Characteristics of meniscus progenitor cells migrated from injured meniscus.

Serious meniscus injuries seldom heal and increase the risk for knee osteoarthritis; thus, there is a need to develop new reparative therapies. In that regard, stimulating tissue regeneration by autologous stem/progenitor cells has emerged as a promising new strategy. We showed previously that migratory chondrogenic progenitor cells (CPCs) were recruited to injured cartilage, where they showed a capability in situ tissue repair. Here, we tested the hypothesis that the meniscus contains a similar population of regenerative cells. Explant studies revealed that migrating cells were mainly confined to the red zone in normal menisci: However, these cells were capable of repopulating defects made in the white zone. In vivo, migrating cell numbers increased dramatically in damaged meniscus. Relative to non-migrating meniscus cells, migrating cells were more clonogenic, overexpressed progenitor cell markers, and included a larger side population. Gene expression profiling showed that the migrating population was more similar to CPCs than other meniscus cells. Finally, migrating cells equaled CPCs in chondrogenic potential, indicating a capacity for repair of the cartilaginous white zone of the meniscus. These findings demonstrate that, much as in articular cartilage, injuries to the meniscus mobilize an intrinsic progenitor cell population with strong reparative potential. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1966-1972, 2017.

The use of autologous adult, allogenic juvenile, and combined juvenile-adult cartilage fragments for the repair of chondral defects.

PURPOSE: The goal of the study was to evaluate the repair of chondral lesions treated with combined autologous adult/allogenic juvenile cartilage fragments, compared with isolated adult and isolated juvenile cartilage fragments. METHODS: Fifty-eight adult (>16 week old) and five juvenile (<6 week old) New Zealand White female rabbits were used. A large osteochondral defect was created in the center of the femoral trochlea of adult rabbits. The rabbits were divided in four groups: Group 1 = untreated defects (controls); Group 2 = adult cartilage fragments; Group 3 = juvenile cartilage fragments; and Group 4 = adult + juvenile cartilage fragments. Killings were performed at 3 and 6 months. The defects were evaluated with ICRS macroscopic score, modified O'Driscoll score, and Collagen type II immunostaining. RESULTS: At 3 months, Group 4 performed better than Group 1, in terms of modified O'Driscoll score (p = 0.001) and Collagen type II immunostaining (p = 0.015). At 6 months, Group 4 showed higher modified O'Driscoll score (p = 0.003) and Collagen type II immunostaining score (p < 0.001) than Group 1. Histologically, also Group 3 performed better than Group 1 (p = 0.03), and Group 4 performed better than Group 2 (p = 0.004). CONCLUSIONS: Mixing adult and juvenile cartilage fragments improved cartilage repair in a rabbit model. In the clinical setting, a new "one-stage" procedure combining the two cartilage sources can be hypothesized, with the advantages of improved chondral repair and large defect coverage, because of the use of an off-the-shelf juvenile allograft. Further studies on larger animals and clinical trials are required to confirm these results.

Chondrogenic progenitor cells respond to cartilage injury.

OBJECTIVE: Hypocellularity resulting from chondrocyte death in the aftermath of mechanical injury is thought to contribute to posttraumatic osteoarthritis. However, we observed that nonviable areas in cartilage injured by blunt impact were repopulated within 7-14 days by cells that appeared to migrate from the surrounding matrix. The aim of this study was to assess our hypothesis that the migrating cell population included chondrogenic progenitor cells that were drawn to injured cartilage by alarmins. METHODS: Osteochondral explants obtained from mature cattle were injured by blunt impact or scratching, resulting in localized chondrocyte death. Injured sites were serially imaged by confocal microscopy, and migrating cells were evaluated for chondrogenic progenitor characteristics. Chemotaxis assays were used to measure the responses to chemokines, injury-conditioned medium, dead cell debris, and high mobility group box chromosomal protein 1 (HMGB-1). RESULTS: Migrating cells were highly clonogenic and multipotent and expressed markers associated with chondrogenic progenitor cells. Compared with chondrocytes, these cells overexpressed genes involved in proliferation and migration and underexpressed cartilage matrix genes. They were more active than chondrocytes in chemotaxis assays and responded to cell lysates, conditioned medium, and HMGB-1. Glycyrrhizin, a chelator of HMGB-1 and a blocking antibody to receptor for advanced glycation end products (RAGE), inhibited responses to cell debris and conditioned medium and reduced the numbers of migrating cells on injured explants. CONCLUSION: Injuries that caused chondrocyte death stimulated the emergence and homing of chondrogenic progenitor cells, in part via HMGB-1 release and RAGE-mediated chemotaxis. Their repopulation of the matrix could promote the repair of chondral damage that might otherwise contribute to progressive cartilage loss.

Distribution and progression of chondrocyte damage in a whole-organ model of human ankle intra-articular fracture.

BACKGROUND: Despite the best current treatments, intra-articular fractures commonly cause posttraumatic osteoarthritis. In this disorder, death and dysfunction of chondrocytes associated with acute cartilage injury presumably plays an important role in triggering the pathomechanical cascade that eventually leads to whole-joint degeneration. Information regarding this cell-level cartilage injury, particularly at the whole-organ level in actual human joints, has been lacking. In this study, the distribution and progression of fracture-associated cell-level cartilage damage were assessed using a novel whole-organ model of human ankle intra-articular fracture. METHODS: Seven normal human ankles harvested immediately following amputation were subjected to a transarticular compressive impaction insult that mimicked an injury mechanism typical of tibial plafond fractures. For each ankle, site-specific, time-dependent changes in chondrocyte viability in the fractured tibial surface were studied by means of live-dead assay, using a confocal laser-scanning microscope. Fractional chondrocyte death was measured at several time points, in the superficial zone of the cartilage in "fracture-edge" regions within 1 mm of the fracture lines, as well as in "non-fracture" regions more than 3 mm centrally away from the fracture lines. RESULTS: All seven experimental fractures morphologically replicated tibial plafond fractures. Immediately post-fracture, superficial-zone chondrocyte death was significantly greater (p = 0.001) in fracture-edge regions (fractional cell death = 7.6%) than in non-fracture regions (1.6%). Progression of cell death over the next forty-eight hours was significantly faster in fracture-edge regions (p = 0.007), with the fractional cell death reaching 25.9%, which was again significantly higher (p < 0.001) than in non-fracture regions (8.6%). CONCLUSIONS: Cell-level cartilage damage in human intra-articular fractures was characterized by acute chondrocyte death that predominated along fracture lines and that spontaneously progressed in the forty-eight hours following injury. CLINICAL RELEVANCE: Progressive chondrocyte damage along fracture lines appears to be a reasonable target of therapeutic treatment to preserve the whole-joint cartilage metabolism in intra-articular fractures, eventually to mitigate the risk of posttraumatic osteoarthritis.