Intervertebral disc (IVD) degeneration is a complicated process that involves both age-related change and tissue damage caused by multiple stresses. In a degenerative IVD, cellular senescence accumulates and is associated with reduced proliferation, compromised self-repair, increased inflammatory response, and enhanced catabolic metabolism. In this review, we decipher the senescence mechanism of IVD degeneration (IVDD) by interpreting how aging coordinates with age-related, microenvironment-derived stresses in promoting disc cell senescence and accelerating IVDD. After chronic and prolonged replication, cell senescence may occur as a natural part of the disc aging process, but can potentially be accelerated by growth factor deficiency, oxidative accumulation, and inflammatory irritation. While acute disc injury, excessive mechanical overloading, diabetes, and chronic tobacco smoking contribute to the amplification of senescence-inducing stresses, the avascular nature of IVD impairs the immune-clearance of the senescent disc cells, which accumulate in cell clusters, demonstrate inflammatory and catabolic phenotypes, deteriorate disc microenvironment, and accelerate IVDD. Anti-senescence strategies, including telomerase transduction, supply of growth factors, and blocking cell cycle inhibitors, have been shown to be feasible in rescuing disc cells from early senescence, but their efficiency for disc regeneration requires more in vivo validations. Guidelines dedicated to avoiding or alleviating senescence-inducing stresses might decelerate cellular senescence and benefit patients with IVD degenerative diseases.

Purpose: With a widening arsenal of cancer therapies available, it is important to develop therapy-specific predictive markers and methods to rapidly assess treatment efficacy. We here evaluated the use of cytokeratin-18 (CK18) as a serum biomarker for monitoring chemotherapy-induced cell death in breast cancer. Experimental Design: Different molecular forms of CK18 (caspase cleaved and total) were assessed by specific ELISA assays. Drug-induced release of CK18 was examined from breast carcinoma cells and tissue. CK18 protein composition was examined in serum. CK18 levels were determined in serum from 61 breast cancer patients during docetaxel or cyclophosphamide/ epirubicin/5-fluorouracil (CEF) therapy. Results: Caspase-cleaved CK18 molecules were released from monolayer cultures and tumor organ cultures to the extracellular compartment. CK18 was present in complexes with other cytokeratins in serum. Such CK18 protein complexes are remarkably stable, leading to favorable performance of CK18 biomarker assays for clinical investigations. Docetaxel induced increased levels of caspase-cleaved CK18 in serum from breast cancer patients, indicating apoptosis. CEF therapy led to increases predominantly in uncleaved CK18, indicating induction of necrotic cell death in many tumors. The increase in total CK18 at 24 h of the first treatment cycle correlated to the clinical response to CEF therapy (P < 0.0001).Conclusions: Induction of necrotic cell death may explain the clinical efficacy of anthracyclinebased therapy for breast carcinomas with defective apoptosis pathways. We suggest that CK18 biomarkers are useful for early prediction of the response to CEF therapy in breast cancer and may be useful biomarkers for clinical trials.

The strategies concerning modification of the complex immune pathological inflammatory environment during acute spinal cord injury remain oversimplified and superficial. Inspired by the acidic microenvironment at acute injury sites, a functional pH-responsive immunoregulation-assisted neural regeneration strategy was constructed. With the capability of directly responding to the acidic microenvironment at focal areas followed by triggered release of the IL-4 plasmid-loaded liposomes within a few hours to suppress the release of inflammatory cytokines and promote neural differentiation of mesenchymal stem cells in vitro, the microenvironment-responsive immunoregulatory electrospun fibers were implanted into acute spinal cord injury rats. Together with sustained release of nerve growth factor (NGF) achieved by microsol core-shell structure, the immunological fiber scaffolds were revealed to bring significantly shifted immune cells subtype to down-regulate the acute inflammation response, reduce scar tissue formation, promote angiogenesis as well as neural differentiation at the injury site, and enhance functional recovery in vivo. Overall, this strategy provided a delivery system through microenvironment-responsive immunological regulation effect so as to break through the current dilemma from the contradiction between immune response and nerve regeneration, providing an alternative for the treatment of acute spinal cord injury.

Although injectable hydrogel microsphere has demonstrated tremendous promise in clinical applications, local overactive inflammation in degenerative diseases could jeopardize biomaterial implantation’s therapeutic efficacy. Herein, an injectable “peptide-cell-hydrogel” microsphere was constructed by covalently coupling of APETx2 and further loading of nucleus pulposus cells, which could inhibit local inflammatory cytokine storms to regulate the metabolic balance of ECM in vitro. The covalent coupling of APETx2 preserved the biocompatibility of the microspheres and achieved a controlled release of APETx2 for more than 28 days in an acidic environment. By delivering “peptide-cell-hydrogel” microspheres to a rat degenerative intervertebral disc at 4 weeks, the expression of ASIC-3 and IL-1β was significantly decreased for 3.53-fold and 7.29-fold, respectively. Also, the content of ECM was significantly recovered at 8 weeks. In summary, the proposed strategy provides an effective approach for tissue regeneration under overactive inflammatory responses.

Intervertebral disc (IVD) degeneration results in segmental instability and irritates neural compressive symptoms, such as low back pain and motor deficiency. The transplanting of stem cell into degenerative discs has attracted increasing clinical attention, as a new and proven approach to alleviating disc degeneration and to relieving discogenic pains. Aside from supplementation with stem cells, the IVD itself already contains a pool of stem and progenitor cells. Since the resident disc stem cells are incapable of reversing the pathologic changes that occur during aging and disc degeneration, it has been debated as to whether transplanted stem cells are capable of providing an efficient and durable therapeutic effect, even though there have been positive outcomes in both animal models and in clinical trials. This review aims to decipher the interactions between the stem cell and the disc microenvironment. Within their new niches in the IVD, the exogenous stem cell shows metabolic adaptation to the low-glucose supply, hypoxia, and compressive loadings, but demonstrates little tolerance to the disc-like acidity and hypertonicity. Similarly, the survival of endogenous stem cells is threatened as well by the harsh disc microenvironment, which may exhaust the stem cell resources and restrict the self-repair capacity of a degenerating IVD. To eliminate the intrinsic obstacles within the stressful disc niches, stem cells should be delivered with an injectable scaffold that provides both survival and mechanical support. Quick healing or concretion of the injection injuries, which minimizes stem cell leakage and disturbance to disc homeostasis, is of equal importance toward achieving efficient stem cell-based disc regeneration.