Genome-Wide MicroRNA and Gene Analysis of Mesenchymal Stem Cell Chondrogenesis Identifies an Essential Role and Multiple Targets for miR-140-5p

Abstract

AbstractmicroRNAs (miRNAs) are abundantly expressed in development where they are critical determinants of cell differentiation and phenotype. Accordingly miRNAs are essential for normal skeletal development and chondrogenesis in particular. However, the question of which miRNAs are specific to the chondrocyte phenotype has not been fully addressed. Using microarray analysis of miRNA expression during mesenchymal stem cell chondrogenic differentiation and detailed examination of the role of essential differentiation factors, such as SOX9, TGF‐β, and the cell condensation phase, we characterize the repertoire of specific miRNAs involved in chondrocyte development, highlighting in particular miR‐140 and miR‐455. Further with the use of mRNA microarray data we integrate miRNA expression and mRNA expression during chondrogenesis to underline the particular importance of miR‐140, especially the ‐5p strand. We provide a detailed identification and validation of direct targets of miR‐140‐5p in both chondrogenesis and adult chondrocytes with the use of microarray and 3′UTR analysis. This emphasizes the diverse array of targets and pathways regulated by miR‐140‐5p. We are also able to confirm previous experimentally identified targets but, additionally, identify a novel positive regulation of the Wnt signaling pathway by miR‐140‐5p. Wnt signaling has a complex role in chondrogenesis and skeletal development and these findings illustrate a previously unidentified role for miR‐140‐5p in regulation of Wnt signaling in these processes. Together these developments further highlight the role of miRNAs during chondrogenesis to improve our understanding of chondrocyte development and guide cartilage tissue engineering. Stem Cells 2015;33:3266–3280

Retracted: MicroRNA‐140‐5p elevates cerebral protection of dexmedetomidine against hypoxic–ischaemic brain damage via the Wnt/β‐catenin signalling pathway

“…Similarly, miR‐142‐3p has been reported to down‐regulate Wnt/β‐catenin signalling, which is largely in line with the central findings presented in this study 25. Moreover, Wnt signalling has been correlated to congenital diseases and cancers, as well as indicating that miR‐140‐5p plays a significant role in the regulation of Wnt signalling 20, 22. Mayorga et al 26 pointed out that miR‐145 expression could be used as a regulator of activity of β‐catenin in terms of hypoxia and ischaemia.…”

Exosomes derived from miR-140-5p-overexpressing human synovial mesenchymal stem cells enhance cartilage tissue regeneration and prevent osteoarthritis of the knee in a rat model

“…Genome-wide and gene analysis identified that miR-140-5p plays an essential role in chondrogenic differentiation of MSCs 35. Recently, miR-140-5p gained a lot of attention for playing dual roles in both cartilage homeostasis and development 36, 37 by targeting RalA to enhance SOX9 and aggrecan (ACAN) 38 and showing potential for preventing OA 39, 40.…”

Emerging Role of Exosomes in the Joint Diseases

“…MiR-140-5p is essential for chondrogenic differentiation of MSCs, shown by analysis of genomes and genes, Tao et al overexpressed miR-140-5p in SMSCs and generated an improved version of exosomes (SMSC-140-Exos) that promoted chondrocyte proliferation and migration with less influence on the secretion of extracellular matrix. In an OA rat model, SMSC-140-Exos prevented OA [36,37]. Kim et al also used modified exosomes for RA [38].…”