia mediated isolation and expansion enhances the chondrogenic capacity of bone marrow mesenchymal stromal cells. Stem Cell Res. Ther. 3:9, 2012.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  3. 3.

    Afizah, H., Z. Yang, J. H. Hui, H. W. Ouyang, and E. H. Lee. A comparison between the chondrogenic potential of human bone marrow stem cells (BMSCs) and adipose-derived stem cells (ADSCs) taken from the same donors. Tissue Eng. 13:659–666, 2007.

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Ahmed, N., R. Dreier, A. Gopferich, J. Grifka, and S. Grassel. Soluble signalling factors derived from differentiated cartilage tissue affect chondrogenic differentiation of rat adult marrow stromal cells. Cell Physiol. Biochem. 20:665–678, 2007.

    CAS  PubMed  Article  Google Scholar 

  5. 5.

    Alsalameh, S., R. Amin, T. Gemba, and M. Lotz. Identification of mesenchymal progenitor cells in normal and osteoarthritic human articular cartilage. Arthritis Rheum. 50:1522–1532, 2004.

    PubMed  Article  Google Scholar 

  6. 6.

    Angele, P., J. U. Yoo, C. Smith, J. Mansour, K. J. Jepsen, M. Nerlich, and B. Johnstone. Cyclic hydrostatic pressure enhances the chondrogenic phenotype of human mesenchymal progenitor cells differentiated in vitro. J. Orthop. Res. 21:451–457, 2003.

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Arufe, M. C., A. De la Fuente, I. Fuentes, F. J. De Toro, and F. J. Blanco. Chondrogenic potential of subpopulations of cells expressing mesenchymal stem cell markers derived from human synovial membranes. J. Cell Biochem. 111:834–845, 2010.

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Aung, A., G. Gupta, G. Majid, and S. Varghese. Osteoarthritic chondrocyte-secreted morphogens induce chondrogenic differentiation of human mesenchymal stem cells. Arthritis Rheum. 63:148–158, 2011.

    PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    Baksh, D., L. Song, and R. S. Tuan. Adult mesenchymal stem cells: characterization, differentiation, and application in cell and gene therapy. J. Cell Mol. Med. 8:301–316, 2004.

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    Baksh, D., R. Yao, and R. S. Tuan. Comparison of proliferative and multilineage differentiation potential of human mesenchymal stem cells derived from umbilical cord and bone marrow. Stem Cells 25:1384–1392, 2007.

    CAS  PubMed  Article  Google Scholar 

  11. 11.

    Barbero, A., S. Grogan, D. Schafer, M. Heberer, P. Mainil-Varlet, and I. Martin. Age related changes in human articular chondrocyte yield, proliferation and post-expansion chondrogenic capacity. Osteoarthr. Cartil. 12:476–484, 2004.

    PubMed  Article  Google Scholar 

  12. 12.

    Bark, S., T. Piontek, P. Behrens, S. Mkalaluh, D. Varoga, and J. Gille. Enhanced microfracture techniques in cartilage knee surgery: fact or fiction? World J. Orthop. 5:444–449, 2014.

    PubMed  PubMed Central  Article  Google Scholar 

  13. 13.

    Bartlett, W., J. A. Skinner, C. R. Gooding, R. W. Carrington, A. M. Flanagan, T. W. Briggs, and G. Bentley. Autologous chondrocyte implantation versus matrix-induced autologous chondrocyte implantation for osteochondral defects of the knee: a prospective, randomised study. J. Bone Joint Surg. Br. 87:640–645, 2005.

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Bathe, M., G. C. Rutledge, A. J. Grodzinsky, and B. Tidor. A coarse-grained molecular model for glycosaminoglycans: application to chondroitin, chondroitin sulfate, and hyaluronic acid. Biophys. J. 88:3870–3887, 2005.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

    Batty, L., S. Dance, S. Bajaj, and B. J. Cole. Autologous chondrocyte implantation: an overview of technique and outcomes. ANZ J. Surg. 81:18–25, 2011.

    PubMed  Article  Google Scholar 

  16. 16.

    Baxter, M. A., R. F. Wynn, S. N. Jowitt, J. E. Wraith, L. J. Fairbairn, and I. Bellantuono. Study of telomere length reveals rapid aging of human marrow stromal cells following in vitro expansion. Stem Cells 22:675–682, 2004.

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Beiser, I. H., and I. O. Kanat. Subchondral bone drilling: a treatment for cartilage defects. J. Foot Surg. 29:595–601, 1990.

    CAS  PubMed  Google Scholar 

  18. 18.

    Bernstein, P., M. Dong, S. Graupher, D. Corbeil, M. Gelinsky, K. P. Gunther, and S. Fickert. Sox9 expression of alginate-encapsulated chondrocytes is stimulated by low cell density. J. Biomed. Mater. Res. A 91:910–918, 2009.

    PubMed  Article  CAS  Google Scholar 

  19. 19.

    Bian, L., D. Y. Zhai, R. L. Mauck, and J. A. Burdick. Coculture of human mesenchymal stem cells and articular chondrocytes reduces hypertrophy and enhances functional properties of engineered cartilage. Tissue Eng. Part A 17:1137–1145, 2011.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. 20.

    Bieback, K., S. Kern, A. Kocaomer, K. Ferlik, and P. Bugert. Comparing mesenchymal stromal cells from different human tissues: bone marrow, adipose tissue and umbilical cord blood. Biomed. Mater. Eng. 18:S71–S76, 2008.

    CAS  PubMed  Google Scholar 

  21. 21.

    Bohme, K., K. H. Winterhalter, and P. Bruckner. Terminal differentiation of chondrocytes in culture is a spontaneous process and is arrested by transforming growth factor-beta 2 and basic fibroblast growth factor in synergy. Exp. Cell Res. 216:191–198, 1995.

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Brittberg, M., A. Lindahl, A. Nilsson, C. Ohlsson, O. Isaksson, and L. Peterson. Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N. Engl. J. Med. 331:889–895, 1994.

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Buckwalter, J. A. Articular cartilage injuries. Clin. Orthop. Relat. Res. 402:21–37, 2002.

    PubMed  Article  Google Scholar 

  24. 24.

    Buravkova, L. B., E. R. Andreeva, V. Gogvadze, and B. Zhivotovsky. Mesenchymal stem cells and hypoxia: where are we? Mitochondrion 19 Pt A:105–112, 2014.

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Candrian, C., D. Vonwil, A. Barbero, E. Bonacina, S. Miot, J. Farhadi, D. Wirz, S. Dickinson, A. Hollander, M. Jakob, Z. Li, M. Alini, M. Heberer, and I. Martin. Engineered cartilage generated by nasal chondrocytes is responsive to physical forces resembling joint loading. Arthritis Rheum. 58:197–208, 2008.

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Chang, Q., W. D. Cui, and W. M. Fan. Co-culture of chondrocytes and bone marrow mesenchymal stem cells in vitro enhances the expression of cartilaginous extracellular matrix components. Braz. J. Med. Biol. Res. 44:303–310, 2011.

    CAS  Article  Google Scholar 

  27. 27.

    Chen, W. H., M. T. Lai, A. T. Wu, C. C. Wu, J. G. Gelovani, C. T. Lin, S. C. Hung, W. T. Chiu, and W. P. Deng. In vitro stage-specific chondrogenesis of mesenchymal stem cells committed to chondrocytes. Arthritis Rheum. 60:450–459, 2009.

    CAS  PubMed  Article  Google Scholar 

  28. 28.

    Chen, F. H., K. T. Rousche, and R. S. Tuan. Technology insight: adult stem cells in cartilage regeneration and tissue engineering. Nat. Clin. Pract. Rheumatol. 2:373–382, 2006.

    CAS  PubMed  Article  Google Scholar 

  29. 29.

    Cherubino, P., F. A. Grassi, P. Bulgheroni, and M. Ronga. Autologous chondrocyte implantation using a bilayer collagen membrane: a preliminary report. J. Orthop. Surg. 11:10–15, 2003.

    CAS  Google Scholar 

  30. 30.

    Cheung, W. H., K. M. Lee, K. P. Fung, P. Y. Lui, and K. S. Leung. TGF-beta1 is the factor secreted by proliferative chondrocytes to inhibit neo-angiogenesis. J. Cell Biochem. Suppl. 36:79–88, 2001.

    PubMed  Google Scholar 

  31. 31.

    Chu, C. R., M. Szczodry, and S. Bruno. Animal models for cartilage regeneration and repair. Tissue Eng. Part B Rev. 16:105–115, 2010.

    PubMed  PubMed Central  Article  Google Scholar 

  32. 32.

    Cook, J. L., C. T. Hung, K. Kuroki, A. M. Stoker, C. R. Cook, F. M. Pfeiffer, S. L. Sherman, and J. P. Stannard. Animal models of cartilage repair. Bone Joint Res. 3:89–94, 2014.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    Cooke, M. E., A. A. Allon, T. Cheng, A. C. Kuo, H. T. Kim, T. P. Vail, R. S. Marcucio, R. A. Schneider, J. C. Lotz, and T. Alliston. Structured three-dimensional co-culture of mesenchymal stem cells with chondrocytes promotes chondrogenic differentiation without hypertrophy. Osteoarthr. Cartil. 19:1210–1218, 2011.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. 34.

    da Silva Meirelles, L., P. C. Chagastelles, and N. B. Nardi. Mesenchymal stem cells reside in virtually all post-natal organs and tissues. J. Cell Sci. 119:2204–2213, 2006.

    CAS  Article  Google Scholar 

  35. 35.

    Dahlin, R. L., L. A. Kinard, J. Lam, C. J. Needham, S. Lu, F. K. Kasper, and A. G. Mikos. Articular chondrocytes and mesenchymal stem cells seeded on biodegradable scaffolds for the repair of cartilage in a rat osteochondral defect model. Biomaterials 35:7460–7469, 2014.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. 36.

    Dahlin, R. L., M. Ni, V. V. Meretoja, F. K. Kasper, and A. G. Mikos. TGF-beta3-induced chondrogenesis in co-cultures of chondrocytes and mesenchymal stem cells on biodegradable scaffolds. Biomaterials 35:123–132, 2014.

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    De Bari, C., F. Dell’Accio, and F. P. Luyten. Failure of in vitro-differentiated mesenchymal stem cells from the synovial membrane to form ectopic stable cartilage in vivo. Arthritis Rheum. 50:142–150, 2004.

    PubMed  Article  CAS  Google Scholar 

  38. 38.

    De Bari, C., F. Dell’Accio, P. Tylzanowski, and F. P. Luyten. Multipotent mesenchymal stem cells from adult human synovial membrane. Arthritis Rheum. 44:1928–1942, 2001.

    PubMed  Article  Google Scholar 

  39. 39.

    Diao, H. J., C. W. Yeung, C. H. Yan, G. C. Chan, and B. P. Chan. Bidirectional and mutually beneficial interactions between human mesenchymal stem cells and osteoarthritic chondrocytes in micromass co-cultures. Regen. Med. 8:257–269, 2013.

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Dickhut, A., K. Pelttari, P. Janicki, W. Wagner, V. Eckstein, M. Egermann, and W. Richter. Calcification or dedifferentiation: requirement to lock mesenchymal stem cells in a desired differentiation stage. J. Cell Physiol. 219:219–226, 2009.

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Djouad, F., B. Delorme, M. Maurice, C. Bony, F. Apparailly, P. Louis-Plence, F. Canovas, P. Charbord, D. Noel, and C. Jorgensen. Microenvironmental changes during differentiation of mesenchymal stem cells towards chondrocytes. Arthritis Res. Ther. 9:R33, 2007.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  42. 42.

    Dominici, M., K. Le Blanc, I. Mueller, I. Slaper-Cortenbach, F. Marini, D. Krause, R. Deans, A. Keating, D. Prockop, and E. Horwitz. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8:315–317, 2006.

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Erices, A., P. Conget, and J. J. Minguell. Mesenchymal progenitor cells in human umbilical cord blood. Br. J. Haematol. 109:235–242, 2000.

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    Fehrer, C., and G. Lepperdinger. Mesenchymal stem cell aging. Exp. Gerontol. 40:926–930, 2005.

    CAS  PubMed  Article  Google Scholar 

  45. 45.

    Fischer, J., A. Dickhut, M. Rickert, and W. Richter. Human articular chondrocytes secrete parathyroid hormone-related protein and inhibit hypertrophy of mesenchymal stem cells in coculture during chondrogenesis. Arthritis Rheum. 62:2696–2706, 2010.

    CAS  PubMed  Article  Google Scholar 

  46. 46.

    Foldager, C. B. Advances in autologous chondrocyte implantation and related techniques for cartilage repair. Dan. Med. J. 60:B4600, 2013.

    PubMed  Google Scholar 

  47. 47.

    Foldager, C. B., C. Bunger, A. B. Nielsen, M. Ulrich-Vinther, S. Munir, H. Everland, and M. Lind. Dermatan sulphate in methoxy polyethylene glycol-polylactide-co-glycolic acid scaffolds upregulates fibronectin gene expression but has no effect on in vivo osteochondral repair. Int. Orthop. 36:1507–1513, 2012.

    PubMed  PubMed Central  Article  Google Scholar 

  48. 48.

    Foldager, C. B., S. Munir, M. Ulrik-Vinther, K. Soballe, C. Bunger, and M. Lind. Validation of suitable house keeping genes for hypoxia-cultured human chondrocytes. BMC Mol. Biol. 10:1471–2199, 2009.

    Article  CAS  Google Scholar 

  49. 49.

    Foldager, C. B., A. B. Nielsen, S. Munir, M. Ulrich-Vinther, K. Soballe, C. Bunger, and M. Lind. Combined 3D and hypoxic culture improves cartilage-specific gene expression in human chondrocytes. Acta Orthop. 82:234–240, 2011.

    PubMed  PubMed Central  Article  Google Scholar 

  50. 50.

    Francioli, S. E., C. Candrian, K. Martin, M. Heberer, I. Martin, and A. Barbero. Effect of three-dimensional expansion and cell seeding density on the cartilage-forming capacity of human articular chondrocytes in type II collagen sponges. J. Biomed. Mater. Res. A 95:924–931, 2010.

    PubMed  Article  CAS  Google Scholar 

  51. 51.

    Fraser, J. K., I. Wulur, Z. Alfonso, and M. H. Hedrick. Fat tissue: an underappreciated source of stem cells for biotechnology. Trends Biotechnol. 24:150–154, 2006.

    CAS  PubMed  Article  Google Scholar 

  52. 52.

    Fu, W. L., C. Y. Zhou, and J. K. Yu. A new source of mesenchymal stem cells for articular cartilage repair: MSCs derived from mobilized peripheral blood share similar biological characteristics in vitro and chondrogenesis in vivo as MSCs from bone marrow in a rabbit model. Am. J. Sports Med. 10:10, 2013.

    Google Scholar 

  53. 53.

    Giovannini, S., J. Diaz-Romero, T. Aigner, P. Heini, P. Mainil-Varlet, and D. Nesic. Micromass co-culture of human articular chondrocytes and human bone marrow mesenchymal stem cells to investigate stable neocartilage tissue formation in vitro. Eur. Cells Mater. 20:245–259, 2010.

    CAS  Google Scholar 

  54. 54.

    Glowacki, J., and S. Mizuno. Collagen scaffolds for tissue engineering. Biopolymers 89:338–344, 2008.

    CAS  PubMed  Article  Google Scholar 

  55. 55.

    Goldring, M. B., and K. B. Marcu. Cartilage homeostasis in health and rheumatic diseases. Arthritis Res. Ther. 11:19, 2009.

    Article  CAS  Google Scholar 

  56. 56.

    Goldring, M. B., M. Otero, D. A. Plumb, C. Dragomir, M. Favero, K. El Hachem, K. Hashimoto, H. I. Roach, E. Olivotto, R. M. Borzi, and K. B. Marcu. Roles of inflammatory and anabolic cytokines in cartilage metabolism: signals and multiple effectors converge upon MMP-13 regulation in osteoarthritis. Eur. Cell Mater. 21:202–220, 2011.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Gooding, C. R., W. Bartlett, G. Bentley, J. A. Skinner, R. Carrington, and A. Flanagan. A prospective, randomised study comparing two techniques of autologous chondrocyte implantation for osteochondral defects in the knee: periosteum covered versus type I/III collagen covered. Knee 13:203–210, 2006.

    CAS  PubMed  Article  Google Scholar 

  58. 58.

    Grad, S., D. Eglin, M. Alini, and M. J. Stoddart. Physical stimulation of chondrogenic cells in vitro: a review. Clin. Orthop. Relat. Res. 469:2764–2772, 2011.

    PubMed  PubMed Central  Article  Google Scholar 

  59. 59.

    Han, B., J. Li, Z. Li, L. Guo, S. Wang, P. Liu, and Y. Wu. Trichostatin A stabilizes the expression of pluripotent genes in human mesenchymal stem cells during ex vivo expansion. PLoS One 8:e81781, 2013.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  60. 60.

    Hansen, O. M., C. B. Foldager, B. B. Christensen, H. Everland, and M. Lind. Increased chondrocyte seeding density has no positive effect on cartilage repair in an MPEG-PLGA scaffold. Knee Surg. Sports Traumatol. Arthrosc. 21:485–493, 2013.

    PubMed  Article  Google Scholar 

  61. 61.

    Hao, H., G. Chen, J. Liu, D. Ti, Y. Zhao, S. Xu, X. Fu, and W. Han. Culturing on Wharton’s jelly extract delays mesenchymal stem cell senescence through p53 and p16INK4a/pRb pathways. Plos One 8:13, 2013.

    Google Scholar 

  62. 62.

    Heath, C. A., and S. R. Magari. Mini-review: mechanical factors affecting cartilage regeneration in vitro. Biotechnol. Bioeng. 50:430–437, 1996.

    CAS  PubMed  Article  Google Scholar 

  63. 63.

    Hildner, F., S. Concaro, A. Peterbauer, S. Wolbank, M. Danzer, A. Lindahl, P. Gatenholm, H. Redl, and M. van Griensven. Human adipose-derived stem cells contribute to chondrogenesis in coculture with human articular chondrocytes. Tissue Eng. Part A 15:3961–3969, 2009.

    CAS  PubMed  Article  Google Scholar 

  64. 64.

    Hilkens, P., P. Gervois, Y. Fanton, J. Vanormelingen, W. Martens, T. Struys, C. Politis, I. Lambrichts, and A. Bronckaers. Effect of isolation methodology on stem cell properties and multilineage differentiation potential of human dental pulp stem cells. Cell Tissue Res. 353:65–78, 2013.

    CAS  PubMed  Article  Google Scholar 

  65. 65.

    Hubka, K. M., R. L. Dahlin, V. V. Meretoja, F. K. Kasper, and A. G. Mikos. Enhancing chondrogenic phenotype for cartilage tissue engineering: monoculture and coculture of articular chondrocytes and mesenchymal stem cells. Tissue Eng. Part B Rev. 20:641–654, 2014.

    PubMed  PubMed Central  Article  Google Scholar 

  66. 66.

    Hunziker, E. B. Articular cartilage repair: basic science and clinical progress. A review of the current status and prospects. Osteoarthr. Cartil. 10:432–463, 2002.

    CAS  PubMed  Article  Google Scholar 

  67. 67.

    Hwang, N. S., and J. Elisseeff. Application of stem cells for articular cartilage regeneration. J. Knee Surg. 22:60–71, 2009.

    PubMed  Article  Google Scholar 

  68. 68.

    Hwang, N. S., S. G. Im, P. B. Wu, D. A. Bichara, X. Zhao, M. A. Randolph, R. Langer, and D. G. Anderson. Chondrogenic priming adipose-mesenchymal stem cells for cartilage tissue regeneration. Pharm. Res. 28:1395–1405, 2011.

    CAS  PubMed  Article  Google Scholar 

  69. 69.

    Hwang, N. S., S. Varghese, C. Puleo, Z. Zhang, and J. Elisseeff. Morphogenetic signals from chondrocytes promote chondrogenic and osteogenic differentiation of mesenchymal stem cells. J. Cell Physiol. 212:281–284, 2007.

    CAS  PubMed  Article  Google Scholar 

  70. 70.

    Ikenoue, T., M. C. Trindade, M. S. Lee, E. Y. Lin, D. J. Schurman, S. B. Goodman, and R. L. Smith. Mechanoregulation of human articular chondrocyte aggrecan and type II collagen expression by intermittent hydrostatic pressure in vitro. J. Orthop. Res. 21:110–116, 2003.

    CAS  PubMed  Article  Google Scholar 

  71. 71.

    Im, G. I., Y. W. Shin, and K. B. Lee. Do adipose tissue-derived mesenchymal stem cells have the same osteogenic and chondrogenic potential as bone marrow-derived cells? Osteoarthr. Cartil. 13:845–853, 2005.

    PubMed  Article  Google Scholar 

  72. 72.

    In ‘t Anker, P. S., S. A. Scherjon, C. Kleijburg-van der Keur, G. M. de Groot-Swings, F. H. Claas, W. E. Fibbe, and H. H. Kanhai. Isolation of mesenchymal stem cells of fetal or maternal origin from human placenta. Stem Cells 22:1338–1345, 2004.

    PubMed  Article  Google Scholar 

  73. 73.

    Inada, M., Y. Wang, M. H. Byrne, M. U. Rahman, C. Miyaura, C. Lopez-Otin, and S. M. Krane. Critical roles for collagenase-3 (Mmp13) in development of growth plate cartilage and in endochondral ossification. Proc. Natl. Acad. Sci. USA 101:17192–17197, 2004.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. 74.

    Iwata, H., S. Ono, K. Sato, T. Sato, and M. Kawamura. Bone morphogenetic protein-induced muscle- and synovium-derived cartilage differentiation in vitro. Clin. Orthop. Relat. Res. 296:295–300, 1993.

    PubMed  Google Scholar 

  75. 75.

    Izadpanah, R., C. Trygg, B. Patel, C. Kriedt, J. Dufour, J. M. Gimble, and B. A. Bunnell. Biologic properties of mesenchymal stem cells derived from bone marrow and adipose tissue. J. Cell Biochem. 99:1285–1297, 2006.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. 76.

    Jakob, M., O. Demarteau, D. Schafer, B. Hintermann, W. Dick, M. Heberer, and I. Martin. Specific growth factors during the expansion and redifferentiation of adult human articular chondrocytes enhance chondrogenesis and cartilaginous tissue formation in vitro. J. Cell Biochem. 81:368–377, 2001.

    CAS  PubMed  Article  Google Scholar 

  77. 77.

    Jakob, M., O. Demarteau, D. Schafer, M. Stumm, M. Heberer, and I. Martin. Enzymatic digestion of adult human articular cartilage yields a small fraction of the total available cells. Connect. Tissue Res. 44:173–180, 2003.

    CAS  PubMed  Article  Google Scholar 

  78. 78.

    Johnson, T. S., J. W. Xu, V. V. Zaporojan, J. M. Mesa, C. Weinand, M. A. Randolph, L. J. Bonassar, J. M. Winograd, and M. J. Yaremchuk. Integrative repair of cartilage with articular and nonarticular chondrocytes. Tissue Eng. 10:1308–1315, 2004.

    CAS  PubMed  Article  Google Scholar 

  79. 79.

    Johnson, K., S. T. Zhu, M. S. Tremblay, J. N. Payette, J. N. Wang, L. C. Bouchez, S. Meeusen, A. Althage, C. Y. Cho, X. Wu, and P. G. Schultz. A stem cell-based approach to cartilage repair. Science 336:717–721, 2012.

    CAS  PubMed  Article  Google Scholar 

  80. 80.

    Johnstone, B., T. M. Hering, A. I. Caplan, V. M. Goldberg, and J. U. Yoo. In vitro chondrogenesis of bone marrow-derived mesenchymal progenitor cells. Exp. Cell Res. 238:265–272, 1998.

    CAS  PubMed  Article  Google Scholar 

  81. 81.

    Jonitz, A., K. Lochner, T. Tischer, D. Hansmann, and R. Bader. TGF-beta1 and IGF-1 influence the re-differentiation capacity of human chondrocytes in 3D pellet cultures in relation to different oxygen concentrations. Int. J. Mol. Med. 30:666–672, 2012.

    CAS  PubMed  Google Scholar 

  82. 82.

    Kafienah, W., M. Jakob, O. Demarteau, A. Frazer, M. D. Barker, I. Martin, and A. P. Hollander. Three-dimensional tissue engineering of hyaline cartilage: comparison of adult nasal and articular chondrocytes. Tissue Eng. 8:817–826, 2002.

    CAS  PubMed  Article  Google Scholar 

  83. 83.

    Kane, P., R. Frederick, B. Tucker, C. C. Dodson, J. A. Anderson, M. G. Ciccotti, and K. B. Freedman. Surgical restoration/repair of articular cartilage injuries in athletes. Phys. Sportsmed. 41:75–86, 2013.

    PubMed  Article  Google Scholar 

  84. 84.

    Keller, B., T. Yang, Y. Chen, E. Munivez, T. Bertin, B. Zabel, and B. Lee. Interaction of TGFbeta and BMP signaling pathways during chondrogenesis. PLoS One 6:0016421, 2011.

    Article  CAS  Google Scholar 

  85. 85.

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

    CAS  PubMed  Article  Google Scholar 

  86. 86.

    Kim, Y. J., H. J. Kim, and G. I. Im. PTHrP promotes chondrogenesis and suppresses hypertrophy from both bone marrow-derived and adipose tissue-derived MSCs. Biochem. Biophys. Res. Commun. 373:104–108, 2008.

    CAS  PubMed  Article  Google Scholar 

  87. 87.

    Kim, J. S., Z. Y. Ryoo, and J. S. Chun. Cytokine-like 1 (Cytl1) regulates the chondrogenesis of mesenchymal cells. J. Biol. Chem. 282:29359–29367, 2007.

    CAS  PubMed  Article  Google Scholar 

  88. 88.

    Kino-Oka, M., S. Yashiki, Y. Ota, Y. Mushiaki, K. Sugawara, T. Yamamoto, T. Takezawa, and M. Taya. Subculture of chondrocytes on a collagen type I-coated substrate with suppressed cellular dedifferentiation. Tissue Eng. 11:597–608, 2005.

    CAS  PubMed  Article  Google Scholar 

  89. 89.

    Knauper, V., S. Cowell, B. Smith, C. Lopez-Otin, M. O’Shea, H. Morris, L. Zardi, and G. Murphy. The role of the C-terminal domain of human collagenase-3 (MMP-13) in the activation of procollagenase-3, substrate specificity, and tissue inhibitor of metalloproteinase interaction. J. Biol. Chem. 272:7608–7616, 1997.

    CAS  PubMed  Article  Google Scholar 

  90. 90.

    Knutsen, G., J. O. Drogset, L. Engebretsen, T. Grontvedt, V. Isaksen, T. C. Ludvigsen, S. Roberts, E. Solheim, T. Strand, and O. Johansen. A Randomized trial comparing autologous chondrocyte implantation with microfracture. J. Bone Joint Surg. Am. 89A:2105–2112, 2007.

    Article  Google Scholar 

  91. 91.

    Komarek, J., P. Valis, M. Repko, R. Chaloupka, and M. Krbec. Treatment of deep cartilage defects of the knee with autologous chondrocyte transplantation: long-term results. Acta Chir. Orthop. Traumatol. Cech. 77:291–295, 2010.

    CAS  PubMed  Google Scholar 

  92. 92.

    Kon, E., A. Roffi, G. Filardo, G. Tesei, and M. Marcacci. Scaffold-based cartilage treatments: with or without cells? A systematic review of preclinical and clinical evidence. Arthroscopy 31:767–775, 2015.

    PubMed  Article  Google Scholar 

  93. 93.

    Kurtz, S., K. Ong, E. Lau, F. Mowat, and M. Halpern. Projections of primary and revision hip and knee arthroplasty in the United States from 2005 to 2030. J. Bone Joint Surg. Am. 89:780–785, 2007.

    PubMed  Article  Google Scholar 

  94. 94.

    Lee, J. S., and G. I. Im. Influence of chondrocytes on the chondrogenic differentiation of adipose stem cells. Tissue Eng. Part A 16:3569–3577, 2010.

    CAS  PubMed  Article  Google Scholar 

  95. 95.

    Lee, R. H., B. Kim, I. Choi, H. Kim, H. S. Choi, K. Suh, Y. C. Bae, and J. S. Jung. Characterization and expression analysis of mesenchymal stem cells from human bone marrow and adipose tissue. Cell. Physiol. Biochem. 14:311–324, 2004.

    CAS  PubMed  Article  Google Scholar 

  96. 96.

    Leyh, M., A. Seitz, L. Durselen, J. Schaumburger, A. Ignatius, J. Grifka, and S. Grassel. Subchondral bone influences chondrogenic differentiation and collagen production of human bone marrow-derived mesenchymal stem cells and articular chondrocytes. Arthritis Res. Ther. 16:453, 2014.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  97. 97.

    Leyh, M., A. Seitz, L. Dürselen, H. R. Springorum, P. Angele, A. Ignatius, J. Grifka, and S. Grässel. Osteoarthritic cartilage explants affect extracellular matrix production and composition in cocultured bone marrow-derived mesenchymal stem cells and articular chondrocytes. Stem Cell Res. Ther. 5:77, 2014.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  98. 98.

    Li, Z., C. Liu, Z. Xie, P. Song, R. C. Zhao, L. Guo, Z. Liu, and Y. Wu. Epigenetic dysregulation in mesenchymal stem cell aging and spontaneous differentiation. PLoS One 6:9, 2011.

    Google Scholar 

  99. 99.

    Lopa, S., A. Colombini, V. Sansone, F. W. Preis, and M. Moretti. Influence on chondrogenesis of human osteoarthritic chondrocytes in co-culture with donor-matched mesenchymal stem cells from infrapatellar fat pad and subcutaneous adipose tissue. Int. J. Immunopathol. Pharmacol. 26:23–31, 2013.

    CAS  PubMed  Google Scholar 

  100. 100.

    Lutolf, M. P., and J. A. Hubbell. Synthetic biomaterials as instructive extracellular microenvironments for morphogenesis in tissue engineering. Nat. Biotechnol. 23:47–55, 2005.

    CAS  PubMed  Article  Google Scholar 

  101. 101.

    Ma, B., J. C. Leijten, L. Wu, M. Kip, C. A. van Blitterswijk, J. N. Post, and M. Karperien. Gene expression profiling of dedifferentiated human articular chondrocytes in monolayer culture. Osteoarthr. Cartil. 21:599–603, 2013.

    CAS  PubMed  Article  Google Scholar 

  102. 102.

    Mahmoudifar, N., and P. M. Doran. Effect of seeding and bioreactor culture conditions on the development of human tissue-engineered cartilage. Tissue Eng. 12:1675–1685, 2006.

    CAS  PubMed  Article  Google Scholar 

  103. 103.

    Makris, E. A., A. H. Gomoll, K. N. Malizos, J. C. Hu, and K. A. Athanasiou. Repair and tissue engineering techniques for articular cartilage. Nat. Rev. Rheumatol. 11:21–34, 2015.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  104. 104.

    Manferdini, C., M. Maumus, E. Gabusi, A. Piacentini, G. Filardo, J. A. Peyrafitte, C. Jorgensen, P. Bourin, S. Fleury-Cappellesso, A. Facchini, D. Noel, and G. Lisignoli. Adipose-derived mesenchymal stem cells exert antiinflammatory effects on chondrocytes and synoviocytes from osteoarthritis patients through prostaglandin E2. Arthritis Rheum. 65:1271–1281, 2013.

    CAS  PubMed  Article  Google Scholar 

  105. 105.

    Marcacci, M., S. Zaffagnini, E. Kon, A. Visani, F. Iacono, and I. Loreti. Arthroscopic autologous chondrocyte transplantation: technical note. Knee Surg. Sports Traumatol. Arthrosc. 10:154–159, 2002.

    CAS  PubMed  Article  Google Scholar 

  106. 106.

    Maumus, M., C. Manferdini, K. Toupet, J. A. Peyrafitte, R. Ferreira, A. Facchini, E. Gabusi, P. Bourin, C. Jorgensen, G. Lisignoli, and D. Noel. Adipose mesenchymal stem cells protect chondrocytes from degeneration associated with osteoarthritis. Stem Cell Res. 11:834–844, 2013.

    CAS  PubMed  Article  Google Scholar 

  107. 107.

    Mayan, M. D., P. Carpintero-Fernandez, R. Gago-Fuentes, O. Martinez-de-Ilarduya, H. Z. Wang, V. Valiunas, P. Brink, and F. J. Blanco. Human articular chondrocytes express multiple gap junction proteins: differential expression of connexins in normal and osteoarthritic cartilage. Am. J. Pathol. 12:018, 2013.

    Google Scholar 

  108. 108.

    Mehlhorn, A. T., P. Niemeyer, S. Kaiser, G. Finkenzeller, G. B. Stark, N. P. Sudkamp, and H. Schmal. Differential expression pattern of extracellular matrix molecules during chondrogenesis of mesenchymal stem cells from bone marrow and adipose tissue. Tissue Eng. 12:2853–2862, 2006.

    CAS  PubMed  Article  Google Scholar 

  109. 109.

    Mesallati, T., E. J. Sheehy, T. Vinardell, C. T. Buckley, and D. J. Kelly. Tissue engineering scaled-up, anatomically shaped osteochondral constructs for joint resurfacing. Eur. Cell Mater. 30:163–185, 2015; (discussion 185–166).

    CAS  PubMed  Google Scholar 

  110. 110.

    Micheli, L. J., J. E. Browne, C. Erggelet, F. Fu, B. Mandelbaum, J. B. Moseley, and D. Zurakowski. Autologous chondrocyte implantation of the knee: multicenter experience and minimum 3-year follow-up. Clin. J. Sport Med. 11:223–228, 2001.

    CAS  PubMed  Article  Google Scholar 

  111. 111.

    Miller, M. J., S. Ahmed, P. Bobrowski, and T. M. Haqqi. The chrondoprotective actions of a natural product are associated with the activation of IGF-1 production by human chondrocytes despite the presence of IL-1beta. BMC Complement Altern. Med. 6:13, 2006.

    PubMed  PubMed Central  Article  Google Scholar 

  112. 112.

    Minas, T. Autologous chondrocyte implantation for focal chondral defects of the knee. Clin. Orthop. Relat. Res. 391:S349–S361, 2001.

    PubMed  Article  Google Scholar 

  113. 113.

    Mo, X.-T., S.-C. Guo, H.-Q. Xie, L. Deng, W. Zhi, Z. Xiang, X.-Q. Li, and Z.-M. Yang. Variations in the ratios of co-cultured mesenchymal stem cells and chondrocytes regulate the expression of cartilaginous and osseous phenotype in alginate constructs. Bone 45:42–51, 2009.

    PubMed  Article  Google Scholar 

  114. 114.

    Moriguchi, Y., K. Tateishi, W. Ando, K. Shimomura, Y. Yonetani, Y. Tanaka, K. Kita, D. A. Hart, A. Gobbi, K. Shino, H. Yoshikawa, and N. Nakamura. Repair of meniscal lesions using a scaffold-free tissue-engineered construct derived from allogenic synovial MSCs in a miniature swine model. Biomaterials 34:2185–2193, 2013.

    CAS  PubMed  Article  Google Scholar 

  115. 115.

    Munir, S., C. B. Foldager, M. Lind, V. Zachar, K. Soballe, and T. G. Koch. Hypoxia enhances chondrogenic differentiation of human adipose tissue-derived stromal cells in scaffold-free and scaffold systems. Cell Tissue Res. 1:1, 2013.

    Google Scholar 

  116. 116.

    Murphy, L., T. A. Schwartz, C. G. Helmick, J. B. Renner, G. Tudor, G. Koch, A. Dragomir, W. D. Kalsbeek, G. Luta, and J. M. Jordan. Lifetime risk of symptomatic knee osteoarthritis. Arthritis Rheum. 59:1207–1213, 2008.

    PubMed  PubMed Central  Article  Google Scholar 

  117. 117.

    Musgrave, D. S., R. Pruchnic, V. Wright, P. Bosch, S. C. Ghivizzani, P. D. Robbins, and J. Huard. The effect of bone morphogenetic protein-2 expression on the early fate of skeletal muscle-derived cells. Bone 28:499–506, 2001.

    CAS  PubMed  Article  Google Scholar 

  118. 118.

    Mwale, F., G. Yao, J. A. Ouellet, A. Petit, and J. Antoniou. Effect of parathyroid hormone on type X and type II collagen expression in mesenchymal stem cells from osteoarthritic patients. Tissue Eng. Part A 16:3449–3455, 2010.

    CAS  PubMed  Article  Google Scholar 

  119. 119.

    Nejadnik, H., J. H. Hui, E. P. Feng Choong, B. C. Tal, and E. H. Lee. Autologous bone marrow-derived mesenchymal stem cells versus autologous chondrocyte implantation: an observational cohort study. Am. J. Sports Med. 38:1110–1116, 2010.

    PubMed  Article  Google Scholar 

  120. 120.

    Nevo, Z., A. Beit-Or, and Y. Eilam. Slowing down aging of cultured embryonal chick chondrocytes by maintenance under lowered oxygen tension. Mech. Ageing Dev. 45:157–165, 1988.

    CAS  PubMed  Article  Google Scholar 

  121. 121.

    Ng, L., A. J. Grodzinsky, P. Patwari, J. Sandy, A. Plaas, and C. Ortiz. Individual cartilage aggrecan macromolecules and their constituent glycosaminoglycans visualized via atomic force microscopy. J. Struct. Biol. 143:242–257, 2003.

    CAS  PubMed  Article  Google Scholar 

  122. 122.

    Noer, A., L. C. Lindeman, and P. Collas. Histone H3 modifications associated with differentiation and long-term culture of mesenchymal adipose stem cells. Stem Cells Dev. 18:725–736, 2009.

    CAS  PubMed  Article  Google Scholar 

  123. 123.

    O’Driscoll, S. W. Preclinical cartilage repair: current status and future perspectives. Clin. Orthop. Relat. Res. 391:S397–S401, 2001.

    PubMed  Article  Google Scholar 

  124. 124.

    Pelttari, K., B. Pippenger, M. Mumme, S. Feliciano, C. Scotti, P. Mainil-Varlet, A. Procino, B. von Rechenberg, T. Schwamborn, M. Jakob, C. Cillo, A. Barbero, and I. Martin. Adult human neural crest-derived cells for articular cartilage repair. Sci. Transl. Med. 6:251ra119, 2014.

    PubMed  Article  CAS  Google Scholar 

  125. 125.

    Pelttari, K., A. Winter, E. Steck, K. Goetzke, T. Hennig, B. G. Ochs, T. Aigner, and W. Richter. Premature induction of hypertrophy during in vitro chondrogenesis of human mesenchymal stem cells correlates with calcification and vascular invasion after ectopic transplantation in SCID mice. Arthritis Rheum. 54:3254–3266, 2006.

    CAS  PubMed  Article  Google Scholar 

  126. 126.

    Peterson, L., M. Brittberg, I. Kiviranta, E. L. Akerlund, and A. Lindahl. Autologous chondrocyte transplantation. Biomechanics and long-term durability. Am. J. Sports Med. 30:2–12, 2002.

    PubMed  Google Scholar 

  127. 127.

    Peterson, L., T. Minas, M. Brittberg, and A. Lindahl. Treatment of osteochondritis dissecans of the knee with autologous chondrocyte transplantation: results at two to ten years. J. Bone Joint Surg. Am. 2:17–24, 2003.

    Google Scholar 

  128. 128.

    Pfeiffer, E., S. M. Vickers, E. Frank, A. J. Grodzinsky, and M. Spector. The effects of glycosaminoglycan content on the compressive modulus of cartilage engineered in type II collagen scaffolds. Osteoarthr. Cartil. 16:1237–1244, 2008.

    CAS  PubMed  Article  Google Scholar 

  129. 129.

    Pittenger, M. F., A. M. Mackay, S. C. Beck, R. K. Jaiswal, R. Douglas, J. D. Mosca, M. A. Moorman, D. W. Simonetti, S. Craig, and D. R. Marshak. Multilineage potential of adult human mesenchymal stem cells. Science 284:143–147, 1999.

    CAS  PubMed  Article  Google Scholar 

  130. 130.

    Poole, A. R., T. Kojima, T. Yasuda, F. Mwale, M. Kobayashi, and S. Laverty. Composition and structure of articular cartilage: a template for tissue repair. Clin. Orthop. Relat. Res. 391:S26–S33, 2001.

    PubMed  Article  Google Scholar 

  131. 131.

    Redman, S. N., S. F. Oldfield, and C. W. Archer. Current strategies for articular cartilage repair. Eur. Cell Mater. 9:23–32, 2005.

    CAS  PubMed  Google Scholar 

  132. 132.

    Richardson, S. M., R. V. Walker, S. Parker, N. P. Rhodes, J. A. Hunt, A. J. Freemont, and J. A. Hoyland. Intervertebral disc cell-mediated mesenchymal stem cell differentiation. Stem Cells 24:707–716, 2006.

    CAS  PubMed  Article  Google Scholar 

  133. 133.

    Rider, D. A., C. Dombrowski, A. A. Sawyer, G. H. Ng, D. Leong, D. W. Hutmacher, V. Nurcombe, and S. M. Cool. Autocrine fibroblast growth factor 2 increases the multipotentiality of human adipose-derived mesenchymal stem cells. Stem Cells 26:1598–1608, 2008.

    CAS  PubMed  Article  Google Scholar 

  134. 134.

    Ronziere, M. C., E. Perrier, F. Mallein-Gerin, and A. M. Freyria. Chondrogenic potential of bone marrow- and adipose tissue-derived adult human mesenchymal stem cells. Biomed. Mater. Eng. 20:145–158, 2010.

    CAS  PubMed  Google Scholar 

  135. 135.

    Rotter, N., L. J. Bonassar, G. Tobias, M. Lebl, A. K. Roy, and C. A. Vacanti. Age dependence of biochemical and biomechanical properties of tissue-engineered human septal cartilage. Biomaterials 23:3087–3094, 2002.

    CAS  PubMed  Article  Google Scholar 

  136. 136.

    Russlies, M., P. Behrens, E. M. Ehlers, C. Brohl, C. Vindigni, M. Spector, and B. Kurz. Periosteum stimulates subchondral bone densification in autologous chondrocyte transplantation in a sheep model. Cell Tissue Res. 319:133–142, 2005.

    PubMed  Article  Google Scholar 

  137. 137.

    Schroer, W. C., K. R. Berend, A. V. Lombardi, C. L. Barnes, M. P. Bolognesi, M. E. Berend, M. A. Ritter, and R. M. Nunley. Why are total knees failing today? Etiology of total knee revision in 2010 and 2011. J. Arthroplast. 28:116–119, 2013.

    Article  Google Scholar 

  138. 138.

    Scotti, C., A. Osmokrovic, F. Wolf, S. Miot, G. M. Peretti, A. Barbero, and I. Martin. Response of human engineered cartilage based on articular or nasal chondrocytes to interleukin-1beta and low oxygen. Tissue Eng. Part A 18:362–372, 2012.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  139. 139.

    Seror, J., Y. Merkher, N. Kampf, L. Collinson, A. J. Day, A. Maroudas, and J. Klein. Articular cartilage proteoglycans as boundary lubricants: structure and frictional interaction of surface-attached hyaluronan and hyaluronan–aggrecan complexes. Biomacromolecules 12:3432–3443, 2011.

    CAS  PubMed  Article  Google Scholar 

  140. 140.

    Shakibaei, M., P. De Souza, and H. J. Merker. Integrin expression and collagen type II implicated in maintenance of chondrocyte shape in monolayer culture: an immunomorphological study. Cell Biol. Int. 21:115–125, 1997.

    CAS  PubMed  Article  Google Scholar 

  141. 141.

    Shapiro, F., S. Koide, and M. J. Glimcher. Cell origin and differentiation in the repair of full-thickness defects of articular cartilage. J. Bone Joint Surg. Am. 75:532–553, 1993.

    CAS  PubMed  Google Scholar 

  142. 142.

    Shen, Y., Y. Fu, J. Wang, G. Li, X. Zhang, Y. Xu, and Y. Lin. Biomaterial and mesenchymal stem cell for articular cartilage reconstruction. Curr. Stem Cell Res. Ther. 9:254–267, 2014.

    CAS  PubMed  Article  Google Scholar 

  143. 143.

    Shintani, N., and E. B. Hunziker. Differential effects of dexamethasone on the chondrogenesis of mesenchymal stromal cells: influence of microenvironment, tissue origin and growth factor. Eur. Cell Mater. 22:302–319, 2011.

    CAS  PubMed  Google Scholar 

  144. 144.

    Shipley, R. J., and S. L. Waters. Fluid and mass transport modelling to drive the design of cell-packed hollow fibre bioreactors for tissue engineering applications. Math. Med. Biol. 29:329–359, 2012.

    PubMed  Article  Google Scholar 

  145. 145.

    Singh, S., C. C. Lee, and B. K. Tay. Results of arthroscopic abrasion arthroplasty in osteoarthritis of the knee joint. Singap. Med. J. 32:34–37, 1991.

    CAS  Google Scholar 

  146. 146.

    Sledge, S. L. Microfracture techniques in the treatment of osteochondral injuries. Clin. Sports Med. 20:365–377, 2001.

    CAS  PubMed  Article  Google Scholar 

  147. 147.

    Slynarski, K., W. Widuchowski, M. Snow, W. Weiss, J. Kruczynski, J. Hendriks, J. Guidoux, and P. Verdonk. Primary chondrocytes and bone marrow cells on a 3D co-polymer scaffold: 2-year results of a prospective, multicenter, single-arm clinical trial in patients with cartilage defects of the knee. Revue de Chirurgie Orthopédique et Traumatologique 101:e17–e18, 2015.

    Article  Google Scholar 

  148. 148.

    Solorio, L. D., E. L. Vieregge, C. D. Dhami, and E. Alsberg. High-density cell systems incorporating polymer microspheres as microenvironmental regulators in engineered cartilage tissues. Tissue Eng. Part B Rev. 19:209–220, 2013.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  149. 149.

    Stickens, D., D. J. Behonick, N. Ortega, B. Heyer, B. Hartenstein, Y. Yu, A. J. Fosang, M. Schorpp-Kistner, P. Angel, and Z. Werb. Altered endochondral bone development in matrix metalloproteinase 13-deficient mice. Development 131:5883–5895, 2004.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  150. 150.

    Stockwell, R. A. The cell density of human articular and costal cartilage. J. Anat. 101:753–763, 1967.

    CAS  PubMed  PubMed Central  Google Scholar 

  151. 151.

    Tan, J., H. Huang, W. Huang, L. Li, J. Guo, B. Huang, and J. Lu. The genomic landscapes of histone H3-Lys9 modifications of gene promoter regions and expression profiles in human bone marrow mesenchymal stem cells. J. Genet. Genom. 35:585–593, 2008.

    CAS  Article  Google Scholar 

  152. 152.

    Taylor, D. W., N. Ahmed, L. Gan, A. E. Gross, and R. A. Kandel. Proteoglycan and collagen accumulation by passaged chondrocytes can be enhanced through side-by-side culture with primary chondrocytes. Tissue Eng. Part A 16:643–651, 2010.

    CAS  PubMed  Article  Google Scholar 

  153. 153.

    Thorpe, S. D., T. Nagel, S. F. Carroll, and D. J. Kelly. Modulating gradients in regulatory signals within mesenchymal stem cell seeded hydrogels: a novel strategy to engineer zonal articular cartilage. PLoS One 8:e60764, 2013.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  154. 154.

    Toyoda, T., B. B. Seedhom, J. Q. Yao, J. Kirkham, S. Brookes, and W. A. Bonass. Hydrostatic pressure modulates proteoglycan metabolism in chondrocytes seeded in agarose. Arthritis Rheum. 48:2865–2872, 2003.

    CAS  PubMed  Article  Google Scholar 

  155. 155.

    Tsuchiya, K., G. Chen, T. Ushida, T. Matsuno, and T. Tateishi. The effect of coculture of chondrocytes with mesenchymal stem cells on their cartilaginous phenotype in vitro. Mater. Sci. Eng. C 24:391–396, 2004.

    Article  CAS  Google Scholar 

  156. 156.

    Tuli, R., W. J. Li, and R. S. Tuan. Current state of cartilage tissue engineering. Arthritis Research & Therapy 5:235–238, 2003.

    CAS  Article  Google Scholar 

  157. 157.

    Ulrich-Vinther, M., M. D. Maloney, E. M. Schwarz, R. Rosier, and R. J. O’Keefe. Articular cartilage biology. J. Am. Acad. Orthop. Surg. 11:421–430, 2003.

    PubMed  Article  Google Scholar 

  158. 158.

    Vavken, P., F. Arrich, M. Pilz, and R. Dorotka. An in vitro model of biomaterial-augmented microfracture including chondrocyte-progenitor cell interaction. Arch. Orthop. Trauma Surg. 130:711–716, 2010.

    PubMed  Article  Google Scholar 

  159. 159.

    Villiger, P. M., and M. Lotz. Differential expression of TGF beta isoforms by human articular chondrocytes in response to growth factors. J. Cell Physiol. 151:318–325, 1992.

    CAS  PubMed  Article  Google Scholar 

  160. 160.

    Viste, A., M. Piperno, R. Desmarchelier, S. Grosclaude, B. Moyen, and M. H. Fessy. Autologous chondrocyte implantation for traumatic full-thickness cartilage defects of the knee in 14 patients: 6-year functional outcomes. Orthop. Traumatol. Surg. Res. 98:737–743, 2012.

    CAS  PubMed  Article  Google Scholar 

  161. 161.

    von der Mark, K., V. Gauss, H. von der Mark, and P. Muller. Relationship between cell shape and type of collagen synthesised as chondrocytes lose their cartilage phenotype in culture. Nature 267:531–532, 1977.

    PubMed  Article  Google Scholar 

  162. 162.

    Vunjak-Novakovic, G., L. E. Freed, R. J. Biron, and R. Langer. Effects of mixing on the composition and morphology of tissue-engineered cartilage. AIChE J. 42:850–860, 1996.

    CAS  Article  Google Scholar 

  163. 163.

    Wakitani, S., K. Imoto, T. Yamamoto, M. Saito, N. Murata, and M. Yoneda. Human autologous culture expanded bone marrow mesenchymal cell transplantation for repair of cartilage defects in osteoarthritic knees. Osteoarthr. Cartil. 10:199–206, 2002.

    CAS  PubMed  Article  Google Scholar 

  164. 164.

    Wakitani, S., T. Mitsuoka, N. Nakamura, Y. Toritsuka, Y. Nakamura, and S. Horibe. Autologous bone marrow stromal cell transplantation for repair of full-thickness articular cartilage defects in human patellae: two case reports. Cell Transpl. 13:595–600, 2004.

    Article  Google Scholar 

  165. 165.

    Wakitani, S., M. Nawata, K. Tensho, T. Okabe, H. Machida, and H. Ohgushi. Repair of articular cartilage defects in the patello-femoral joint with autologous bone marrow mesenchymal cell transplantation: three case reports involving nine defects in five knees. J. Tissue Eng. Regen. Med. 1:74–79, 2007.

    PubMed  Article  Google Scholar 

  166. 166.

    Wakitani, S., T. Okabe, S. Horibe, T. Mitsuoka, M. Saito, T. Koyama, M. Nawata, K. Tensho, H. Kato, K. Uematsu, R. Kuroda, M. Kurosaka, S. Yoshiya, K. Hattori, and H. Ohgushi. Safety of autologous bone marrow-derived mesenchymal stem cell transplantation for cartilage repair in 41 patients with 45 joints followed for up to 11 years and 5 months. J. Tissue Eng. Regen. Med. 5:146–150, 2011.

    PubMed  Article  Google Scholar 

  167. 167.

    Wang, T. Y., and J. H. Wu. A continuous perfusion bioreactor for long-term bone marrow culture. Ann. N. Y. Acad. Sci. 665:274–284, 1992.

    CAS  PubMed  Article  Google Scholar 

  168. 168.

    Watt, F. M. Effect of seeding density on stability of the differentiated phenotype of pig articular chondrocytes in culture. J. Cell Sci. 89(Pt 3):373–378, 1988.

    PubMed  Google Scholar 

  169. 169.

    Weiss, S., T. Hennig, R. Bock, E. Steck, and W. Richter. Impact of growth factors and PTHrP on early and late chondrogenic differentiation of human mesenchymal stem cells. J. Cell Physiol. 223:84–93, 2010.

    CAS  PubMed  Google Scholar 

  170. 170.

    Wescoe, K. E., R. C. Schugar, C. R. Chu, and B. M. Deasy. The role of the biochemical and biophysical environment in chondrogenic stem cell differentiation assays and cartilage tissue engineering. Cell Biochem. Biophys. 52:85–102, 2008.

    CAS  PubMed  Article  Google Scholar 

  171. 171.

    Winter, A., S. Breit, D. Parsch, K. Benz, E. Steck, H. Hauner, R. M. Weber, V. Ewerbeck, and W. Richter. Cartilage-like gene expression in differentiated human stem cell spheroids: a comparison of bone marrow-derived and adipose tissue-derived stromal cells. Arthritis Rheum. 48:418–429, 2003.

    CAS  PubMed  Article  Google Scholar 

  172. 172.

    Wu, L., H. J. Prins, M. N. Helder, C. A. van Blitterswijk, and M. Karperien. Trophic effects of mesenchymal stem cells in chondrocyte co-cultures are independent of culture conditions and cell sources. Tissue Eng. Part A 18:1542–1551, 2012.

    CAS  PubMed  Article  Google Scholar 

  173. 173.

    Yang, Y. H., A. J. Lee, and G. A. Barabino. Coculture-driven mesenchymal stem cell-differentiated articular chondrocyte-like cells support neocartilage development. Stem Cells Transl. Med. 1:843–854, 2012.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  174. 174.

    Yonenaga, K., S. Nishizawa, Y. Fujihara, Y. Asawa, K. Sanshiro, S. Nagata, T. Takato, and K. Hoshi. The optimal conditions of chondrocyte isolation and its seeding in the preparation for cartilage tissue engineering. Tissue Eng. Part C Methods 16:1461–1469, 2010.

    CAS  PubMed  Article  Google Scholar 

  175. 175.

    Zaslav, K., B. Cole, R. Brewster, T. DeBerardino, J. Farr, P. Fowler, and C. Nissen. A prospective study of autologous chondrocyte implantation in patients with failed prior treatment for articular cartilage defect of the knee: results of the Study of the Treatment of Articular Repair (STAR) clinical trial. Am. J. Sports Med. 37:42–55, 2009.

    PubMed  Article  Google Scholar 

  176. 176.

    Zeifang, F., D. Oberle, C. Nierhoff, W. Richter, B. Moradi, and H. Schmitt. Autologous chondrocyte implantation using the original periosteum-cover technique versus matrix-associated autologous chondrocyte implantation: a randomized clinical trial. Am. J. Sports Med. 38:924–933, 2010.

    PubMed  Article  Google Scholar 

  177. 177.

    Zhang, Y., L. Cao, C. Kiani, B. L. Yang, W. Hu, and B. B. Yang. Promotion of chondrocyte proliferation by versican mediated by G1 domain and EGF-like motifs. J. Cell Biochem. 73:445–457, 1999.

    CAS  PubMed  Article  Google Scholar 

  178. 178.

    Zhang, L. M., P. Q. Su, C. X. Xu, J. L. Yang, W. H. Yu, and D. S. Huang. Chondrogenic differentiation of human mesenchymal stem cells: a comparison between micromass and pellet culture systems. Biotechnol. Lett. 32:1339–1346, 2010.

    CAS  PubMed  Article  Google Scholar 

  179. 179.

    Zuk, P. A., M. Zhu, H. Mizuno, J. Huang, J. W. Futrell, A. J. Katz, P. Benhaim, H. P. Lorenz, and M. H. Hedrick. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng. 7:211–228, 2001.

    CAS  PubMed  Article  Google Scholar 

  180. 180.

    Zuo, Q., W. Cui, F. Liu, Q. Wang, Z. Chen, and W. Fan. Co-cultivated mesenchymal stem cells support chondrocytic differentiation of articular chondrocytes. Int. Orthop. 37:747–752, 2013.

    PubMed  PubMed Central  Article  Google Scholar 

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Acknowledgments

The authors gratefully acknowledge NSF support through CBET EAGER Award #1212573, Regeneron Pharmaceuticals, Inc., and USDA NIFA WN.P WNP00807 for salary support. The efforts of Professor Elizabeth Siler in editing this manuscript are appreciated.

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The authors have no conflict of interest to disclose.

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Correspondence to B. J. Van Wie.

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Associate Editor Michael S. Detamore oversaw the review of this article.

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Nazempour, A., Van Wie, B.J. Chondrocytes, Mesenchymal Stem Cells, and Their Combination in Articular Cartilage Regenerative Medicine. Ann Biomed Eng 44, 1325–1354 (2016). https://doi.org/10.1007/s10439-016-1575-9

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Keywords

  • Articular cartilage
  • Articular cartilage tissue engineering
  • Chondrocytes
  • Autologous chondrocyte implantation
  • Mesenchymal stem cells
  • Autologous mesenchymal stem cell transplantation
  • Co-culture of mesenchymal stem cells with articular chondrocytes