Abstract
Matrix remodeling of cells is highly regulated by proteases and their inhibitors. Nevertheless, how would the chondrogenesis of mesenchymal stem cells (MSCs) be affected, when the balance of the matrix remodeling is disturbed by inhibiting matrix proteases, is incompletely known. Using a previously developed collagen microencapsulation platform, we investigated whether exposing chondrogenically differentiating MSCs to intracellular and extracellular protease inhibitors will affect the extracellular matrix remodeling and hence the outcomes of chondrogenesis. Results showed that inhibition of matrix proteases particularly the extracellular ones favors the phenotype of fibrocartilage rather than hyaline cartilage in chondrogenically differentiating hMSCs by upregulating type I collagen protein deposition and type II collagen gene expression without significantly altering the hypertrophic markers at gene level. This study suggests the potential of manipulating extracellular proteases to alter the outcomes of hMSC chondrogenesis, contributing to future development of differentiation protocols for fibrocartilage tissues for intervertebral disc and meniscus tissue engineering.
Highlights
The process of chondrogenesis occurs in stages beginning with mesenchymal cell condensation followed by chondrocyte differentiation and maturation [1]
The extracellular matrix is being remodeled by human mesenchymal stem cells (hMSCs) as simultaneous synthesis of human type I collagen was shown by the intense immunofluorescence staining of human type I collagen at the intracellular space (Fig 1B) and the slight extracellular deposition overlaying with both DQ collagen (Fig 1E) and rat collagen (Fig 1F)
Extracellular matrix remodeling is important in tissue dynamic states including development, homeostasis and regeneration, it is logical to hypothesize that manipulating the matrix remodeling process through the inhibition of matrix proteases will affect the outcomes of chondrogenic differentiation of hMSCs in this 3D platform
Summary
The process of chondrogenesis occurs in stages beginning with mesenchymal cell condensation followed by chondrocyte differentiation and maturation [1]. This process is characterized by a series of differentiation stages with extracellular matrix (ECM) remodeling. The stage-specific changes of pre-cartilaginous ECM containing fibronectin and type I collagen to cartilaginous ECM containing type II collagen and aggrecan as chondrocytic cells differentiate [2], and to a matrix rich in type X collagen during terminal differentiation of chondrocytes [1]. Matrix remodeling involving degradation of the old ECM and deposition of the new ECM is important for tissue dynamic processes such as development, homeostasis and wound healing.
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