HA-coated collagen nanofibers for urethral regeneration via in situ polarization of M2 macrophages.
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ABSTRACT:
SUBMITTER: Niu Y
PROVIDER: S-EPMC8456673 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Tissue regeneration requires exogenous and endogenous signals, and there is increasing evidence that the exogenous microenvironment may play an even more dominant role in the complex process of coordinated multiple cells. The short-distance peripheral nerve showed a spontaneous regenerative phenomenon, which was initiated by the guiding role of macrophages. However, it cannot sufficiently restore long-distance nerve injury by itself. Based on this principle, we firstly constructed a proinflammatory model to prove that abnormal M2 expression reduce the guidance and repair effect of long-distance nerves. Furthermore, a bionic peptide hydrogel scaffold based on self-assembly was developed to envelop M2-derived regenerative cytokines and extracellular vesicles (EVs). The cytokines and EVs were quantified to mimic the guidance and regenerative microenvironment in a direct and mild manner. The bionic scaffold promoted M2 transformation in situ and led to proliferation and migration of Schwann cells, neuron growth and motor function recovery. Meanwhile, the peptide scaffold combined with CX3CL1 recruited more blood-derived M2 macrophages to promote long-distance nerve reconstruction. Overall, we systematically confirmed the important role of M2 in regulating and restoring the injury peripheral nerve. This bionic peptide hydrogel scaffold mimicked and remodeled the local environment for M2 transformation and recruitment, favoring long-distance peripheral nerve regeneration. It can help to explicate regulative effect of M2 may be a cause not just a consequence in nerve repair and tissue integration, which facilitating the development of pro-regenerative biomaterials.
| S-EPMC10412994 | biostudies-literature
Project description:The specific objective of this study was to stabilize a simple valid method to prepare pure nanorod hydroxyapatite (HA) mixed with berberine chloride (BER) and Moghat water extract (ME) as composites for incorporation into cellulose acetate (CA) nanofibers to be used as novel bone scaffolds and to determine their efficacy in bone regeneration process In Vitro. Preparation of HA/BER and HA/ME composites were performed by mixing powders using the ball-milling machine. The HA, HA/BER, and HA/ME composites at a concentration of 6.25, 12.5, 25, 50, 100, and 200 mg were mixed with CA solution (13%), then the fiber was formed using electrospinning technique. The properties of the obtained CA fibers were investigated (SEM, TEM, EDX, FTIR, TGA, water uptake, porosity, and mechanical tests). The efficacy of HA and HA composites loaded into CA nanofiber on osteoblast and osteoclast differentiation were measured by tacking ALP, osteocalcin, TRAcP, calcium, and total protein concentration. Moreover, their effects on cell differentiation (CD90 and PARP- ɣ) and death markers (GSK3b, MAPK, Wnt-5 and β-catenin) were evaluated by using ELISA and qPCR. The obtained TEM results indicated that the continuous CA and CA/HA composites electrospun fibers have ultrafine fiber diameters of about 200 nm and uniform distribution of discrete n-HA clusters throughout. In addition, hydrocortisone (HCT) was found to increase the formation of adipocytes and osteoclastic markers CD90 and p38-MAPK which indicated the bone lose process take placed. Treatment with CA loaded with HA, HA/BER or HA/ME decreased CD90, Wnt-5, PARP- ɣ, GSK3b and p38-MAPK associated elevation of osteogenic markers: ALP and osteocalcin. Moreover, HCT overexpressed RANKL and down expressed Osterix gene. Treatment with CA/HA/BER or CA/HA/ME downregulated RANKL and upregulated Osterix associated with a reduction in RANKL/OPG ratio, at p < 0.05. In conclusion, novel CA composite nanofibers (CA/HA/BER and CA/HA/ME) reversed the HCT adverse effect on osteoblast cell death through canonical and non-canonical pathways regulated by Wnt/β-catenin and Wnt/Ca(2+) pathways. Furthermore, our data confirmed that the novel scaffolds create a crosstalk between RUNX-2, RANKL, p38-MAPK, and Wnt signals which positively impact bone regeneration process. Treatment with CA/HA/BER is better compared to the treatment with CA/HA/ME. Nevertheless, both are considered as alternative biomaterial scaffolds with a potential for biomedical applications in the field of bone tissue engineering.
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Project description:There is a need for efficient and "off-the-shelf" grafts in urethral reconstructive surgery. Currently available surgical techniques require harvesting of grafts from autologous sites, with increased risk of surgical complications and added patient discomfort. Therefore, a cost-effective and cell-free graft with adequate regenerative potential has a great chance to be translated into clinical practice. Tubular cell-free collagen grafts were prepared by varying the collagen density and fiber distribution, thereby creating a polarized low fiber density collagen graft (LD-graft). A uniform, high fiber density collagen graft (HD-graft) was engineered as a control. These two grafts were implanted to bridge a 2?cm long iatrogenic urethral defect in a rabbit model. Histology revealed that rabbits implanted with the LD-graft had a better smooth muscle regeneration compared to the HD-graft. The overall functional outcome assessed by contrast voiding cystourethrography showed patency of the urethra in 90% for the LD-graft and in 66.6% for the HD-graft. Functional regeneration of the rabbit implanted with the LD-graft could further be demonstrated by successful mating, resulting in healthy offspring. In conclusion, cell-free low-density polarized collagen grafts show better urethral regeneration than high-density collagen grafts.
| S-EPMC6030124 | biostudies-other
Project description:Current studies have found that low-dose irradiation (IR) can promote bone regeneration. However, mechanism studies of IR-triggered bone regeneration mainly focus on the effects of osteoblasts, neglecting the role of the surrounding immune microenvironment. Here in this study, in vitro proliferation experiments showed that low-dose IR ≤2 Gy could promote the proliferation of bone marrow mesenchymal stem cells (BMSCs), and qRT-PCR assay showed that low-dose IR ≤2 Gy could exert the M2 polarization of Raw264.7 cells, while IR >2 Gy inhibited BMSC proliferation and triggered M1 polarization in Raw264.7 cells. The ALP and mineralized nodules staining showed that low-dose IR ≤2 Gy not only promoted osteoblast mineralization through IR-triggered osteoblast proliferation but also through M2 polarization of Raw264.7 cells, while high-dose IR >2 Gy had the opposite effect. The co-incubation of BMSC with low-dose IR irradiated Raw264.7 cell supernatants increased the mRNA expression of BMP-2 and Osx. The rat cranial defects model revealed that low-dose IR ≤2 Gy gradually promoted bone regeneration, while high-dose IR >2 Gy inhibited bone regeneration. Detection of macrophage polarity in peripheral blood samples showed that low-dose IR ≤2 Gy increased the expression of CD206 and CD163, but decreased the expression of CD86 and CD80 in macrophages, which indicated M2 polarization of macrophages in vivo, while high-dose IR had the opposite effect. Our finding innovatively revealed that low-dose IR ≤2 Gy promotes bone regeneration not only by directly promoting the proliferation of osteoblasts but also by triggering M2 polarization of macrophages, which provided a new perspective for immune mechanism study in the treatment of bone defects with low-dose IR.
| S-EPMC10098298 | biostudies-literature
Project description:Multiple sclerosis (MS) is a chronic and debilitating neurological disorder of the central nervous system (CNS), characterized by infiltration of leukocytes into CNS and subsequent demyelination. Emerging evidences have revealed the beneficial roles of M2 macrophages in ameliorating experimental autoimmune encephalomyelitis (EAE), a model for MS. Here, we identify that lenalidomide alone could promote macrophages M2 polarization to prevent the progression of EAE, which is associated with subsequent inhibition of proinflammatory Th1 and Th17 cells both in peripheral lymph system and CNS. Depletion of macrophages by pharmacology treatment of clodronate liposomes or transferring lenalidomide-induced BMDMs in EAE mice completely abolished the therapeutic effect of lenalidomide or prevented EAE development, respectively. The macrophages-derived IL10 was upregulated both in vivo and in vitro after lenalidomide treatment. Moreover, lenalidomide-treated IL10-dificient EAE mice had higher clinical scores and more severe CNS damage, and intravenous injection of lenalidomide-treated IL10-/- BMDMs into mice with EAE at disease onset did not reverse disease severity, implying IL10 may be essential in lenalidomide-ameliorated EAE. Mechanistically, lenalidomide significantly increased expression and autocrine secretion of IL10, subsequently activated STAT3-mediated expression of Ym1. These studies facilitate the development of potential novel therapeutic application of lenalidomide for the treatment of MS.
| S-EPMC5833426 | biostudies-literature
Project description:Vascular restenosis is the main factor affecting the prognosis of angioplasty in cardiovascular diseases, and inflammation is a central link in the progression of restenosis. Previous research that applies interleukin 10 (IL10) nanoparticles can effectively regulate local inflammation, but their targeted delivery efficacy remains to be improved. In this study, IL10 nanoparticles were successfully prepared and then coated by a preactive platelet membrane. The ability to target and regulate macrophage polarization has been demonstrated, thereby regulating smooth muscle cell and endothelial cell functions. In vivo experiments were carried out in a carotid artery injury model and verified the above functions and the effect on inhibiting vascular restenosis. Immune regulation-based platelet membrane coated nanoparticle loaded with IL10 proved to be an excellent candidate for targeting vascular injury and holds promise as an innovative drug delivery system for suppressing vascular restenosis.
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Project description:The ectoenzyme CD73 catalyzes the hydrolysis of AMP, and is one of the most important producers of extracellular adenosine. On regulatory T cells, CD73 is necessary for immunosuppressive functions, and on Th17 cells CD73-generated adenosine exerts anti-inflammatory effects. However, the expression and function of CD73 in pro-inflammatory M1 and in immunosuppressive M2 macrophages is largely unknown. Here we show that CD73 expression and enzyme activity were induced in in vitro polarized pro-inflammatory human M(LPS+TNF) monocytes/macrophages, while CD73 was absent from immunosuppressive M(IL-4+M-CSF)-polarized macrophages. Inhibition of CD73 activity with the inhibitor AMPCP did not affect the polarization of human monocytes. In mice, CD73 was present on resident peritoneal macrophages. In striking contrast, elicited peritoneal macrophages remained CD73 negative regardless of their polarization towards either a pro-inflammatory M(LPS) or anti-inflammatory M(IL-4c) direction. Finally, the ability of peritoneal macrophages to polarize to pro- and anti-inflammatory cells was perfectly normal in CD73-deficient mice in vivo. These data indicate that, in contrast to other major leukocyte subpopulations, CD73 activity on macrophages does not play a major role in their polarization and that in mice host CD73 on any cell type is not required in vivo for peritoneal macrophage polarization towards either a pro- or an anti-inflammatory direction.
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Project description:Procyanidins, a subclass of flavonoids found in commonly consumed foods, possess potential anti-inflammatory activity. Manipulation of M1/M2 macrophage homeostasis is an effective strategy for the treatment of metabolic inflammatory diseases. The objective of this study was to determine the effect of procyanidins on macrophage polarization. Procyanidin B2 (PCB2), the most widely distributed natural procyanidins, enhanced the expressions of M2 macrophage markers (Arg1, Ym1, and Fizz1). PCB2 activated peroxisome proliferator-activated receptor γ (PPARγ) activity and increased the expressions of PPARγ target genes (CD36 and ABCG1) in macrophages. Inhibition of PPARγ using siRNA or antagonist GW9662 attenuated the PCB2-induced expressions of M2 macrophage markers. In addition, we identified cognate PPAR-responsive elements (PPREs) within the 5'-flanking regions of the mouse Arg1, Ym1, and Fizz1 genes. Furthermore, macrophages isolated from db/db diabetic mice showed lower expressions of M2 markers. PCB2 effectively restored the Arg1, Ym1, and Fizz1 expressions in a PPARγ-dependent manner. These findings support the notion that PCB2 regulated macrophage M2 polarization via the activation of PPARγ. Our results provide a new mechanism by which procyanidins exert their beneficial anti-inflammatory effects.
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Project description:Wound healing is regulated by a complex series of events and overlapping phases. A delicate balance of cytokines and mediators in tissue repair is required for optimal therapy in clinical applications. Molecular imaging technologies, with their versatility in monitoring cellular and molecular events in living organisms, offer tangible options to better guide tissue repair by regulating the balance of cytokines and mediators at injured sites. Methods: A murine cutaneous wound healing model was developed to investigate if incorporation of prostaglandin E2 (PGE2) into chitosan (CS) hydrogel (CS+PGE2 hydrogel) could enhance its therapeutic effects. Bioluminescence imaging (BLI) was used to noninvasively monitor the inflammation and angiogenesis processes at injured sites during wound healing. We also investigated the M1 and M2 paradigm of macrophage activation during wound healing. Results: CS hydrogel could prolong the release of PGE2, thereby improving its tissue repair and regeneration capabilities. Molecular imaging results showed that the prolonged release of PGE2 could ameliorate inflammation by promoting the M2 phenotypic transformation of macrophages. Also, CS+PGE2 hydrogel could augment angiogenesis at the injured sites during the early phase of tissue repair, as revealed by BLI. Furthermore, our results demonstrated that CS+PGE2 hydrogel could regulate the balance among the three overlapping phases-inflammation, regeneration (angiogenesis), and remodeling (fibrosis)-during cutaneous wound healing. Conclusion: Our findings highlight the potential of the CS+PGE2 hydrogel as a novel therapeutic strategy for promoting tissue regeneration via M2 macrophage polarization. Moreover, molecular imaging provides a platform for monitoring cellular and molecular events in real-time during tissue repair and facilitates the discovery of optimal therapeutics for injury repair by regulating the balance of cytokines and mediators at injured sites.
| S-EPMC6276096 | biostudies-literature
Project description:Hemangiosarcoma (HSA) is a malignant tumor derived from endothelial cells. Tumor-associated macrophages are one of the major components of tumor microenvironment and crucial for cancer development. The presence and function of macrophages in HSA have not been studied because there is no syngeneic model for HSA. In this study, we evaluated two mouse HSA cell lines and one immortalized mouse endothelial cell line for their usefulness as syngeneic models for canine HSA. Our results showed that the ISOS-1 cell line developed tumors with similar morphology to canine HSA. ISOS-1 cells highly expressed KDM2B and had similar KDM2B target expression patterns with canine HSA. Moreover, we determined that in both ISOS-1 and canine HSA tumors, macrophages were present as a major constituent of the tumor microenvironment. These macrophages were positive for CD204, an M2 macrophage marker, and express PD-L1, an immune checkpoint molecule. Canine HSA with macrophages expressing PD-L1 had a smaller number of T-cells in tumor tissues than tumors with PD-L1 negative macrophages. ISOS-1-conditioned medium could induce M2 polarization and PD-L1 expression in RAW264.7 mouse macrophage cell line and mouse peritoneal macrophages. These results show that ISOS-1 can be used as a syngenic model for canine HSA and suggest that macrophages play an important role in immune evasion in HSA. Using the syngeneic mouse model for canine HSA, we can further study the role of immune cells in the pathology of HSA.
| S-EPMC8826392 | biostudies-literature