Enhanced Early Tissue Regeneration after Matrix-Assisted Autologous Mesenchymal Stem Cell Transplantation in Full Thickness Chondral Defects in a Minipig Model

Adult mesenchymal stem cells (MSCs) are an attractive cell source for new treatment strategies in regenerative medicine. This study investigated the potential effect of matrix assisted MSC transplantation for articular cartilage regeneration in a large-animal model 8 weeks postoperatively. MSCs from bone marrow aspirates of eight Goettingen minipigs were isolated and expanded prior to surgery. Articular cartilage defects of 5.4 mm were created bilaterally in the medial patellar groove without penetrating the subchondral bone plate. Defects were either left empty ( n = 4), covered with a collagen type I/III membrane ( n = 6) or additionally treated with autologous MSC transplantation (2 × 106; n = 6). After 8 weeks animals were euthanized and the defect area was assessed for its gross appearance. Histomorphological analysis of the repair tissue included semiquantitative scoring (O'Driscoll score) and quantitative histomorphometric analysis for its glycosaminoglycan (GAG) and collagen type II content. All membranes were found to cover the defect area 8 weeks postoperatively. Median defect filling was 115.8% (membrane), 117.8% (empty), and 100.4% (MSC), respectively (not significant). Histomorphological scoring revealed significantly higher values in MSC-treated defects (median 16.5) when compared to membrane treatment (median 9.5) or empty defects (median 11.5; p = 0.015 and p = 0.038). Histomorphometric analysis showed larger GAG/collagen type II-positive areas in the MSC-treated group (median 24.6%/29.5% of regeneration tissue) compared to 13.6%/33.1% (empty defects) and 1.7%/6.2% (membrane group; p = 0.066). Cell distribution was more homogeneous in MSC compared to membrane-only group, where cells were found mainly near the subchondral zone. In conclusion, autologous matrix-assisted MSC transplantation significantly increased the histomorphological repair tissue quality during early articular cartilage defect repair and resulted in higher GAG/collagen type II-positive cross-sectional areas of the regenerated tissue.

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Chicken collagen type II reduces articular cartilage destruction in a model of osteoarthritis in rats

West Indian Medical Journal ◽

10.1590/s0043-31442007000300002 ◽

2007 ◽

Vol 56 (3) ◽

Cited By ~ 4

Author(s):

D Xu ◽

W Shen

Keyword(s):

Articular Cartilage ◽

Collagen Type ◽

Cartilage Destruction ◽

Type Ii ◽

Collagen Type Ii

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Phenotypic maintenance of articular chondrocytes in vitro requires BMP activity

Veterinary and Comparative Orthopaedics and Traumatology ◽

10.1160/vcot-06-07-0061 ◽

2007 ◽

Vol 20 (03) ◽

pp. 185-191 ◽

Cited By ~ 18

Author(s):

A. O. Oshin ◽

E. Caporali ◽

C. R. Byron ◽

A. A. Stewart ◽

M. C. Stewart

Keyword(s):

Articular Cartilage ◽

Collagen Type ◽

Articular Chondrocytes ◽

Soluble Form ◽

Mrna Levels ◽

Type Ii ◽

Collagen Type Ii ◽

Endogenous Expression ◽

Chondrocytic Phenotype

SummaryArticular chondrocytes are phenotypically unique cells that are responsible for the maintenance of articular cartilage. The articular chondrocytic phenotype is influenced by a range of soluble factors. In particular, members of the bone morphogenetic protein (BMP) family support the articular chondrocytic phenotype and stimulate synthesis of cartilaginous matrix. This study was carried out to determine the importance of BMPs in supporting the differentiated phenotype of articular chondrocytes in vitro. Exogenous BMP-2 supported expression of collagen type II and aggrecan in monolayer chondrocyte cultures, slowing the dedifferentiation process that occurs under these conditions. In contrast, BMP-2 had little effect on expression of these genes in three-dimensional aggregate cultures. Endogenous BMP-2 expression was lost in monolayer cultures, coincident with the down-regulation of collagen type II and aggrecan mRNAs, whereas BMP-2 mRNA levels were stable in aggregate cultures. Antagonism of endogenous BMP activity in aggregate cultures by Noggin or a soluble form of the BMP receptor resulted in reduced expression of collagen type II and aggrecan mRNAs, reduced collagen type II protein and sulfated glycosaminoglycan (GAG) deposition into the aggregate matrices and reduced secretion of GAGs into the culture media. These results indicate that endogenous BMPs are required for maintenance of the differentiated articular chondrocytic phenotype in vitro. These findings are of importance to cell-based strategies designed to repair articular cartilage. Articular chondrocytes require conditions that will support endogenous expression of BMPs to maintain the specialized phenotype of these cells.

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Limb bud mesenchyme cultured under tensile strain remodel collagen type I tubes to produce fibrillar collagen type II

Biorheology ◽

10.3233/bir-2009-0553 ◽

2009 ◽

Vol 46 (6) ◽

pp. 439-450 ◽

Cited By ~ 1

Author(s):

Jennifer R. Amos ◽

Shigeng Li ◽

Michael Yost ◽

Harry Phloen ◽

Jay D. Potts

Keyword(s):

Tensile Strain ◽

Collagen Type ◽

Collagen Type I ◽

Limb Bud ◽

Type I ◽

Fibrillar Collagen ◽

Type Ii ◽

Collagen Type Ii

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The utility of measuring C-terminal telopeptides of collagen type II (CTX-II) in serum and synovial fluid samples for estimation of articular cartilage status in experimental models of destructive joint diseases

Osteoarthritis and Cartilage ◽

10.1016/j.joca.2006.01.004 ◽

2006 ◽

Vol 14 (7) ◽

pp. 670-679 ◽

Cited By ~ 36

Author(s):

S. Oestergaard ◽

L. Chouinard ◽

N. Doyle ◽

M.A. Karsdal ◽

S.Y. Smith ◽

...

Keyword(s):

Articular Cartilage ◽

Synovial Fluid ◽

Collagen Type ◽

Experimental Models ◽

Joint Diseases ◽

Type Ii ◽

Collagen Type Ii

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Maintenance of chondrocyte phenotype during expansion on PLLA microtopographies

Journal of Tissue Engineering ◽

10.1177/2041731418789829 ◽

2018 ◽

Vol 9 ◽

pp. 204173141878982 ◽

Cited By ~ 6

Author(s):

Elisa Costa ◽

Cristina González-García ◽

José Luis Gómez Ribelles ◽

Manuel Salmerón-Sánchez

Keyword(s):

Lactic Acid ◽

Type I Collagen ◽

Collagen Type ◽

Articular Chondrocytes ◽

Collagen Type I ◽

Cell Phenotype ◽

Type I ◽

Type Ii ◽

Collagen Type Ii ◽

Chondrocyte Phenotype

Articular chondrocytes are difficult to grow, as they lose their characteristic phenotype following expansion on standard tissue culture plates. Here, we show that culturing them on surfaces of poly(L-lactic acid) of well-defined microtopography allows expansion and maintenance of characteristic chondrogenic markers. We investigated the dynamics of human chondrocyte dedifferentiation on the different poly(L-lactic acid) microtopographies by the expression of collagen type I, collagen type II and aggrecan at different culture times. When seeded on poly(L-lactic acid), chondrocytes maintained their characteristic hyaline phenotype up to 7 days, which allowed to expand the initial cell population approximately six times without cell dedifferentiation. Maintenance of cell phenotype was afterwards correlated to cell adhesion on the different substrates. Chondrocytes adhesion occurs via the α5 β1 integrin on poly(L-lactic acid), suggesting cell–fibronectin interactions. However, α2 β1 integrin is mainly expressed on the control substrate after 1 day of culture, and the characteristic chondrocytic markers are lost (collagen type II expression is overcome by the synthesis of collagen type I). Expanding chondrocytes on poly(L-lactic acid) might be an effective solution to prevent dedifferentiation and improving the number of cells needed for autologous chondrocyte transplantation.

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Limb bud mesenchyme cultured under tensile strain remodel collagen type I tubes to produce fibrillar collagen type II

Biorheology ◽

10.3233/bir-2010-0571 ◽

2010 ◽

Vol 47 (2) ◽

pp. 163-163

Author(s):

Jennifer R. Amos ◽

Shigeng Li ◽

Michael Yost ◽

Harry Phloen ◽

Jay D. Potts

Keyword(s):

Tensile Strain ◽

Collagen Type ◽

Collagen Type I ◽

Limb Bud ◽

Type I ◽

Fibrillar Collagen ◽

Type Ii ◽

Collagen Type Ii

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Inducible chondrocyte-specific overexpression of BMP2 in young mice results in severe aggravation of osteophyte formation in experimental OA without altering cartilage damage

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2013-204528 ◽

2014 ◽

Vol 74 (6) ◽

pp. 1257-1264 ◽

Cited By ~ 34

Author(s):

E N Blaney Davidson ◽

E L Vitters ◽

M B Bennink ◽

P L E M van Lent ◽

A P M van Caam ◽

...

Keyword(s):

Articular Cartilage ◽

Structural Damage ◽

Medial Meniscus ◽

Collagen Type ◽

Cartilage Damage ◽

Bone Morphogenetic Protein 2 ◽

Type Ii ◽

Collagen Type Ii ◽

Osteophyte Formation ◽

Young Mice

ObjectivesIn osteoarthritis (OA) chondrocytes surrounding lesions express elevated bone morphogenetic protein 2 (BMP2) levels. To investigate the functional consequence of chondrocyte-specific BMP2 expression, we made a collagen type II dependent, doxycycline (dox)-inducible BMP2 transgenic mouse and studied the effect of elevated BMP2 expression on healthy joints and joints with experimental OA.MethodsWe cloned a lentivirus with BMP2 controlled by a tet-responsive element and transfected embryos of mice containing a collagen type II driven cre-recombinase and floxed rtTA to gain a mouse expressing BMP2 solely in chondrocytes and only upon dox exposure (Col2-rtTA-TRE-BMP2). Mice were treated with dox to induce elevated BMP2 expression. In addition, experimental OA was induced (destabilisation of the medial meniscus model) with or without dox supplementation and knee joints were isolated for histology.ResultsDox treatment resulted in chondrocyte-specific upregulation of BMP2 and severely aggravated formation of osteophytes in experimental OA but not in control mice. Moreover, elevated BMP2 levels did not result in alterations in articular cartilage of young healthy mice, although BMP2-exposure did increase VDIPEN expression in the articular cartilage. Strikingly, despite apparent changes in knee joint morphology due to formation of large osteophytes there were no detectible differences in articular cartilage: none with regard to structural damage nor in Safranin O staining intensity when comparing destabilisation of the medial meniscus with or without dox exposure.ConclusionsOur data show that chondrocyte-specific elevation of BMP2 levels does not alter the course of cartilage damage in an OA model in young mice but results in severe aggravation of osteophyte formation.

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