Macrophage Immunomodulation Through New Polymers that Recapitulate Functional Effects of Itaconate as a Power House of Innate Immunity

Itaconate (ITA) is an emerging powerhouse of innate immunity with therapeutic potential that is limited in its ability to be administered in a soluble form. A library of polyester materials that incorporate ITA into polymer backbones resulting in materials with inherent immunoregulatory behavior is developed. Harnessing hydrolytic degradation release from polyester backbones, ITA polymers result in the mechanism specific immunoregulatory properties on macrophage polarization in vitro. In a functional assay, the polymer-released ITA inhibits bacterial growth on acetate. Translation to an in vivo model of biomaterial associated inflammation, intraperitoneal injection of ITA polymers demonstrate a rapid resolution of inflammation in comparison to a control polymer silicone, demonstrating the value of sustained biomimetic presentation of ITA.     

HIF-1α and Pro-Inflammatory Signaling Improves the Immunomodulatory Activity of MSC-Derived Extracellular Vesicles

Despite the strong evidence for the immunomodulatory activity of mesenchymal stromal cells (MSCs), clinical trials have so far failed to clearly show benefit, likely reflecting methodological shortcomings and lack of standardization. MSC-mediated tissue repair is commonly believed to occur in a paracrine manner, and it has been stated that extracellular vesicles (EVs) secreted by MSCs (EVMSC) are able to recapitulate the immunosuppressive properties of parental cells. As a next step, clinical trials to corroborate preclinical studies should be performed. However, effective dose in large mammals, including humans, is quite high and EVs industrial production is hindered by the proliferative senescence that affects MSCs during massive cell expansion. We generated a genetically modified MSC cell line overexpressing hypoxia-inducible factor 1-alpha and telomerase to increase the therapeutic potency of EVMSC and facilitate their large-scale production. We also developed a cytokine-based preconditioning culture medium to prime the immunomodulatory response of secreted EVs (EV_MSC-T-HIF^c). We tested the efficacy of this system in vitro and in a delayed-type hypersensitivity mouse model. MSC-T with an HIF-1α-GFP lentiviral vector (MSC-T-HIF) can be effectively expanded to obtain large amounts of EVs without major changes in cell phenotype and EVs composition. EV_MSC-T-HIF^c suppressed the proliferation of activated T-cells more effectively than did EVs from unmodified MSC in vitro, and significantly blunted the ear-swelling response in vivo by inhibiting cell infiltration and improving tissue integrity. We have developed a long-lived EV source that secretes high quantities of immunosuppressive EVs, facilitating a more standard and cost-effective therapeutic product.     

Simulation of Cortical and Cancellous Bone to Accelerate Tissue Regeneration

Different tissues have complex anisotropic structures to support biological functions. Mimicking these complex structures in vitro remains a challenge in biomaterials designs. Here, inspired by different types of silk nanofibers, a composite materials strategy is pursued toward this challenge. A combination of fabrication methods is utilized to achieve separate control of amorphous and beta-sheet rich silk nanofibers in the same solution. Aqueous solutions containing two types of silk nanofibers are simultaneously treated with an electric field and with ethylene glycol diglycidyl ether (EGDE). Under these conditions, the beta-sheet rich silk nanofibers in the mixture responded to the electric field while the amorphous nanofibers are active in the crosslinking process with the EGDE. As a result, cryogels with anisotropic structures are prepared, including mimics for cortical- and cancellous-like bone biomaterials as a complex osteoinductive niche. In vitro studies revealed that mechanical cues of the cryogels induced osteodifferentiation of stem cells while the anisotropy inside the cryogels influenced immune reactions of macrophages. These bioactive cryogels also stimulated improved bone regeneration in vivo through modulation of inflammation, angiogenesis and osteogenesis responses, suggesting an effective strategy to develop bioactive matrices with complex anisotropic structures beneficial to tissue regeneration.     

裙带菜孢子多糖的体内抗氧化和免疫调节活性

采用D-半乳糖建立氧化损伤小鼠模型,考察了裙带菜孢子叶多糖对模型小鼠体内抗氧化能力和免疫调节能力的影响。结果表明,裙带菜孢子叶多糖能够增强小鼠血清和脑中超氧化物歧化酶(SOD)和谷胱甘肽过氧化物酶(GSH-Px)的活性,有效降低丙二醛(MDA)水平;显著提高了氧化损伤小鼠胸腺和脾脏的相对量、淋巴细胞增殖活性、NK细胞杀伤活性和抗体生成能力。裙带菜孢子叶多糖具有良好的体内抗氧化活性和免疫调节活性,具有潜在开发利用价值。     

Advances and Perspectives in Dental Pulp Stem Cell Based Neuroregeneration Therapies

Human dental pulp stem cells (hDPSCs) are some of the most promising stem cell types for regenerative therapies given their ability to grow in the absence of serum and their realistic possibility to be used in autologous grafts. In this review, we describe the particular advantages of hDPSCs for neuroregenerative cell therapies. We thoroughly discuss the knowledge about their embryonic origin and characteristics of their postnatal niche, as well as the current status of cell culture protocols to maximize their multilineage differentiation potential, highlighting some common issues when assessing neuronal differentiation fates of hDPSCs. We also review the recent progress on neuroprotective and immunomodulatory capacity of hDPSCs and their secreted extracellular vesicles, as well as their combination with scaffold materials to improve their functional integration on the injured central nervous system (CNS) and peripheral nervous system (PNS). Finally, we offer some perspectives on the current and possible future applications of hDPSCs in neuroregenerative cell therapies.     

Polysaccharides in Lentinus edodes: Isolation,Structure, Immunomodulating Activity and Future Prospective

Lentinus edodes has been valued as edible and medical resources. Polysaccharides have been known to be the most potent antitumor and immunomodulating substance in Lentinus edodes. In this review, we summarize the current knowledge of the polysaccharides isolated from Lentinus edodes, including extraction and purification methods, chemical structure and chain conformation, the effects on innate and adaptive immunity and their mechanism, relationship between structure and function, and the future prospects.     

State of the Art: The Immunomodulatory Role of MSCs for Osteoarthritis

Osteoarthritis (OA) has generally been introduced as a degenerative disease; however, it has recently been understood as a low-grade chronic inflammatory process that could promote symptoms and accelerate the progression of OA. Current treatment strategies, including corticosteroid injections, have no impact on the OA disease progression. Mesenchymal stem cells (MSCs) based therapy seem to be in the spotlight as a disease-modifying treatment because this strategy provides enlarged anti-inflammatory and chondroprotective effects. Currently, bone marrow, adipose derived, synovium-derived, and Wharton’s jelly-derived MSCs are the most widely used types of MSCs in the cartilage engineering. MSCs exert immunomodulatory, immunosuppressive, antiapoptotic, and chondrogenic effects mainly by paracrine effect. Because MSCs disappear from the tissue quickly after administration, recently, MSCs-derived exosomes received the focus for the next-generation treatment strategy for OA. MSCs-derived exosomes contain a variety of miRNAs. Exosomal miRNAs have a critical role in cartilage regeneration by immunomodulatory function such as promoting chondrocyte proliferation, matrix secretion, and subsiding inflammation. In the future, a personalized exosome can be packaged with ideal miRNA and proteins for chondrogenesis by enriching techniques. In addition, the target specific exosomes could be a gamechanger for OA. However, we should consider the off-target side effects due to multiple gene targets of miRNA.     

The Role of Vitamin D in Supporting Health in the COVID-19 Era

The genomic activity of vitamin D is associated with metabolic effects, and the hormone has a strong impact on several physiological functions and, therefore, on health. Among its renowned functions, vitamin D is an immunomodulator and a molecule with an anti-inflammatory effect, and, recently, it has been much studied in relation to its response against viral infections, especially against COVID-19. This review aims to take stock of the correlation studies between vitamin D deficiency and increased risks of severe COVID-19 disease and, similarly, between vitamin D deficiency and acute respiratory distress syndrome. Based on this evidence, supplementation with vitamin D has been tested in clinical trials, and the results are discussed. Finally, this study includes a biochemical analysis on the effects of vitamin D in the body’s defense mechanisms against viral infection. In particular, the antioxidant and anti-inflammatory functions are considered in relation to energy metabolism, and the potential, beneficial effect of vitamin D in COVID-19 is described, with discussion of its influence on different biochemical pathways. The proposed, broader view of vitamin D activity could support a better-integrated approach in supplementation strategies against severe COVID-19, which could be valuable in a near future of living with an infection becoming endemic.     

龙须菜酸性多糖对H22荷瘤小鼠的抗肿瘤作用

本文主要研究龙须菜酸性多糖(GLSPs)对H22荷瘤小鼠的肿瘤抑制作用。通过流式细胞术检测GLSPs对小鼠体内肿瘤细胞的细胞凋亡和细胞周期的影响;MTT法检测GLSPs对荷瘤小鼠脾淋巴细胞增殖能力和NK细胞杀伤活性的影响;组织病理学方法检测GLSPs对荷瘤小鼠肿瘤和免疫器官(脾脏、胸腺)的影响。结果显示,GLSPs能够促进荷瘤小鼠体内H22肝癌细胞凋亡,显著抑制肿瘤生长。以200 mg/(kg?d)和600 mg/(kg?d)GLSPs灌胃管理荷瘤小鼠28 d,小鼠的平均体积抑瘤率分别为84.65%和94.58%。免疫学试验显示,GLSPs能够明显改善荷瘤小鼠脾脏肿大和胸腺萎缩的组织病变情况,增强荷瘤小鼠免疫器官的免疫功能,同时能够有效调节荷瘤小鼠白细胞和淋巴细胞的激增,显著增强荷瘤小鼠由ConA和LPS诱导的T、B细胞的增殖能力,提高脾NK细胞的杀伤活性,多方面提高荷瘤小鼠机体的免疫水平,提示GLSPs通过免疫调节作用达到体内抗肿瘤效果。     

软枣猕猴桃多糖的免疫活性

利用DEAE-纤维素阴离子交换层析、SephadexG-100凝胶柱层析对微波辅助提取的软枣猕猴桃多糖进行分离纯化,对主要洗脱组分0.1 mol/L盐洗组分的免疫活性进行研究。以正常大鼠为试验对象,设2、10、20mg/(kg.d)3个多糖水平处理,饲养28 d后观察软枣猕猴桃多糖对大鼠免疫器官指数、巨噬细胞吞噬指数及脾淋巴细胞转化指数的影响。试验结果表明,多糖低剂量组[2 mg/(kg.d)]对免疫的促进效果不明显;多糖中剂量组[10 mg/(kg.d)]免疫增强效果明显,与空白对照组差异显著;高剂量组[20 mg/(kg.d)]与中剂量组相比,除免疫器官指数外,其他免疫促进活性无显著差异。