Intra-articular injection of human mesenchymal stem cells (MSCs) promote rat meniscal regeneration by being activated to express Indian hedgehog that enhances expression of type II collagen

Abstract

Objective Meniscal regeneration was previously shown to be enhanced by injection of mesenchymal stem/stromal cells (MSCs) but the mode of action of the MSCs was not established. The aim of this study was to define how injection of MSCs enhances meniscal regeneration. Design A hemi-meniscectomy model in rats was used. Rat-MSCs (rMSCs) or human-MSCs (hMSCs) were injected into the right knee joint after the surgery, and PBS was injected into the left. The groups were compared macroscopically and histologically at 2, 4, and 8 w. The changes in transcription in both human and rat genes were assayed by species-specific microarrays and real-time RT-PCRs. Results Although the number of hMSCs decreased with time, hMSCs enhanced meniscal regeneration in a manner similar to rMSCs. hMSCs injection increased expression of rat type II collagen (rat-Col II), and inhibited osteoarthritis progression. The small fraction of hMSCs were activated to express high levels of a series of genes including Indian hedgehog (Ihh), parathyroid hormone-like hormone (PTHLH), and bone morphogenetic protein 2 (BMP2). The presence of hMSCs triggered the subsequent expression of rat-Col II. An antagonist of hedgehog signaling inhibited the expression of rat-Col II and an agonist increased expression of rat-Col II in the absence of hMSCs. Conclusions Despite rapid reduction in cell numbers, intra-articular injected hMSCs were activated to express Ihh, PTHLH, and BMP2 and contributed to meniscal regeneration. The hedgehog signaling was essential in enhancing the expression of rat-Col II, but several other factors provided by the hMSCs probably contributed to the repair.

Effect of self-assembled peptide–mesenchymal stem cell complex on the progression of osteoarthritis in a rat model

“…36 Thus, this persistence of SAP at 6 weeks postinjection in SD rats is enough time to show the effect of SAP or SAP-MSC on the progression of arthritis. We did not study the status of MSCs and SAP-MSC in the joint cavity using cell markers, but considering that injected MSCs were still detected at 8 weeks in the rat joint cavity in a previous study, 37 we believe our MSCs and SAP-MSC would have been present in the joint cavity 6 weeks after the injection.…”

A study to identify and characterize the stem/progenitor cell in rabbit meniscus

“…Several studies have proven the role and effectiveness of MSCs using a wide range of delivery techniques-intra-articular injection (Horie et al 2012), scaffolds (Yamasaki et al 2008), and aggregates (Katagiri et al 2013). Although these meniscus explant systems have successfully demonstrated the therapeutic potential of MSCs, few techniques have reached clinical application.…”

Treatment of osteoarthritis with mesenchymal stem cells

“…These data suggest that intra-articular injection of hMSCs repaired cartilage by activating the Indian hedgehog signaling pathway [93]. The expression of Notch-1 was also found in MSCs from healthy and OA articular cartilage, but the numbers of Notch-1-positive MSCs were much larger when isolated from OA articular cartilage than healthy samples [94], indicating that Notch signaling is overexpressed during OA progression and that intra-articular therapy with normal MSCs down-regulates the Notch signaling pathway.…”