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Intervertebral disc degeneration (IDD) is an age‐related disease and is responsible for low back pain. Oxidative stress‐induced cell death plays a fundamental role in IDD pathogenesis. Cuproptosis is a recently discovered form of programmed cell death dependent on copper availability. Whether cuproptosis is involved in IDD progression remains unknown. Herein, we established in vitro and in vivo models to investigate cuproptosis in IDD and the mechanisms by which oxidative stress interacts with copper sensitivity in nucleus pulposus cells (NPCs). We found that ferredoxin‐1 (FDX1) content increased in both rat and human degenerated discs. Sublethal oxidative stress on NPCs led to increased FDX1 expression, tricarboxylic acid (TCA) cycle‐related proteins lipoylation and aggregation, and cell death in the presence of Cu2+ at physiological concentrations, while FDX1 knockdown inhibited cell death. Since copper homeostasis is involved in copper‐induced cytotoxicity, we investigated the role of copper transport‐related proteins, including importer (CTR1) and efflux pumps (ATPase transporter, ATP7A, and ATP7B). CTR1 and ATP7A content increased under oxidative stress, and blocking CTR1 reduced oxidative stress/copper‐induced TCA‐related protein aggregation and cell death. Moreover, oxidative stress promoted the expression of specific protein 1 (SP1) and SP1‐mediated CTR1 transcription. SP1 inhibition decreased cell death rates, preserved disc hydration, and alleviated tissue degeneration. This suggests that oxidative stress upregulates FDX1 expression and copper flux through promoting SP1‐mediated CTR1 transcription, leading to increased TCA cycle‐related protein aggregation and cuproptosis. This study highlights the importance of cuproptosis in IDD progression and provides a promising therapeutic target for IDD treatment. [ABSTRACT FROM AUTHOR]

Exogenous stem cell therapy and endogenous repair has shown great potential in intervertebral disc regeneration. However, limited nutrients and accumulation of lactate largely impair the survival and regenerative capacity of implanted stem cells and endogenous nucleus pulposus cells (NPCs). Herein, an injectable hydrogel microsphere (LMGDNPs) have been developed by immersing lactate oxidase (LOX)‐manganese dioxide (MnO2) nanozyme (LM) into glucose‐enriched decellularized nucleus pulposus hydrogel microspheres (GDNPs) through a microfluidic system. LMGDNPs showed a delayed release profile of LOX and satisfactory enzymatic capacity in consuming lactate. Mesenchymal stem cells (MSCs) plated on LMGDNPs exhibited better cell viability than cells on GelMA and decellularized nucleus pulposus microspheres (DNP) and showed a obviously increased NPCs phenotype. LMGDNPs prevented MSCs and NPCs death and promoted extracellular matrix synthesis by exhausting lactate. It is determined that LMGDNPs promoted NPCs autophagy by activating transforming growth factor β2 overlapping transcript 1 (TGFB2‐OT1), relying on the nanozyme. MSCs‐loaded LMGDNPs largely preserved disc hydration and alleviated matrix degradation in vivo. Summarily, LMGDNPs promoted cell survival and matrix regeneration by providing a nutrient supply, exhausting lactate, and activating autophagy via TGFB2‐OT1 and its downstream pathway and may serve as an ideal delivery system for exogenous stem cell therapy and endogenous repair. [ABSTRACT FROM AUTHOR]

The development of tissue engineering has led to new strategies for mitigating clinical problems; however, the design of the tissue engineering materials remains a challenge. The limited sources and inadequate function, potential risk of microbial or pathogen contamination, and high cost of cell expansion impair the efficacy and limit the application of exogenous cells in tissue engineering. However, endogenous cells in native tissues have been reported to be capable of spontaneous repair of the damaged tissue. These cells exhibit remarkable plasticity, and thus can differentiate or be reprogrammed to alter their phenotype and function after stimulation. After a comprehensive review, we found that the plasticity of these cells plays a major role in establishing the cell source in the mechanism involved in tissue regeneration. Tissue engineering materials that focus on assisting and promoting the natural self-repair function of endogenous cells may break through the limitations of exogenous seed cells and further expand the applications of tissue engineering materials in tissue repair. This review discusses the effects of endogenous cells, especially stem cells, on injured tissue repairing, and highlights the potential utilisation of endogenous repair in orthopaedic biomaterial constructions for bone, cartilage, and intervertebral disc regeneration.

Low back pain is a vital musculoskeletal disease that impairs life quality, leads to disability and imposes heavy economic burden on the society, while it is greatly attributed to intervertebral disc degeneration (IDD). However, the existing treatments, such as medicines, chiropractic adjustments and surgery, cannot achieve ideal disc regeneration. Therefore, advanced bioactive therapies are implemented, including stem cells delivery, bioreagents administration, and implantation of biomaterials etc. Among these researches, few reported unsatisfying regenerative outcomes. However, these advanced therapies have barely achieved successful clinical translation. The main reason for the inconsistency between satisfying preclinical results and poor clinical translation may largely rely on the animal models that cannot actually simulate the human disc degeneration. The inappropriate animal model also leads to difficulties in comparing the efficacies among biomaterials in different reaches. Therefore, animal models that better simulate the clinical charateristics of human IDD should be acknowledged. In addition, in vivo regenerative outcomes should be carefully evaluated to obtain robust results. Nevertheless, many researches neglect certain critical characteristics, such as adhesive properties for biomaterials blocking annulus fibrosus defects and hyperalgesia that is closely related to the clinical manifestations, e.g., low back pain. Herein, in this review, we summarized the animal models established for IDD, and highlighted the proper models and parameters that may result in acknowledged IDD models. Then, we discussed the existing biomaterials for disc regeneration and the characteristics that should be considered for regenerating different parts of discs. Finally, well-established assays and parameters for in vivo disc regeneration are explored.

Programmed necrosis of nucleus pulposus (NP) cells caused by excessive compression is a crucial factor in the etiopathogenesis of intervertebral disc degeneration (IVDD). The endoplasmic reticulum (ER) and mitochondria are crucial regulators of the cell death signaling pathway, and their involvement in IVDD has been reported. However, the specific role of ER stress (ERS) and ER-mitochondria interaction in compression-induced programmed necrosis of NP cells remains unknown. Our studies revealed that compression enhanced ERS and the association between ER and mitochondria in NP cells. Suppression of ERS via 4-phenylbutyrate (4-PBA) or ER-mitochondrial Ca 2+ crosstalk by inhibiting the inositol 1,4,5-trisphosphate receptor, glucose-regulated protein 75, voltage-dependent anion-selective channel 1 complex (IP 3 R-GRP75-VDAC1 complex) protected NP cells against programmed necrosis related to the poly(ADP-ribose) polymerase (PARP) apoptosis-inducing factor (AIF) pathway. Moreover, excessive reactive oxygen species are critical activators of ERS, leading to mitochondrial Ca 2+ accumulation and consequent programmed necrosis. These data indicate that ERS and ER-mitochondrial Ca 2+ crosstalk may be potential therapeutic targets for the treatment of IVDD-associated disorders. These findings provide new insights into the molecular mechanisms underlying IVDD and may provide novel therapeutic targets., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2021 Hui Lin et al.)