Abstract
Menisci play an essential role in shock absorption, joint stability, load resistance and its transmission thanks to their conformation. Adult menisci can be divided in three zones based on the vascularization: an avascular inner zone with no blood supply, a fully vascularized outer zone, and an intermediate zone. This organization, in addition to the incomplete knowledge about meniscal biology, composition, and gene expression, makes meniscal regeneration still one of the major challenges both in orthopedics and in tissue engineering. To overcome this issue, we aimed to investigate the role of hypoxia in the differentiation of the three anatomical areas of newborn piglet menisci (anterior horn (A), central body (C), and posterior horn (P)) and its effects on vascular factors. After sample collection, menisci were divided in A, C, P, and they were cultured in vitro under hypoxic (1% O2) and normoxic (21% O2) conditions at four different experimental time points (T0 = day of explant; T7 = day 7; T10 = day 10; T14 = day 14); samples were then evaluated through immune, histological, and molecular analyses, cell morpho-functional characteristics; with particular focus on matrix composition and expression of vascular factors. It was observed that hypoxia retained the initial phenotype of cells and induced extracellular matrix production resembling a mature tissue. Hypoxia also modulated the expression of angiogenic factors, especially in the early phase of the study. Thus, we observed that hypoxia contributes to the fibro-chondrogenic differentiation with the involvement of angiogenic factors, especially in the posterior horn, which corresponds to the predominant weight-bearing portion.
Highlights
The meniscus physiologically survives in a hypoxic environment; fibro-chondrocytes are cells that have adapted to the low-oxygen tension, and supporting this idea recent evidence demonstrated that hypoxia promotes the human and bovine chondrocyte phenotype differentiation at 5% oxygen tension [42,43]
It has been observed that the change in cell phenotype coincides with a change in the vascularity of the tissue in the meniscus [29,45]; in this study we focused our attention on two particular vascular factors, the pro-angiogenic factor CD31 and the anti-angiogenic factor endostatin
Type I collagen, type II collagen, and SOX9 were evaluated. These analyses revealed that hypoxia accentuated the downregulation of COL1A1 in the three portions, but it acted in the posterior horn, where the genes COL2A1 and SOX9 were upregulated after 14 days
Summary
The meniscus is divided into an inner and an outer region [5]. The inner portion (known as white-white zone) is avascular, tapering to a thin free edge, and it is close to the condyles; whereas, the outer part (known as red-red zone) receives blood supply, and it represents the thickest border close to the synovial joint capsule [1,2,3,4,6]. The outer region is composed of fibroblast-like cells, which produce a matrix rich in collagen type I and poor in glycosaminoglycans (GAGs) [7,8]. The inner portion resembles the hyaline cartilage, and it contains chondrocyte-like cells and a matrix abundant in type II collagen, in combination with small amounts of type I collagen and GAGs [9,10]. Collagen type II and GAGs are abundant in the anterior horn to resist to compression during loading. Healing potential of the meniscus is limited due to the low blood supply especially in adults [13,14,15,16]
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