Bone, cartilage, and soft tissue regeneration is a complex spatiotemporal process recruiting a variety of cell types, whose activity and interplay must be precisely mediated for effective healing post-injury. Although extensive strides have been made in the understanding of the immune microenvironment processes governing bone, cartilage, and soft tissue regeneration, effective clinical translation of these mechanisms remains a challenge. Regulation of the immune microenvironment is increasingly becoming a favorable target for bone, cartilage, and soft tissue regeneration; therefore, an in-depth understanding of the communication between immune cells and functional tissue cells would be valuable. Herein, we review the regulatory role of the immune microenvironment in the promotion and maintenance of stem cell states in the context of bone, cartilage, and soft tissue repair and regeneration. We discuss the roles of various immune cell subsets in bone, cartilage, and soft tissue repair and regeneration processes and introduce novel strategies, for example, biomaterial-targeting of immune cell activity, aimed at regulating healing. Understanding the mechanisms of the crosstalk between the immune microenvironment and regeneration pathways may shed light on new therapeutic opportunities for enhancing bone, cartilage, and soft tissue regeneration through regulation of the immune microenvironment.

Microglia play an important role in neuronal protection and damage. However, the molecular and cellular relationship between microglia and neurons is unclear. We carried out a prospective study to detect that activation of BV2 microglia induced PC12 cell apoptosis in vitro through the TLR4/adapter protein myeloid differentiation factor 88 (MyD88)/nuclear factor-κB (NF-κB) signaling pathway. BV2 microglia were treated with different concentrations of LPS for 24 h. Western blot was utilized to detect the expression of TLR4 and the downstream signaling pathway. The level of inflammatory mediator was quantified using a specific ELISA kit. The supernatant of 10 μg/ml LPS-treated BV2 cells was used as conditioned medium (CM). PC12 cells were co-culture with CM for 24 h. Cell viability was determined by MTT assay and cell apoptosis was tested by flow cytometry. BV2 microglia were treated with 10, 20, or 30 μg/ml LPS for 24 h. The expression of TLR4, MyD88, and NF-κB significantly increased. When PC12 cells were co-cultured with CM for 24 h, cell viability decreased. CM up-regulated the Bax level and down-regulated the Bcl-2 protein level in PC12 cells. PC12 cells pretreated with interleukin-1 receptor antagonist (IL-1RA) for 30 min, significantly alleviated CMinduced PC12 cell apoptosis. These results suggest that BV2 microglia activated by LPS triggered TLR4/MyD88/NF-κB signaling pathway that induced the release of IL-1β and could participate in the PC12 cells injury.

Chronic pain is still a basic science and clinical challenge. Unraveling of the neurobiological mechanisms involved in chronic pain will offer novel targets for the development of therapeutic strategies. It is well known that central sensitization in the anterior cingulate cortex (ACC) plays a critical role in initiation, development, and maintenance of chronic pain. However, the underlying mechanisms still remain elusive. Here, we reported that caveolin-1 (Cav-1), a scaffolding protein in membrane rafts, was persistently upregulated and activated in the ACC neurons after chronic constriction injury (CCI) in mice. Knockdown or blocking of Cav-1 in the contralateral ACC to the injury side reversed CCI-induced pain behavioral and neuronal sensitization and overexpression of Cav-1 in the ipsilateral ACC-induced pain behavior in the unaffected hindpaw. Furthermore, we found that Cav-1 directly binding with NMDA receptor 2B subunit (NR2B) and promotion of NR2B surface levels in the ACC contributed to modulation of chronic neuropathic pain. Disrupting the interaction of Cav-1 and NR2B through microinjection of a short peptide derived from the C-terminal of NR2B into the ACC exhibited a significant antinociception effect associated with decrease of surface NR2B expression. Moreover, Cav-1 increased intracellular Ca 2ϩ concentration and activated the ERK/CREB signaling pathway in an NR2B-dependent manner in the ACC. Our findings implicate that Cav-1 in the ACC neurons modulates chronic neuropathic pain via regulation of NR2B and subsequent activation of ERK/CREB signaling, suggesting a possible caveolin-mediated process would participate in neuronal transmission pathways implicated in pain modulation.

Background During wound healing, the overproduction of reactive oxygen species (ROS) can break the cellular oxidant/antioxidant balance, which prolongs healing. The wound dressings targeting the mitigation of ROS will be of great advantages for the wound healing. puerarin (PUE) and ferulic acid (FA) are natural compounds derived from herbs that exhibit multiple pharmacological activities, such as antioxidant and anti-inflammatory effects. Polydopamine (PDA) is made from natural dopamine and shows excellent antioxidant function. Therefore, the combination of natural antioxidants into hydrogel dressing is a promising therapy for wound healing. Results Hydrogel wound dressings have been developed by incorporating PUE or FA via PDA nanoparticles (NPs) into polyethylene glycol diacrylate (PEG-DA) hydrogel. This hydrogel can load natural antioxidant drugs and retain the drug in the gel network for a long period due to the presence of PDA NPs. Under oxidative stress, this hydrogel can improve the activity of superoxide dismutase and glutathione peroxidase and reduce the levels of ROS and malondialdehyde, thus preventing oxidative damage to cells, and then promoting wound healing, tissue regeneration, and collagen accumulation. Conclusion Overall, this triple antioxidant hydrogel accelerates wound healing by alleviating oxidative injury. Our study thus provides a new way about co-delivery of multiple antioxidant natural molecules from herbs via antioxidant nanoparticles for wound healing and skin regeneration. Graphic Abstract