European Cells & Materials (Feb 2024)
Alginate hydrogel-guided rAAV-mediated FGF-2 and TGF-β delivery and overexpression stimulates the biological activities of human meniscal fibrochondrocytes for meniscus repair
Abstract
Meniscus lesions are unsolved problems that impede the functions of stability, load bearing, and shock absorption in the knee joint and for which there is no satisfying therapeutic option to date. Gene therapy using clinically adapted recombinant adeno-associated virus (rAAV) vectors is a powerful tool to enhance meniscus repair, especially when applied in combination with tissue engineering strategies that may allow to counteract a possible neutralization and/or dissemination of the rAAV particles in the recipient. Here, we examined the ability of an alginate (AlgPH155) hydrogel to formulate and deliver rAAV vectors carrying the genes for the reparative fibroblast growth factor (FGF-2) and transforming growth factor beta (TGF-β) as a means to trigger the biological activities in human meniscal fibrochondrocytes. The results show that effective rAAV-mediated FGF-2 and TGF-β overexpression via alginate (AlgPH155) hydrogel-guided vector administration equally led to enhanced levels of cell proliferation and of specific matrix deposition (proteoglycans, type-I/-III collagen) in the cells over an extended period of time (21 days, the latest time point evaluated) relative to the control treatments (hydrogel without vector or with a vector carrying the reporter lacZ gene). These effects were associated with an increase in the expression of the contractile alpha smooth muscle actin (α-SMA) marker, a determinant of the meniscus response injury, and with decreased levels of pro-inflammatory markers (interleukin 1 beta—IL1β, tumor necrosis factor alpha—TNF-α). These findings show the potential of alginate hydrogel-guided rAAV-mediated gene therapy as a new, off-the-shelf therapeutic system for meniscus repair.
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