The Importance of Physioxia in Mesenchymal Stem Cell Chondrogenesis and the Mechanisms Controlling Its Response

Abstract

Articular cartilage covers the surface of synovial joints and enables joint movement. However, it is susceptible to progressive degeneration with age that can be accelerated by either previous joint injury or meniscectomy. This degenerative disease is known as osteoarthritis (OA) and it greatly affects the adult population. Cell-based tissue engineering provides a possible solution for treating OA at its earliest stages, particularly focal cartilage lesions. A candidate cell type for treating these focal defects are Mesenchymal Stem Cells (MSCs). However, present methods for differentiating these cells towards the chondrogenic lineage lead to hypertrophic chondrocytes and bone formation in vivo. Environmental stimuli that can stabilise the articular chondrocyte phenotype without compromising tissue formation have been extensively investigated. One factor that has generated intensive investigation in MSC chondrogenesis is low oxygen tension or physioxia (2–5% oxygen). In vivo articular cartilage resides at oxygen tensions between 1–4%, and in vitro results suggest that these conditions are beneficial for MSC expansion and chondrogenesis, particularly in suppressing the cartilage hypertrophy. This review will summarise the current literature regarding the effects of physioxia on MSC chondrogenesis with an emphasis on the pathways that control tissue formation and cartilage hypertrophy.

Combining Innovative Bioink and Low Cell Density for the Production of 3D-Bioprinted Cartilage Substitutes: A Pilot Study

“…The major effect of hypoxia was to prevent the occurrence of intra-ECM microcalcifications [88], which are characteristic of the phenotypic drift towards an osteoblast phenotype, as demonstrated herein with alizarin red staining. As extensively reported by Pattappa et al [89], COL10A1 and BGLAP expression was strongly inhibited on D28 under hypoxia (or chondroxia/physioxia), thus preventing hypertrophy and ancillary ECM calcification/ossification [89][90][91][92].…”

Physioxia stimulates extra-cellular matrix deposition and increases mechanical properties of human chondrocyte-derived tissue-engineered cartilage

“…A circular biochamber design with a 1.13 cm 2 cell seeding area (1) was used with three seeding chambers (3) stacked on top of each other giving a 2.1 ml seeding volume. Stainless steel screws (2) were used to raise the biochambers 1.2 cm allowing media access to the cell sheet through the polyester membrane (7) sandwiched between the bottom 0.2 cm plate and the seeding chambers. Biochambers were assembled and placed in Nalgene containers (6) with a ceramic filter on the lid (4).…”

“…It is increasingly apparent that physiological oxygen tension should be the standard culture method to grow tissue engineered human articular cartilage whether it be from mesenchymal stem cells [7] , chondrocytes [8][9][10][11][12][13][14][15][16][17] or chondroprogenitors [18] . The selection of cell type for engineered tissue raises some interesting issues, mesenchymal stem cells commonly progress to hypertrophy [19] as do iPSCs driven down the mesenchymal pathway [20] , a negative scenario for the production of hyaline cartilage.…”

Osteoarthritis and Cartilage Regeneration: Focus on Pathophysiology and Molecular Mechanisms

“…It has been a long-term hypothesis that application of factors reflecting for the native articular cartilage environment, such as mechanical stimulation, oxygen tension or osmolarity, during expansion of mesenchymal stem cells (MSCs) or chondrocytes is vital for the development of cell-based tissue engineering constructs for cartilage repair. The review by Pattappa et al provides a comprehensive insight into the role of hypoxia/physioxia for chondrogenic differentiation of adult MSCs [19]. Exposure to physioxic conditions (1-5% O 2 ) is beneficial for MSC isolation, expansion and chondrogenic differentiation compared to normal oxygen tension (20% O2).…”