Cartilage cell clusters

Lotz, Martin; Otsuki, Shuhei; Grogan, Shawn P.; Sah, Robert L.; Terkeltaub, Robert; D’Lima, Darryl D.

doi:10.1002/art.27528

Cited by 187 publications

(178 citation statements)

References 238 publications

(133 reference statements)

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“…The formation of chondrocyte aggregates or clusters in OA occurs by increased cell proliferation or active movement of the chondrocytes (Kouri et al, 1998;Pfander et al, 2001;McGlashan et al, 2008). Chondrocyte clusters can be composed by more than 20 cells and are localised in the proximity of fissures in the upper cartilage layers (Lotz et al, 2010;Schumacher et al, 2002). Although previous studies have investigated the effect of chondrocyte clustering on cartilage formation, these aggregates were formed either in insufficient quantity, with improper or poorly controlled size ranges, or attached to scaffold sheets (de Chalain et al, 1999;Kelm and Fussenegger, 2004;Penick et al, 2005;Fukuda et al, 2006;Hamilton et al, 2006;Khademhosseini et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

High throughput generated micro-aggregates of chondrocytes stimulate cartilage formation in vitro and in vivo

Teixeira

Leijten²,

Sobral³

et al. 2012

eCM

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Cell-based cartilage repair strategies such as matrixinduced autologous chondrocyte implantation (MACI) could be improved by enhancing cell performance. We hypothesised that micro-aggregates of chondrocytes generated in high-throughput prior to implantation in a defect could stimulate cartilaginous matrix deposition and remodelling. To address this issue, we designed a micromould to enable controlled high-throughput formation of micro-aggregates. Morphology, stability, gene expression profiles and chondrogenic potential of micro-aggregates of human and bovine chondrocytes were evaluated and compared to single-cells cultured in micro-wells and in 3D after encapsulation in Dextran-Tyramine (Dex-TA) hydrogels in vitro and in vivo. We successfully formed micro-aggregates of human and bovine chondrocytes with highly controlled size, stability and viability within 24 hours. Micro-aggregates of 100 cells presented a superior balance in Collagen type I and Collagen type II gene expression over single cells and micro-aggregates of 50 and 200 cells. Matrix metalloproteinases 1, 9 and 13 mRNA levels were decreased in micro-aggregates compared to singlecells. Histological and biochemical analysis demonstrated enhanced matrix deposition in constructs seeded with micro-aggregates cultured in vitro and in vivo, compared to single-cell seeded constructs. Whole genome microarray analysis and single gene expression profiles using human chondrocytes confirmed increased expression of cartilagerelated genes when chondrocytes were cultured in microaggregates. In conclusion, we succeeded in controlled highthroughput formation of micro-aggregates of chondrocytes. Compared to single cell-seeded constructs, seeding of constructs with micro-aggregates greatly improved neocartilage formation. Therefore, micro-aggregation prior to chondrocyte implantation in current MACI procedures, may effectively accelerate hyaline cartilage formation.

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Section: Discussionmentioning

confidence: 99%

High throughput generated micro-aggregates of chondrocytes stimulate cartilage formation in vitro and in vivo

Teixeira

Leijten²,

Sobral³

et al. 2012

eCM

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“…These cells exhibit an interesting replicative biology, showing extremely low proliferation rates in adult humans and mice during homeostasis (Aigner et al., 2001; Decker et al., 2017). Chondrocyte proliferation can occur during the development of osteoarthritis (OA) in the form of cell clusters, but it is not known if this replicative response is regenerative, pathologic, or epiphenomenal (Lotz et al., 2010). Chondrocytes also display features of senescence with aging and OA, likely in response to macromolecular damage that accumulates in these long‐lived cells (Martin & Buckwalter, 2001; McCulloch, Litherland & Rai, 2017; Price et al., 2002; Rose et al., 2012).…”

Section: Introductionmentioning

confidence: 99%

Expression of p16^INK^4a is a biomarker of chondrocyte aging but does not cause osteoarthritis

et al. 2018

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SummaryCellular senescence drives a functional decline of numerous tissues with aging by limiting regenerative proliferation and/or by producing pro‐inflammatory molecules known as the senescence‐associated secretory phenotype (SASP). The senescence biomarker p16 INK 4a is a potent inhibitor of the cell cycle but is not essential for SASP production. Thus, it is unclear whether p16 INK 4a identifies senescence in hyporeplicative cells such as articular chondrocytes and whether p16 INK 4a contributes to pathologic characteristics of cartilage aging. To address these questions, we examined the role of p16 INK 4a in murine and human models of chondrocyte aging. We observed that p16 INK 4a mRNA expression was significantly upregulated with chronological aging in murine cartilage (~50‐fold from 4 to 18 months of age) and in primary human chondrocytes from 57 cadaveric donors (r 2 = .27, p < .0001). Human chondrocytes exhibited substantial replicative potential in vitro that depended on the activity of cyclin‐dependent kinases 4 or 6 (CDK4/6), and proliferation was reduced in cells from older donors with increased p16 INK 4a expression. Moreover, increased chondrocyte p16 INK 4a expression correlated with several SASP transcripts. Despite the relationship between p16 INK 4a expression and these features of senescence, somatic inactivation of p16 INK 4a in chondrocytes of adult mice did not mitigate SASP expression and did not alter the rate of osteoarthritis (OA) with physiological aging or after destabilization of the medial meniscus. These results establish that p16 INK 4a expression is a biomarker of dysfunctional chondrocytes, but that the effects of chondrocyte senescence on OA are more likely driven by production of SASP molecules than by loss of chondrocyte replicative function.

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“…3 One of the characteristic changes observed in OA progression is chondrocyte clustering within articular cartilage. 4 However, the time point at which these chondrocyte clusters first appear is uncertain because the human OA samples used to study OA pathogenesis mostly are taken at the late or end stages of the disease. Recent data from animal models of OA show that chondrocyte clustering, with intensive pericellular proteoglycan staining, is one of the earliest pathologic changes seen in OA progression.…”

mentioning

confidence: 99%

Intact Pericellular Matrix of Articular Cartilage Is Required for Unactivated Discoidin Domain Receptor 2 in the Mouse Model

Polur

Servais

et al. 2011

The American Journal of Pathology

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Increased expression of the discoidin domain receptor 2 (DDR2) results from its interaction with collagen type II. This induces expression of matrix metalloproteinase (MMP)-13, leading to osteoarthritis (OA). To investigate the impact of the pericellular matrix of chondrocytes on DDR2, we generated a mouse model with inducible overexpression of DDR2 in cartilage. Conditional overexpression of DDR2 in mature mouse articular cartilage was controlled via the cartilage oligomeric matrix protein promoter using the Tet-Off-inducible system. Doxycycline was withdrawn at 1 month of age, and knee joints were examined at 2, 3, and 4 months of age. Microsurgery was performed on 3-month-old transgenic mice overexpressing DDR2 to destabilize the medial meniscus, and serial paraffin sections were examined at 2, 4, 8, and 12 weeks after surgery. DDR2 expression increased in the knee joints of transgenic mice. However, the increased DDR2 did not induce MMP-13 expression. No OA-like changes were observed in the transgenic mice at the age of 4 months. When transgenic mice were subjected to destabilizing of the medial meniscus, we observed accelerated progression to OA, which was associated with DDR2 activation. Therefore, conditionally overexpressing DDR2 in the mature articular cartilage of mouse knee joints requires activation to induce OA, and altered biomechanical stress can accelerate the onset of cartilage loss and progression to OA in transgenic mice.

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Cartilage cell clusters

Cited by 187 publications

References 238 publications

High throughput generated micro-aggregates of chondrocytes stimulate cartilage formation in vitro and in vivo

High throughput generated micro-aggregates of chondrocytes stimulate cartilage formation in vitro and in vivo

Expression of p16^INK^4a is a biomarker of chondrocyte aging but does not cause osteoarthritis

Intact Pericellular Matrix of Articular Cartilage Is Required for Unactivated Discoidin Domain Receptor 2 in the Mouse Model

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Cartilage cell clusters

Cited by 187 publications

References 238 publications

High throughput generated micro-aggregates of chondrocytes stimulate cartilage formation in vitro and in vivo

High throughput generated micro-aggregates of chondrocytes stimulate cartilage formation in vitro and in vivo

Expression of p16INK4a is a biomarker of chondrocyte aging but does not cause osteoarthritis

Intact Pericellular Matrix of Articular Cartilage Is Required for Unactivated Discoidin Domain Receptor 2 in the Mouse Model

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Expression of p16^INK^4a is a biomarker of chondrocyte aging but does not cause osteoarthritis