Induction of iPSC-derived Prg4-positive cells with characteristics of superficial zone chondrocytes and fibroblast-like synovial cells

Lubricin, a proteoglycan encoded by the PRG4 gene, is synthesised by superficial zone (SFZ) chondrocytes and synovial cells. It reduces friction between joints and allows smooth sliding of tendons. Although lubricin has been shown to be effective against osteoarthritis and synovitis in animals, its...

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Bibliographic Details
Published in:BMC cell biology 2022-07, Vol.23 (1), p.1-30, Article 30
Main Authors: Satake, Takashi, Komura, Shingo, Aoki, Hitomi, Hirakawa, Akihiro, Imai, Yuuki, Akiyama, Haruhiko
Format: Article
Language:English
Subjects:
Activin
Amino acids
Analysis
Arthritis
Care and treatment
Cartilage
Cartilage cells
Cell differentiation
Chondrocytes
Chondrogenesis
Cloning
Cytokines
Diagnosis
Fibroblast growth factor 2
Fibroblast-like synovial cells
Fibroblasts
Gene expression
Genetic engineering
Growth factors
Immunodeficiency
Inflammation
iPSCs
Joint diseases
KLF4 protein
Knee
Methods
Myc protein
Oct-4 protein
Osteoarthritis
Pluripotency
Prg4
Proteoglycans
Risk factors
Rodents
Software
Statistical analysis
Stem cell transplantation
Stem cells
Superficial zone chondrocytes
Synovitis
Tendons
Transforming growth factor-b1
Transgenic animals
Transgenic mice
Transplantation
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Summary:Lubricin, a proteoglycan encoded by the PRG4 gene, is synthesised by superficial zone (SFZ) chondrocytes and synovial cells. It reduces friction between joints and allows smooth sliding of tendons. Although lubricin has been shown to be effective against osteoarthritis and synovitis in animals, its clinical application remains untested. In this study, we aimed to induce lubricin-expressing cells from pluripotent stem cells (iPSCs) and applied them locally via cell transplantation. To generate iPSCs, OCT3/4, SOX2, KLF4, and L-MYC were transduced into fibroblasts derived from Prg4-mRFP1 transgenic mice. We established a protocol for the differentiation of iPSC-derived Prg4-mRFP1-positive cells and characterised their mRNA expression profile. Finally, we injected Prg4-mRFP1-positive cells into the paratenon, surrounding the Achilles tendons and knee joints of severe combined immunodeficient mice and assessed lubricin expression. Wnt3a, activin A, TGF-[beta]1, and bFGF were applied to induce the differentiation of iPSC-derived Prg4-mRFP1-positive cells. Markers related to SFZ chondrocytes and fibroblast-like synovial cells (FLSs) were expressed during differentiation. RNA-sequencing indicated that iPSC-derived Prg4-mRFP1-positive cells manifested expression profiles typical of SFZ chondrocytes and FLSs. Transplanted iPSC-derived Prg4-mRFP1-positive cells survived around the Achilles tendons and in knee joints. The present study describes a protocol for the differentiation of iPSC-derived Prg4-positive cells with characteristics of SFZ chondrocytes and FLSs. Transplantation of lubricin-expressing cells offers promise as a therapy against arthritis and synovitis.
ISSN:2661-8850
2661-8850
1471-2121
DOI:10.1186/s12860-022-00431-8