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Injectable kartogenin and apocynin loaded micelle enhances the alleviation of intervertebral disc degeneration by adipose-derived stem cell.

ABSTRACT: Cell transplantation has been proved the promising therapeutic effects on intervertebral disc degeneration (IVDD). However, the increased levels of reactive oxygen species (ROS) in the degenerated region will impede the efficiency of human adipose-derived stem cells (human ADSCs) transplantation therapy. It inhibits human ADSCs proliferation, and increases human ADSCs apoptosis. Herein, we firstly devised a novel amphiphilic copolymer PEG-PAPO, which could self-assemble into a nanosized micelle and load lipophilic kartogenin (KGN), as a single complex (PAKM). It was an injectable esterase-responsive micelle, and showed controlled release ability of KGN and apocynin (APO). Oxidative stimulation promoted the esterase activity in human ADSCs, which accelerate degradation of esterase-responsive micelle. Compared its monomer, the PAKM micelle possessed better bioactivities, which were attributed to their synergistic effect. It enhanced the viability, autophagic activation (P62, LC3 II), ECM-related transcription factor (SOX9), and ECM (Collagen II, Aggrecan) maintenance in human ADSCs. Furthermore, it is demonstrated that the injection of PAKM with human ADSCs yielded higher disc height and water content in rats. Therefore, PAKM micelles perform promoting cell survival and differentiation effects, and may be a potential therapeutic agent for IVDD.

SUBMITTER: Yu C

PROVIDER: S-EPMC8022109 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionOver-activation of oxidative stress due to impaired antioxidant functions in nucleus pulpous (NP) has been identified as a key factor contributing to intervertebral disc degeneration (IVDD). While Kartogenin (KGN) has previously demonstrated antioxidant properties on articular cartilage against osteoarthritis, its effects on NP degeneration have yet to be fully understood.ObjectivesThis study aimed to investigate the protective effects of KGN on nucleus pulpous cells (NPCs) against an inflammatory environment induced by interleukin (IL)-1β, as well as to explore the therapeutic potential of KGN-enhanced dynamic hydrogel in preventing IVDD.MethodsNPCs were isolated from rat caudal IVDs and subjected to treatment with KGN at varying concentrations (ranging from 0.01 to 1 μM) in the presence of IL-1β. The expression of extracellular matrix (ECM) anabolism markers was quantitatively assessed at both the mRNA and protein levels. Additionally, intracellular reactive oxygen species and antioxidant enzyme expression were evaluated, along with the role of nuclear factor erythroid 2-related factor 2 (NRF2). Based on these findings, a dynamic self-healing hydrogel loaded with KGN was developed through interconnecting networks. Subsequently, KGN-enhanced dynamic hydrogel was administered into rat caudal IVDs that had undergone puncture injury, followed by radiographic analysis and immunohistochemical staining to evaluate the therapeutic efficacy.ResultsIn vitro treatments utilizing KGN were observed to maintain ECM synthesis and inhibit catabolic activities in IL-1β-stimulated NPCs. The mechanism behind this protective effect of KGN on NPCs was found to involve the asctivation of NRF2 and downstream antioxidant enzymes, including glutathione peroxidase 1 and heme oxygenase 1. This was further supported by the loss of both antioxidant and anabolic effects upon pharmacological inhibition of NRF2. Furthermore, a self-healing hydrogel was developed and loaded with KGN to achieve localized and sustained release of the compound. The injection of KGN-enhanced hydrogel effectively ameliorated the degradation of NP ECM and mitigated inflammation in a rat model of puncture-induced IVDD.ConclusionsOur results indicate that KGN exhibits potential as a therapeutic agent for NP degeneration, and that KGN-enhanced dynamic hydrogel represents a novel approach for treating IVDD by restoring redox homeostasis in NP.The translational potential of this article: The dysregulation of oxidant and antioxidant balance has been shown to impede the repair and regeneration of NP, thereby hastening the progression of IVDD following injury. The present investigation has demonstrated that the sustained release of KGN promotes the synthesis of ECM in vitro and mitigates the progression of IVDD in vivo by restoring redox equilibrium, thereby presenting a novel therapeutic candidate based on the antioxidant properties of KGN for the treatment of IVDD.

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Injectable kartogenin and apocynin loaded micelle enhances the alleviation of intervertebral disc degeneration by adipose-derived stem cell.

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