Inflammation and regeneration最新文献

Since chimeric antigen receptor T (CAR-T) cells were introduced three decades ago, the treatment using these cells has led to outstanding outcomes, and at the moment, CAR-T cell therapy is a well-established mainstay for treating CD19 + malignancies and multiple myeloma. Despite the astonishing results of CAR-T cell therapy in B-cell-derived malignancies, several bottlenecks must be overcome to promote its safety and efficacy and broaden its applicability. These bottlenecks include cumbersome production process, safety concerns of viral vectors, poor efficacy in treating solid tumors, life-threatening side effects, and dysfunctionality of infused CAR-T cells over time. Exosomes are nano-sized vesicles that are secreted by all living cells and play an essential role in cellular crosstalk by bridging between cells. In this review, we discuss how the existing bottlenecks of CAR-T cell therapy can be overcome by focusing on exosomes. First, we delve into the effect of tumor-derived exosomes on the CAR-T cell function and discuss how inhibiting their secretion can enhance the efficacy of CAR-T cell therapy. Afterward, the application of exosomes to the manufacturing of CAR-T cells in a non-viral approach is discussed. We also review the latest advancements in ex vivo activation and cultivation of CAR-T cells using exosomes, as well as the potential of engineered exosomes to in vivo induction or boost the in vivo proliferation of CAR-T cells. Finally, we discuss how CAR-engineered exosomes can be used as a versatile tool for the direct killing of tumor cells or delivering intended therapeutic payloads in a targeted manner.

Background: Keloids are currently challenging to treat because they recur after resection which may affect patients' quality of life. At present, no universal consensus on treatment regimen has been established. Thus, finding new molecular mechanisms underlying keloid formation is imminent. This study aimed to explore the function of secreted protein acidic and cysteine rich (SPARC) on keloids and its behind exact mechanisms.

Methods: The expression of SPARC, p38γ, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), α-SMA, and Ki67 in patients with keloid and bleomycin (BLM)-induced fibrosis mice was assessed utilizing western blot, qRT-PCR, and immunohistochemical staining. After transfected with pcDNA-SPARC, si-SPARC-1#, si-SPARC-2#, and si-p38γ, and treated with glycolytic inhibitor (2-DG) or p38 inhibitor (SB203580), CCK-8, EdU, transwell, and western blot were utilized for assessing the proliferation, migration, and collagen production of keloid fibroblasts (KFs).

Results: SPARC, p38γ, and PFKFB3 were highly expressed in patients with keloid and BLM-induced fibrosis mice. SPARC promoted the proliferation, migration, and collagen production of KFs via inducing glycolysis. Moreover, SPARC could activate p38γ signaling to stabilize PFKFB3 protein expression in KFs. Next, we demonstrated that SPARC promoted the proliferation, migration, collagen production, and glycolysis of KFs via regulating p38γ signaling. In addition, in BLM-induced fibrosis mice, inhibition of p38γ and PFKFB3 relieved skin fibrosis.

Conclusions: Our findings indicated that SPARC could activate p38γ pathway to stabilize the expression of PFKFB3, and thus promote the glycolysis of KFs and the progression of keloid.

Background: Acetaminophen (APAP)-induced liver injury is the most common cause of acute liver failure. Macrophages are key players in liver restoration following APAP-induced liver injury. Thromboxane A₂ (TXA₂) and its receptor, thromboxane prostanoid (TP) receptor, have been shown to be involved in tissue repair. However, whether TP signaling plays a role in liver repair after APAP hepatotoxicity by affecting macrophage function remains unclear.

Methods: Male TP knockout (TP^-/-) and C57BL/6 wild-type (WT) mice were treated with APAP (300 mg/kg). In addition, macrophage-specific TP-knockout (TP^△mac) and control WT mice were treated with APAP. We explored changes in liver inflammation, liver repair, and macrophage accumulation in mice treated with APAP.

Results: Compared with WT mice, TP^-/- mice showed aggravated liver injury as indicated by increased levels of alanine transaminase (ALT) and necrotic area as well as delayed liver repair as indicated by decreased expression of proliferating cell nuclear antigen (PCNA). Macrophage deletion exacerbated APAP-induced liver injury and impaired liver repair. Transplantation of TP-deficient bone marrow (BM) cells to WT or TP^-/- mice aggravated APAP hepatotoxicity with suppressed accumulation of macrophages, while transplantation of WT-BM cells to WT or TP^-/- mice attenuated APAP-induced liver injury with accumulation of macrophages in the injured regions. Macrophage-specific TP^-/- mice exacerbated liver injury and delayed liver repair, which was associated with increased pro-inflammatory macrophages and decreased reparative macrophages and hepatocyte growth factor (HGF) expression. In vitro, TP signaling facilitated macrophage polarization to a reparative phenotype. Transfer of cultured BM-derived macrophages from control mice to macrophage-specific TP^-/- mice attenuated APAP-induced liver injury and promoted liver repair. HGF treatment mitigated APAP-induced inflammation and promoted liver repair after APAP-induced liver injury.

Conclusions: Deletion of TP signaling in macrophages delays liver repair following APAP-induced liver injury, which is associated with reduced accumulation of reparative macrophages and the hepatotrophic factor HGF. Specific activation of TP signaling in macrophages may be a potential therapeutic target for liver repair and regeneration after APAP hepatotoxicity.

Skeletal muscle possesses remarkable regenerative capabilities, fully recovering within a month following severe acute damage. Central to this process are muscle satellite cells (MuSCs), a resident population of somatic stem cells capable of self-renewal and differentiation. Despite the highly predictable course of muscle regeneration, evaluating this process has been challenging due to the heterogeneous nature of myogenic precursors and the limited insight provided by traditional markers with overlapping expression patterns. Notably, recent advancements in single-cell technologies, such as single-cell (scRNA-seq) and single-nucleus RNA sequencing (snRNA-seq), have revolutionized muscle research. These approaches allow for comprehensive profiling of individual cells, unveiling dynamic heterogeneity among myogenic precursors and their contributions to regeneration. Through single-cell transcriptome analyses, researchers gain valuable insights into cellular diversity and functional dynamics of MuSCs post-injury. This review aims to consolidate classical and new insights into the heterogeneity of myogenic precursors, including the latest discoveries from novel single-cell technologies.

The transplantation of human mesenchymal stromal/stem cells (hMSCs) has potential as a curative and permanent therapy for congenital skeletal diseases. However, the self-renewal and differentiation capacities of hMSCs markedly vary. Therefore, cell proliferation and trilineage differentiation capacities were tested in vitro to characterize hMSCs before their clinical use. However, it remains unclear whether the ability of hMSCs in vitro accurately predicts that in living animals. The xenograft model is an alternative method for validating clinical MSCs. Nevertheless, the protocol still needs refinement, and it has yet to be established whether hMSCs, which are expanded in culture for clinical use, retain the ability to engraft and differentiate into adipogenic, osteogenic, and chondrogenic lineage cells in transplantation settings. In the present study, to establish a robust xenograft model of MSCs, we examined the delivery routes of hMSCs and the immunological state of recipients. The intra-arterial injection of hMSCs into X-ray-irradiated (IR) NOG, a severely immunodeficient mouse, achieved the highest engraftment but failed to sustain long-term engraftment. We demonstrated that graft cells localized to a collagenase-released fraction (CR), in which endogenous colony-forming cells reside. We also showed that Pdgfrα⁺Sca1⁺ MSCs (PαS), which reside in the CR fraction, resisted IR. These results show that our protocol enables hMSCs to fulfill a high level of engraftment in mouse bone marrow in the short term. In contrast, long-term reconstitution was restricted, at least partially, because of IR-resistant endogenous MSCs.

The neural and immune systems sense and respond to external stimuli to maintain tissue homeostasis. These systems do not function independently but rather interact with each other to effectively exert biological actions and prevent disease pathogenesis, such as metabolic, inflammatory, and infectious disorders. Mutual communication between these systems is also affected by tissue niche-specific signals that reflect the tissue environment. However, the regulatory mechanisms underlying these interactions are not completely understood. In addition to the peripheral regulation of neuro-immune crosstalk, recent studies have reported that the central nervous system plays essential roles in the regulation of systemic neuro-immune interactions. In this review, we provide an overview of the molecular basis of peripheral and systemic neuro-immune crosstalk and explore how these multilayered interactions are maintained.

The gastrointestinal tract harbors diverse microorganisms in the lumen. Epithelial cells segregate the luminal microorganisms from immune cells in the lamina propria by constructing chemical and physical barriers through the production of various factors to prevent excessive immune responses against microbes. Therefore, perturbations of epithelial integrity are linked to the development of gastrointestinal disorders. Several mesenchymal stromal cell populations, including fibroblasts, myofibroblasts, pericytes, and myocytes, contribute to the establishment and maintenance of epithelial homeostasis in the gut through regulation of the self-renewal, proliferation, and differentiation of intestinal stem cells. Recent studies have revealed alterations in the composition of intestinal mesenchymal stromal cells in patients with inflammatory bowel disease and colorectal cancer. A better understanding of the interplay between mesenchymal stromal cells and epithelial cells associated with intestinal health and diseases will facilitate identification of novel biomarkers and therapeutic targets for gastrointestinal disorders. This review summarizes the key findings obtained to date on the mechanisms by which functionally distinct mesenchymal stromal cells regulate epithelial integrity in intestinal health and diseases at different developmental stages.

Background: Inflammatory respiratory diseases, such as interstitial lung disease (ILD), bronchial asthma (BA), chronic obstructive pulmonary disease (COPD), and respiratory infections, remain significant global health concerns owing to their chronic and severe nature. Emerging as a valuable resource, blood extracellular vesicles (EVs) offer insights into disease pathophysiology and biomarker discovery in these conditions.

Main body: This review explores the advancements in blood EV proteomics for inflammatory respiratory diseases, highlighting their potential as non-invasive diagnostic and prognostic tools. Blood EVs offer advantages over traditional serum or plasma samples. Proteomic analyses of blood EVs have revealed numerous biomarkers that can be used to stratify patients, predict disease progression, and identify candidate therapeutic targets. Blood EV proteomics has identified proteins associated with progressive fibrosis in ILD, offering new avenues of treatment. In BA, eosinophil-derived EVs harbor biomarkers crucial for managing eosinophilic inflammation. Research on COPD has also identified proteins that correlate with lung function. Moreover, EVs play a critical role in respiratory infections such as COVID-19, and disease-associated proteins are encapsulated. Thus, proteomic studies have identified key molecules involved in disease severity and immune responses, underscoring their role in monitoring and guiding therapy.

Conclusion: This review highlights the potential of blood EV proteomics as a non-invasive diagnostic and prognostic tool for inflammatory respiratory diseases, providing a promising avenue for improved patient management and therapeutic development.

Mesenchymal stem/stromal cells (MSCs) are distributed in various tissues and are used in clinical applications as a source of transplanted cells because of their easy harvestability. Although MSCs express numerous cell-surface antigens, single-cell analyses have revealed a highly heterogeneous cell population depending on the original tissue and donor conditions, including age and interindividual differences. This heterogeneity leads to differences in their functions, such as multipotency and immunomodulatory effects, making it challenging to effectively treat targeted diseases. The therapeutic efficacy of MSCs is controversial and depends on the implantation site. Thus, there is no established recipe for the transplantation of MSCs (including the type of disease, type of origin, method of cell culture, form of transplanted cells, and site of delivery). Our recent preclinical study identified appropriate MSCs and their suitable transplantation routes in a mouse model of inflammatory bowel disease (IBD). Three-dimensional (3D) cultures of MSCs have been demonstrated to enhance their properties and sustain engraftment at the lesion site. In this note, we explore the methods of MSC transplantation for treating IBDs, especially Crohn's disease, from clinical trials published over the past decade. Given the functional changes in MSCs in 3D culture, we also investigate the clinical trials using 3D constructs of MSCs and explore suitable diseases that might benefit from this approach. Furthermore, we discuss the advantages of the prospective isolation of MSCs in terms of interindividual variability. This note highlights the need to define the method of MSC transplantation, including interindividual variability, the culture period, and the transplantation route.

Background: Recent single-cell RNA sequencing (scRNA-seq) analysis revealed the functional heterogeneity and pathogenic cell subsets in immune cells, synovial fibroblasts and bone cells in rheumatoid arthritis (RA). JAK inhibitors which ameliorate joint inflammation and bone destruction in RA, suppress the activation of various types of cells in vitro. However, the key cellular and molecular mechanisms underlying the potent clinical effects of JAK inhibitors on RA remain to be determined. Our aim is to identify a therapeutic target for JAK inhibitors in vivo.

Methods: We performed scRNA-seq analysis of the synovium of collagen-induced arthritis (CIA) mice treated with or without a JAK inhibitor, followed by a computational analysis to identify the drug target cells and signaling pathways. We utilized integrated human RA scRNA-seq datasets and genetically modified mice administered with the JAK inhibitor for the confirmation of our findings.

Results: scRNA-seq analysis revealed that oncostatin M (OSM) driven macrophage-fibroblast interaction is highly activated under arthritic conditions. OSM derived from macrophages, acts on OSM receptor (OSMR)-expressing synovial fibroblasts, activating both inflammatory and tissue-destructive subsets. Inflammatory synovial fibroblasts stimulate macrophages, mainly through IL-6, to exacerbate inflammation. Tissue-destructive synovial fibroblasts promote osteoclast differentiation by producing RANKL to accelerate bone destruction. scRNA-seq analysis also revealed that OSM-signaling in synovial fibroblasts is the main signaling pathway targeted by JAK inhibitors in vivo. Mice specifically lacking OSMR in synovial fibroblasts (Osmr^∆Fibro) displayed ameliorated inflammation and joint destruction in arthritis. The JAK inhibitor was effective on the arthritis of the control mice while it had no effect on the arthritis of Osmr^∆Fibro mice.

Conclusions: OSM functions as one of the key cytokines mediating pathogenic macrophage-fibroblast interaction. OSM-signaling in synovial fibroblasts is one of the main signaling pathways targeted by JAK inhibitors in vivo. The critical role of fibroblast-OSM signaling in autoimmune arthritis was shown by a combination of mice specifically deficient for OSMR in synovial fibroblasts and administration of the JAK inhibitor. Thus, the OSM-driven synovial macrophage-fibroblast circuit is proven to be a key driver of autoimmune arthritis, serving as a crucial drug target in vivo.