Advancing osteochondral tissue engineering: bone morphogenetic protein, transforming growth factor, and fibroblast growth factor signaling drive ordered differentiation of periosteal cells resulting in stable cartilage and bone formation in vivo

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Abstract

Background

Chondrogenic mesenchymal stem cells (MSCs) have not yet been used to address the clinical demands of large osteochondral joint surface defects. In this study, self-assembling tissue intermediates (TIs) derived from human periosteum-derived stem/progenitor cells (hPDCs) were generated and validated for stable cartilage formation in vivo using two different animal models.

Methods

hPDCs were aggregated and cultured in the presence of a novel growth factor (GF) cocktail comprising of transforming growth factor (TGF)-β1, bone morphogenetic protein (BMP)2, growth differentiation factor (GDF)5, BMP6, and fibroblast growth factor (FGF)2. Quantitative polymerase chain reaction (PCR) and immunohistochemistry were used to study in vitro differentiation. Aggregates were then implanted ectopically in nude mice and orthotopically in critical-size osteochondral defects in nude rats and evaluated by microcomputed tomography (µCT) and immunohistochemistry.

Results

Gene expression analysis after 28 days of in vitro culture revealed the expression of early and late chondrogenic markers and a significant upregulation of NOGGIN as compared to human articular chondrocytes (hACs). Histological examination revealed a bilayered structure comprising of chondrocytes at different stages of maturity. Ectopically, TIs generated both bone and mineralized cartilage at 8 weeks after implantation. Osteochondral defects treated with TIs displayed glycosaminoglycan (GAG) production, type-II collagen, and lubricin expression. Immunostaining for human nuclei protein suggested that hPDCs contributed to both subchondral bone and articular cartilage repair.

Conclusion

Our data indicate that in vitro derived osteochondral-like tissues can be generated from hPDCs, which are capable of producing bone and cartilage ectopically and behave orthotopically as osteochondral units.

Electronic supplementary material

The online version of this article (10.1186/s13287-018-0787-3) contains supplementary material, which is available to authorized users.

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Most cited references 38

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Recapitulation of endochondral bone formation using human adult mesenchymal stem cells as a paradigm for developmental engineering.

Javier Ríos, Andrea Barbero, Beatrice Tonnarelli … (2010)

Mesenchymal stem/stromal cells (MSC) are typically used to generate bone tissue by a process resembling intramembranous ossification, i.e., by direct osteoblastic differentiation. However, most bones develop by endochondral ossification, i.e., via remodeling of hypertrophic cartilaginous templates. To date, endochondral bone formation has not been reproduced using human, clinically compliant cell sources. Here, we aimed at engineering tissues from bone marrow-derived, adult human MSC with an intrinsic capacity to undergo endochondral ossification. By analogy to embryonic limb development, we hypothesized that successful execution of the endochondral program depends on the initial formation of hypertrophic cartilaginous templates. Human MSC, subcutaneously implanted into nude mice at various stages of chondrogenic differentiation, formed bone trabeculae only when they had developed in vitro hypertrophic tissue structures. Advanced maturation in vitro resulted in accelerated formation of larger bony tissues. The underlying morphogenetic process was structurally and molecularly similar to the temporal and spatial progression of limb bone development in embryos. In particular, Indian hedgehog signaling was activated at early stages and required for the in vitro formation of hypertrophic cartilage. Subsequent development of a bony collar in vivo was followed by vascularization, osteoclastic resorption of the cartilage template, and appearance of hematopoietic foci. This study reveals the capacity of human MSC to generate bone tissue via an endochondral program and provides a valid model to study mechanisms governing bone development. Most importantly, this process could generate advanced grafts for bone regeneration by invoking a "developmental engineering" paradigm.

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Cell-based tissue engineering strategies used in the clinical repair of articular cartilage.

Brian Huang, Jerry Hu, Kyriacos Athanasiou (2016)

One of the most important issues facing cartilage tissue engineering is the inability to move technologies into the clinic. Despite the multitude of current research in the field, it is known that 90% of new drugs that advance past animal studies fail clinical trials. The objective of this review is to provide readers with an understanding of the scientific details of tissue engineered cartilage products that have demonstrated a certain level of efficacy in humans, so that newer technologies may be developed upon this foundation. Compared to existing treatments, such as microfracture or autologous chondrocyte implantation, a tissue engineered product can potentially provide more consistent clinical results in forming hyaline repair tissue and in filling the entirety of the defect. The various tissue engineering strategies (e.g., cell expansion, scaffold material, media formulations, biomimetic stimuli, etc.) used in forming these products, as collected from published literature, company websites, and relevant patents, are critically discussed. The authors note that many details about these products remain proprietary, not all information is made public, and that advancements to the products are continuously made. Nevertheless, by understanding the design and production processes of these emerging technologies, one can gain tremendous insight into how to best use them and also how to design the next generation of tissue engineered cartilage products.

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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.

Shigeyuki Wakitani, Masashi Nawata, Keiji Tensho … (2015)

To investigate the effectiveness of autologous culture-expanded bone marrow mesenchymal cell transplantation for repairing articular cartilage defects, we transplanted autologous culture-expanded bone marrow mesenchymal cells into nine full-thickness articular cartilage defects of the patello-femoral joints (including two kissing lesions) in the knees of three patients, a 31 year-old female, a 44 year-old male and a 45 year-old male. Three weeks before transplantation, bone marrow blood was aspirated from the iliac crest. Adherent cells were cultured with media containing autologous serum. Single-passaged cells were collected, embedded in a collagen solution (5 x 10(6) cells/ml), placed on a collagen sheet, gelated, transplanted into the defect and covered with autologous periosteum or synovium. Six months after transplantation, the patients' clinical symptoms had improved and the improvements have been maintained over the follow-up periods (17-27 months). Histology of the first patient 12 months after the transplantation revealed that the defect had been repaired with the fibrocartilaginous tissue. Magnetic resonance imaging of the second patient 1 year after transplantation revealed complete coverage of the defect, but we were unable to determine whether or not the material that covered the defects was hyaline cartilage. Autologous bone marrow mesenchymal cells transplantation may be an effective approach to promote the repair of articular cartilage defects. 2007 John Wiley & Sons, Ltd

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Author and article information

Contributors

L. F. Mendes: luis.mendes@kuleuven.be

H. Katagiri: katagiri.orj@tmd.ac.jp

W. L. Tam: wailong.tam@kuleuven.be

Y. C. Chai: yoke.chin.chai@vub.ac.be

L. Geris: liesbet.geris@ulg.ac.be

S. J. Roberts: scott.roberts@ucl.ac.uk

F. P. Luyten: + 32 16 342541 , frank.luyten@uzleuven.be

Journal

Journal ID (nlm-ta): Stem Cell Res Ther

Journal ID (iso-abbrev): Stem Cell Res Ther

Title: Stem Cell Research & Therapy

Publisher: BioMed Central (London )

ISSN (Electronic): 1757-6512

Publication date (Electronic): 21 February 2018

Publication date PMC-release: 21 February 2018

Publication date Collection: 2018

Volume: 9

Electronic Location Identifier: 42

Affiliations

[1 ]ISNI 0000 0001 0668 7884, GRID grid.5596.f, Tissue Engineering Laboratory, Skeletal Biology and Engineering Research Center, , KU Leuven, ; Campus Gasthuisberg O&N 1, Herestraat 49, bus 813, 3000 Leuven, Belgium

[2 ]ISNI 0000 0001 0668 7884, GRID grid.5596.f, Prometheus, Division of Skeletal Tissue Engineering, , KU Leuven, ; O&N 1, Herestraat 49, bus 813, 3000 Leuven, Belgium

[3 ]ISNI 0000 0001 0805 7253, GRID grid.4861.b, Biomechanics Research Unit, , University of Liege, ; Chemin des Chevreuils 1 – BAT 52/3, 4000 Liege 1, Belgium

[4 ]ISNI 0000 0001 0668 7884, GRID grid.5596.f, Biomechanics Section, , KU Leuven, ; Celestijnenlaan 300C bus 2419, 3001 Leuven, Belgium

[5 ]ISNI 0000000121901201, GRID grid.83440.3b, Institute of Orthopaedics and Musculoskeletal Science, Division of Surgery & Interventional Science, , University College London, ; The Royal National Orthopaedic Hospital, Stanmore, Middlesex, HA7 4LP UK

Article

Publisher ID: 787

DOI: 10.1186/s13287-018-0787-3

PMC ID: 5822604

PubMed ID: 29467016

SO-VID: 4bb81ae1-ce5e-4a83-859b-9830a8c9e646

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 22 October 2017

Date revision received : 4 January 2018

Date accepted : 22 January 2018

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100000781, European Research Council;

Award ID: 294191

Award ID: 279100

Custom metadata

ScienceOpen disciplines: Molecular medicine

Keywords: periosteal cells,osteochondral defect,cartilage tissue engineering,growth factors,subchondral bone regeneration

Data availability:

ScienceOpen disciplines: Molecular medicine

Keywords: periosteal cells, osteochondral defect, cartilage tissue engineering, growth factors, subchondral bone regeneration

Advancing osteochondral tissue engineering: bone morphogenetic protein, transforming growth factor, and fibroblast growth factor signaling drive ordered differentiation of periosteal cells resulting in stable cartilage and bone formation in vivo

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Conclusion

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Most cited references 38

Recapitulation of endochondral bone formation using human adult mesenchymal stem cells as a paradigm for developmental engineering.

Cell-based tissue engineering strategies used in the clinical repair of articular cartilage.

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.

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