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miR-4780 Derived from N2-Like Neutrophil Exosome Aggravates Epithelial-Mesenchymal Transition and Angiogenesis in Colorectal Cancer. 源自 N2 类中性粒细胞外泌体的 miR-4780 会加剧结直肠癌的上皮-间充质转化和血管生成
IF 4.3 3区 医学 Q2 CELL & TISSUE ENGINEERING Pub Date : 2023-08-04 eCollection Date: 2023-01-01 DOI: 10.1155/2023/2759679
Liang Wang, Yuqiang Shan, Sixin Zheng, Jiangtao Li, Peng Cui

Despite significant advances in diagnostic methods and treatment strategies, the prognosis for patients with advanced colon cancer remains poor, and mortality rates are often high due to metastasis. Increasing evidence showed that it is of significant importance to investigate how the tumor microenvironment participates in the development of colorectal cancer (CRC). In this manuscript, neutrophils were sequentially stimulated with all-trans retinoic acid and transforming growth factor-β in turn to induce the neutrophil polarization. Differentially expressed miRNA in neutrophil exosomes have been sequenced by microarray profile, and the effect of N2-like neutrophil-derived exosomal miR-4780 on epithelial-mesenchymal transition (EMT) and angiogenesis was investigated. In our results, we found that neutrophils were enriched in CRC tumor tissue and that CD11b expression correlated with tumor site and serous membrane invasion. At the same time, we demonstrated that internalization of N2 exosomes exacerbated the viability, migration, and invasion of CRC cell lines and inhibited apoptosis. To further investigate the molecular mechanism, we analyzed the miRNA expression profile in the N2-like neutrophils, which led to the selection of hsa-miR-4780 for the subsequent experiment. The overexpression of miR-4780 from N2-like neutrophil-derived exosomes exacerbated EMT and angiogenesis. Moreover, miR-4780 can regulate its target gene SOX11 to effect EMT and angiogenesis in CRC cell lines. CRC with liver metastasis model also validated that aberrant expression of miR-4780 in N2-like neutrophil exosomes exacerbated tumor metastasis and development of tumor via EMT and angiogenesis. In conclusion, our current findings reveal an important mechanism by which mR-4780 from N2-like neutrophil exosomes exacerbates tumor metastasis and progression via EMT and angiogenesis.

尽管诊断方法和治疗策略取得了重大进展,但晚期结肠癌患者的预后仍然很差,而且由于转移,死亡率往往很高。越来越多的证据表明,研究肿瘤微环境如何参与结直肠癌(CRC)的发展具有重要意义。在本稿件中,中性粒细胞依次受到全反式维甲酸和转化生长因子-β的刺激,以诱导中性粒细胞极化。通过芯片图谱对中性粒细胞外泌体中差异表达的miRNA进行了测序,并研究了N2样中性粒细胞衍生的外泌体miR-4780对上皮-间质转化(EMT)和血管生成的影响。结果发现,中性粒细胞在 CRC 肿瘤组织中富集,CD11b 表达与肿瘤部位和浆膜侵袭相关。同时,我们还证明了 N2 外泌体的内化会加剧 CRC 细胞株的活力、迁移和侵袭,并抑制细胞凋亡。为了进一步研究其分子机制,我们分析了 N2 样中性粒细胞中 miRNA 的表达谱,并由此选择了 hsa-miR-4780 进行后续实验。N2样中性粒细胞外泌体中miR-4780的过表达加剧了EMT和血管生成。此外,miR-4780 还能调控其靶基因 SOX11,从而影响 CRC 细胞株的 EMT 和血管生成。CRC肝转移模型也验证了N2样中性粒细胞外泌体中miR-4780的异常表达通过EMT和血管生成加剧了肿瘤的转移和发展。总之,我们目前的研究结果揭示了N2样中性粒细胞外泌体中的mR-4780通过EMT和血管生成加剧肿瘤转移和发展的重要机制。
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引用次数: 0
The Effect of Mesenchymal Stem Cell-Derived Exosomes and miR17-5p Inhibitor on Multicellular Liver Fibrosis Microtissues. 间充质干细胞来源的外泌体和miR17-5p抑制剂对多细胞肝纤维化微组织的影响。
IF 4.3 3区 医学 Q2 CELL & TISSUE ENGINEERING Pub Date : 2023-08-04 eCollection Date: 2023-01-01 DOI: 10.1155/2023/8836452
Farnaz Sani, Mina Soufi Zomorrod, Negar Azarpira, Masoud Soleimani

Background: Although several studies have been conducted on modeling human liver disease, it is still challenging to mimic nonalcoholic fatty liver disease in vitro. Here, we aimed to develop a fibrotic liver microtissue composed of hepatocytes, hepatic stellate, and endothelial cells. In addition, the therapeutic effects of umbilical cord mesenchymal stem cell-derived exosomes (UC-MSC-EXO) and anti-miR17-5p as new antifibrotic drugs were investigated.

Methods: To create an effective preclinical fibrosis model, multicellular liver microtissues (MLMs) consisting of HepG2, LX2, and HUVECs were cultured and supplemented with a mixture of palmitic acid and oleic acid for 96 hr. Then, MLMs were exposed to UC-MSC-EXO and anti-miR17-5p in different groups. The results of cell viability, reactive oxygen species (ROS) production, liver enzyme levels, inflammation, and histopathology were analyzed to assess the treatment efficacy. Furthermore, the expression of collagen I (COL I) and α-smooth muscle actin (α-SMA) as critical matrix components, transforming growth factor beta (TGF-β), and miR-17-5p were measured.

Results: Free fatty acid supplementation causes fibrosis in MLMs. Our results demonstrated that UC-MSC-EXO and anti-miR17-5p attenuated TGF-β1, interleukin-1β, and interleukin-6 in all experimental groups. According to the suppression of the TGF-β1 pathway, LX2 activation was inhibited, reducing extracellular matrix proteins, including COL I and α-SMA. Also, miR-17-5p expression was elevated in fibrosis conditions. Furthermore, we showed that our treatments decreased alanine aminotransferase and aspartate aminotransferase, and increased albumin levels in the culture supernatant. We also found that both MSC-EXO and MSC-EXO + anti-miR17-5p treatments could reduce ROS production.

Conclusion: Our findings indicated that anti-miR17-5p and MSC-EXO might be promising therapeutic options for treating liver fibrosis. Furthermore, EXO + anti-miR had the best effects on boosting the fibrotic markers. Therefore, we propose this novel MLM model to understand fibrosis mechanisms better and develop new drugs.

背景:尽管已经对人类肝病建模进行了几项研究,但在体外模拟非酒精性脂肪性肝病仍然具有挑战性。在此,我们旨在开发一种由肝细胞、肝星状细胞和内皮细胞组成的纤维化肝脏微组织。此外,还研究了脐带间充质干细胞衍生的外泌体(UC-MSC-EXO)和抗miR17-5p作为新的抗纤维化药物的治疗效果。方法:为了建立有效的临床前纤维化模型,将由HepG2、LX2和HUVECs组成的多细胞肝微组织(MLM)培养并补充棕榈酸和油酸的混合物96 然后,将MLM暴露于不同组的UC-MSC-EXO和抗miR17-5p。分析细胞活力、活性氧(ROS)产生、肝酶水平、炎症和组织病理学的结果,以评估治疗效果。此外,还测量了作为关键基质成分的I型胶原(COL I)和α-平滑肌肌动蛋白(α-SMA)、转化生长因子β(TGF-β)和miR-17-5p的表达。结果:补充游离脂肪酸可导致MLM纤维化。我们的结果表明,在所有实验组中,UC-MSC-EXO和抗miR17-5p都能减弱TGF-β1、白细胞介素-1β和白细胞介素-6。根据对TGF-β1通路的抑制,LX2的激活受到抑制,减少了细胞外基质蛋白,包括COL I和α-SMA。此外,miR-17-5p的表达在纤维化条件下升高。此外,我们发现我们的处理降低了丙氨酸氨基转移酶和天冬氨酸氨基转移酶,并增加了培养上清液中的白蛋白水平。我们还发现MSC-EXO和MSC-EXO + 抗miR17-5p处理可以减少ROS的产生。结论:我们的研究结果表明,抗miR17-5p和MSC-EXO可能是治疗肝纤维化的有前景的选择。此外,EXO + 抗miR对提高纤维化标志物的作用最好。因此,我们提出了这种新的MLM模型,以更好地了解纤维化机制并开发新药。
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引用次数: 0
Donor Mesenchymal Stem Cells Program Bone Marrow, Altering Macrophages, and Suppressing Endometriosis in Mice. 供体间充质干细胞计划骨髓、改变巨噬细胞并抑制小鼠子宫内膜异位症。
IF 3.8 3区 医学 Q2 CELL & TISSUE ENGINEERING Pub Date : 2023-07-28 eCollection Date: 2023-01-01 DOI: 10.1155/2023/1598127
Shutaro Habata, Ramanaiah Mamillapalli, Abdullah Ucar, Hugh S Taylor

Endometriosis is a chronic inflammatory gynecological disorder regulated by estrogen and characterized by the growth of endometrial tissue outside the uterus. We have previously demonstrated that mesenchymal stem cells (MSCs) contribute directly to endometriosis. Here, we investigated an indirect effect; we hypothesized that MSCs may also impact the bone marrow (BM) by regulating bone marrow-derived inflammatory cells. Endometriosis was induced in mice by transplanting uterine tissue into recipient mice followed by BM transplant. Control or MSC conditioned BM was injected retro-orbitally. Direct administration of MSCs outside of the setting of BM conditioning did not alter endometriosis. Coculture of an undifferentiated macrophage cell line with MSCs in vitro led to a reduction of M1 and increased M2 macrophages as determined by fluorescence-activated cell sorting and western blot. Conditioning of BM with MSCs and transplantation into a mouse model inhibited endometriotic lesion development and reduced lesion volume by sevenfold compared to BM transplant without MSCs conditioning. Immunohistochemistry and immunofluorescence showed that MSC conditioned BM reduced the infiltration of macrophages and neutrophils into endometriotic lesions by twofold and decreased the proportion of M1 compared to M2 macrophages, reducing inflammation and likely promoting tissue repair. Expression of several inflammatory markers measured by quantitative real-time polymerase chain reaction, including tumor necrosis factor alpha and CXCR4, was decreased in the conditioned BM. Donor MSCs were not detected in recipient BM or endometriotic lesions, suggesting that MSCs actively program the transplanted BM. Taken together, these data show that individual characteristics of BM have an unexpected role in the development of endometriosis. BM remodeling and alterations in the inflammatory response are also potential treatments for endometriosis. Identification of the molecular basis for BM programing by MSCs will lead to a better understanding of the immune system contribution to this disease and may lead to new therapeutic targets for endometriosis.

子宫内膜异位症是一种受雌激素调控的慢性妇科炎症,其特点是子宫内膜组织在子宫腔外生长。我们之前已经证明,间充质干细胞(MSCs)直接导致子宫内膜异位症。在此,我们研究了间接影响;我们假设间充质干细胞也可能通过调节骨髓衍生的炎症细胞来影响骨髓(BM)。将子宫组织移植到受体小鼠体内,然后进行骨髓移植,从而诱发小鼠子宫内膜异位症。对照组或经间叶干细胞调节的骨髓经轨道后方注射。在调制间充质干细胞的情况下直接注射间充质干细胞不会改变子宫内膜异位症。通过荧光激活细胞分选和蛋白印迹法测定,在体外将未分化的巨噬细胞系与间充质干细胞共培养会导致 M1 型巨噬细胞减少和 M2 型巨噬细胞增加。用间叶干细胞调节骨髓并将其移植到小鼠模型中可抑制子宫内膜异位症病灶的发展,与未调节间叶干细胞的骨髓移植相比,病灶体积减少了七倍。免疫组化和免疫荧光显示,间充质干细胞调控的生化干细胞能将渗入子宫内膜异位症病灶的巨噬细胞和中性粒细胞减少两倍,并降低 M1 型巨噬细胞的比例,从而减轻炎症反应并促进组织修复。通过实时定量聚合酶链式反应测定的几种炎症标志物(包括肿瘤坏死因子α和CXCR4)在调节性基质中的表达均有所下降。在受体间充质干细胞或子宫内膜异位症病灶中未检测到捐献的间充质干细胞,这表明间充质干细胞对移植的间充质干细胞进行了积极的编程。总之,这些数据表明,间充质干细胞的个体特征在子宫内膜异位症的发展过程中起着意想不到的作用。基质重塑和炎症反应的改变也是治疗子宫内膜异位症的潜在方法。鉴定间叶干细胞对基质编程的分子基础将有助于更好地了解免疫系统对这种疾病的作用,并可能为子宫内膜异位症找到新的治疗靶点。
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引用次数: 0
Mesenchymal Stem Cells Inhibit Epithelial-to-Mesenchymal Transition by Modulating the IRE1α Branch of the Endoplasmic Reticulum Stress Response. 间充质干细胞通过调节内质网应激反应的 IRE1α 分支抑制上皮细胞向间充质细胞的转化
IF 3.8 3区 医学 Q2 CELL & TISSUE ENGINEERING Pub Date : 2023-07-26 eCollection Date: 2023-01-01 DOI: 10.1155/2023/4483776
Ruixi Luo, Yaqiong Wei, Peng Chen, Jing Zhang, La Wang, Wenjia Wang, Ping Wang, Weiyi Tian

Background: Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial lung disease, and it carries a poor prognosis due to a lack of efficient diagnosis methods and treatments. Epithelial-mesenchymal transition (EMT) plays a key role in IPF pathogenesis. Endoplasmic reticulum (ER) stress contributes to fibrosis via EMT-mediated pathways. Mesenchymal stem cell (MSC) transplantation is a promising treatment strategy for pulmonary fibrosis and ameliorates lung fibrosis in animal models via paracrine effects. However, the specific mechanisms underlying the effect of transplanted MSCs are not known. We previously reported that MSCs attenuate endothelial injury by modulating ER stress and endothelial-to-mesenchymal transition. The present study investigated whether modulation of ER stress- and EMT-related pathways plays essential roles in MSC-mediated alleviation of IPF.

Methods and results: We constructed a A549 cell model of transforming growth factor-β1 (TGF-β1)-induced fibrosis. TGF-β1 was used to induce EMT in A549 cells, and MSC coculture decreased EMT, as indicated by increased E-cadherin levels and decreased vimentin levels. ER stress participated in TGF-β1-induced EMT in A549 cells, and MSCs inhibited the expression of XBP-1s, XBP-1u, and BiP, which was upregulated by TGF-β1. Inhibition of ER stress contributed to MSC-mediated amelioration of EMT in A549 cells, and modulation of the IRE1α-XBP1 branch of the ER stress pathway may have played an important role in this effect. MSC transplantation alleviated bleomycin (BLM)-induced pulmonary fibrosis in mice. MSC treatment decreased the expression of ER stress- and EMT-related genes and proteins, and the most obvious effect of MSC treatment was inhibition of the IRE1α/XBP1 pathway.

Conclusions: The present study demonstrated that MSCs decrease EMT by modulating ER stress and that blockade of the IRE1α-XBP1 pathway may play a critical role in this effect. The current study provides novel insight for the application of MSCs for IPF treatment and elucidates the mechanism underlying the preventive effects of MSCs against pulmonary fibrosis.

背景:特发性肺纤维化(IPF)是最常见的特发性间质性肺病:特发性肺纤维化(IPF)是最常见的特发性间质性肺病,由于缺乏有效的诊断方法和治疗手段,其预后较差。上皮-间质转化(EMT)在 IPF 发病机制中起着关键作用。内质网(ER)应激通过EMT介导的途径导致纤维化。间充质干细胞(MSC)移植是一种很有前景的肺纤维化治疗策略,可通过旁分泌效应改善动物模型的肺纤维化。然而,移植间充质干细胞作用的具体机制尚不清楚。我们以前曾报道过间叶干细胞通过调节ER应激和内皮细胞向间质转化来减轻内皮损伤。本研究探讨了调节ER应激和EMT相关通路是否在间充质干细胞介导的IPF缓解中发挥重要作用:我们构建了转化生长因子-β1(TGF-β1)诱导纤维化的 A549 细胞模型。TGF-β1用于诱导A549细胞的EMT,间充质干细胞共培养可减少EMT,表现为E-cadherin水平升高和波形蛋白水平降低。ER应激参与了TGF-β1诱导的A549细胞EMT,间充质干细胞抑制了TGF-β1上调的XBP-1s、XBP-1u和BiP的表达。ER应激的抑制有助于间充质干细胞介导的A549细胞EMT的改善,而ER应激通路的IRE1α-XBP1分支的调节可能在这一效应中发挥了重要作用。间充质干细胞移植缓解了博莱霉素(BLM)诱导的小鼠肺纤维化。间充质干细胞治疗降低了ER应激和EMT相关基因和蛋白的表达,间充质干细胞治疗最明显的作用是抑制IRE1α/XBP1通路:本研究表明,间充质干细胞通过调节ER应激减少EMT,而阻断IRE1α-XBP1通路可能在这一效应中发挥了关键作用。本研究为应用间充质干细胞治疗IPF提供了新的见解,并阐明了间充质干细胞预防肺纤维化的作用机制。
{"title":"Mesenchymal Stem Cells Inhibit Epithelial-to-Mesenchymal Transition by Modulating the IRE1<i>α</i> Branch of the Endoplasmic Reticulum Stress Response.","authors":"Ruixi Luo, Yaqiong Wei, Peng Chen, Jing Zhang, La Wang, Wenjia Wang, Ping Wang, Weiyi Tian","doi":"10.1155/2023/4483776","DOIUrl":"10.1155/2023/4483776","url":null,"abstract":"<p><strong>Background: </strong>Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial lung disease, and it carries a poor prognosis due to a lack of efficient diagnosis methods and treatments. Epithelial-mesenchymal transition (EMT) plays a key role in IPF pathogenesis. Endoplasmic reticulum (ER) stress contributes to fibrosis via EMT-mediated pathways. Mesenchymal stem cell (MSC) transplantation is a promising treatment strategy for pulmonary fibrosis and ameliorates lung fibrosis in animal models via paracrine effects. However, the specific mechanisms underlying the effect of transplanted MSCs are not known. We previously reported that MSCs attenuate endothelial injury by modulating ER stress and endothelial-to-mesenchymal transition. The present study investigated whether modulation of ER stress- and EMT-related pathways plays essential roles in MSC-mediated alleviation of IPF.</p><p><strong>Methods and results: </strong>We constructed a A549 cell model of transforming growth factor-<i>β</i>1 (TGF-<i>β</i>1)-induced fibrosis. TGF-<i>β</i>1 was used to induce EMT in A549 cells, and MSC coculture decreased EMT, as indicated by increased E-cadherin levels and decreased vimentin levels. ER stress participated in TGF-<i>β</i>1-induced EMT in A549 cells, and MSCs inhibited the expression of XBP-1s, XBP-1u, and BiP, which was upregulated by TGF-<i>β</i>1. Inhibition of ER stress contributed to MSC-mediated amelioration of EMT in A549 cells, and modulation of the IRE1<i>α</i>-XBP1 branch of the ER stress pathway may have played an important role in this effect. MSC transplantation alleviated bleomycin (BLM)-induced pulmonary fibrosis in mice. MSC treatment decreased the expression of ER stress- and EMT-related genes and proteins, and the most obvious effect of MSC treatment was inhibition of the IRE1<i>α</i>/XBP1 pathway.</p><p><strong>Conclusions: </strong>The present study demonstrated that MSCs decrease EMT by modulating ER stress and that blockade of the IRE1<i>α</i>-XBP1 pathway may play a critical role in this effect. The current study provides novel insight for the application of MSCs for IPF treatment and elucidates the mechanism underlying the preventive effects of MSCs against pulmonary fibrosis.</p>","PeriodicalId":21962,"journal":{"name":"Stem Cells International","volume":"2023 ","pages":"4483776"},"PeriodicalIF":3.8,"publicationDate":"2023-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10397497/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9949049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Abnormal Decrease of Macrophage ALKBH5 Expression Causes Abnormal Polarization and Inhibits Osteoblast Differentiation. 巨噬细胞ALKBH5表达异常降低导致异常极化,抑制成骨细胞分化。
IF 4.3 3区 医学 Q2 CELL & TISSUE ENGINEERING Pub Date : 2023-07-19 eCollection Date: 2023-01-01 DOI: 10.1155/2023/9974098
Junquan Weng, Haidong Fan, Huijuan Liu, Su Tang, Yuyan Zheng

Peri-implant tissue inflammation is an inflammatory injury that occurs in the soft and hard tissues surrounding the implant and is the main cause of short- or long-term failure of implant prosthetic restorations, which is compounded by bone loss and bone destruction in the alveolar bone of diabetes patients with peri-implantitis. However, the mechanisms underlying the persistence of diabetic peri-implantitis, as well as the essential connections and key molecules that regulate its start and progression, remain unknown. In this study, we discovered that M1 macrophage polarization was abnormally enhanced in diabetic peri-implantitis and influenced the osteogenic differentiation of mesenchymal stem cells. RNA sequencing revealed that ALKBH5 expression was abnormally reduced in diabetic peri-implantitis. Further mechanism study showed that ALKBH5 and its mediated m6A can influence osteogenic differentiation, which in turn influences the persistence of diabetic peri-implantitis. Our findings present a new mechanism for the suppression of osteoblast development in diabetic peri-implantitis and a new treatment strategy to promote anabolism by inhibiting ALKBH5.

种植体周围组织炎症是一种发生在种植体周围软组织和硬组织中的炎症损伤,是种植体假体修复短期或长期失败的主要原因,糖尿病种植体周围炎患者的牙槽骨会出现骨丢失和骨破坏。然而,糖尿病种植体周围炎持续存在的机制,以及调节其开始和发展的重要联系和关键分子,仍然未知。在本研究中,我们发现糖尿病种植体周围炎中M1巨噬细胞极化异常增强,并影响间充质干细胞的成骨分化。RNA测序显示,ALKBH5在糖尿病种植体周围炎中的表达异常降低。进一步的机制研究表明,ALKBH5及其介导的m6A可以影响成骨分化,进而影响糖尿病种植体周围炎的持续性。我们的研究结果提出了一种抑制糖尿病种植体周围炎成骨细胞发育的新机制,以及一种通过抑制ALKBH5促进合成代谢的新治疗策略。
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引用次数: 0
Human Umbilical Mesenchymal Stem Cells-Derived Microvesicles Attenuate Formation of Hypertrophic Scar through Multiple Mechanisms 人脐间充质干细胞衍生的微泡通过多种机制减轻增生性瘢痕的形成
IF 4.3 3区 医学 Q2 CELL & TISSUE ENGINEERING Pub Date : 2023-07-15 DOI: 10.1155/2023/9125265
Qun Qian, N. Zhu, Wenzhe Li, Songlin Wan, Dongcheng Wu, Yun-hua Wu, Weicheng Liu
Mesenchymal stem cells and the derived extracellular microvesicles are potential promising therapy for many disease conditions, including wound healing. Since current therapeutic approaches do not satisfactorily attenuate or ameliorate formation of hypertrophic scars, it is necessary to develop novel drugs to achieve better outcomes. In this study, we investigated the effects and the underlying mechanisms of human umbilical mesenchymal stem cells (HUMSCs)-derived microvesicles (HUMSCs-MVs) on hypertrophic scar formation using a rabbit ear model and a human foreskin fibroblasts (HFF) culture model. The results showed that HUMSCs-MVs reduced formation of hypertrophic scar tissues in the rabbit model based on appearance observation, and hematoxylin and eosin (H&E), Masson, and immunohistochemical stainings. HUMSCs-MVs inhibited invasion of HFF cells and decreased the levels of the α-SMA, N-WASP, and cortacin proteins. HUMSCs-MVs also inhibited cell proliferation of HFF cells. The MMP-1, MMP-3, and TIMP-3 mRNA levels were significantly increased, and the TIMP-4 mRNA level and the NF-kB p65/β-catenin protein levels were significantly decreased in HFF cells after HUMSCs-MVs treatment. The p-SMAD2/3 levels and the ratios of p-SMAD2/3/SMAD2/3 were significantly decreased in both the wound healing tissues and HFF cells after HUMSCs-MVs treatment. CD34 levels were significantly decreased in both wound healing scar tissues and HFF cells after HUMSCs-MVs treatment. The VEGF-A level was also significantly decreased in HFF cells after HUMSCs-MVs treatment. The magnitudes of changes in these markers by HUMSCs-MVs were mostly higher than those by dexamethasone. These results suggested that HUMSCs-MVs attenuated formation of hypertrophic scar during wound healing through inhibiting proliferation and invasion of fibrotic cells, inflammation and oxidative stress, Smad2/3 activation, and angiogenesis. HUMSCs-MVs is a potential promising drug to attenuate formation of hypertrophic scar during wound healing.
间充质干细胞及其衍生的细胞外微泡是许多疾病的潜在治疗方法,包括伤口愈合。由于目前的治疗方法不能令人满意地减轻或改善增生性疤痕的形成,有必要开发新的药物来达到更好的效果。在这项研究中,我们通过兔耳模型和人包皮成纤维细胞(HFF)培养模型研究了人脐间充质干细胞(HUMSCs)来源的微泡(HUMSCs- mv)对增生性瘢痕形成的影响及其潜在机制。外观观察、苏木精和伊红(H&E)、Masson和免疫组化染色结果显示,humscs - mv减少了兔模型增生性瘢痕组织的形成。humscs - mv抑制HFF细胞的侵袭,降低α-SMA、N-WASP和cortacin蛋白的水平。HUMSCs-MVs还能抑制HFF细胞的增殖。humscs - mv处理HFF细胞后,MMP-1、MMP-3和TIMP-3 mRNA水平显著升高,TIMP-4 mRNA水平和NF-kB p65/β-catenin蛋白水平显著降低。humscs - mv处理后,伤口愈合组织和HFF细胞中p-SMAD2/3水平和p-SMAD2/3/ 3比值均显著降低。humscs - mv处理后,伤口愈合瘢痕组织和HFF细胞中的CD34水平均显著降低。humscs - mv处理后,HFF细胞中VEGF-A水平也显著降低。这些指标的变化幅度大多高于地塞米松。这些结果表明,humscs - mv通过抑制纤维化细胞的增殖和侵袭、炎症和氧化应激、Smad2/3的激活和血管生成,减轻了创面愈合过程中增生性瘢痕的形成。humscs - mv是一种潜在的有前景的药物,可以减轻创面愈合过程中增生性瘢痕的形成。
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引用次数: 0
Factors Associated with 28-day Critical Illness Development During the First Wave of COVID-19. COVID-19 第一波期间与 28 天危重病发展相关的因素。
3区 医学 Q2 CELL & TISSUE ENGINEERING Pub Date : 2023-06-23 eCollection Date: 2023-06-01 DOI: 10.36519/idcm.2023.206
Uluhan Sili, Pınar Ay, Hüseyin Bilgin, Ahmet Topuzoğlu, Elif Tükenmez-Tigen, Buket Ertürk-Şengel, Dilek Yağçı-Çağlayık, Baran Balcan, Derya Kocakaya, Şehnaz Olgun-Yıldızeli, Fethi Gül, Beliz Bilgili, Rabia Can-Sarınoğlu, Ayşegül Karahasan-Yağcı, Lütfiye Mülazimoğlu-Durmuşoğlu, Emel Eryüksel, Zekaver Odabaşı, Haner Direskeneli, Sait Karakurt, Volkan Korten

Objective: This study aimed to define the predictors of critical illness development within 28 days postadmission during the first wave of the COVID-19 pandemic.

Materials and methods: We conducted a prospective cohort study including 477 PCR-positive COVID-19 patients admitted to a tertiary care hospital in Istanbul from March 12 to May 12, 2020.

Results: The most common presenting symptoms were cough, dyspnea, and fatigue. Critical illness developed in 45 (9.4%; 95% CI=7.0%-12.4%) patients. In the multivariable analysis, age (hazard ratio (HR)=1.05, p<0.001), number of comorbidities (HR=1.33, p=0.02), procalcitonin ≥0.25 µg/L (HR=2.12, p=0.03) and lactate dehydrogenase (LDH) ≥350 U/L (HR=2.04, p=0.03) were independently associated with critical illness development. The World Health Organization (WHO) ordinal scale for clinical improvement on admission was the strongest predictor of critical illness (HR=4.15, p<0.001). The patients hospitalized at the end of the study period had a much better prognosis compared to the patients hospitalized at the beginning (HR=0.14; p=0.02). The C-index of the model was 0.92.

Conclusion: Age, comorbidity number, the WHO scale, LDH, and procalcitonin were independently associated with critical illness development. Mortality from COVID-19 seemed to be decreasing as the first wave of the pandemic advanced.

Graphic abstract: Graphic Abstract.

研究目的本研究旨在确定 COVID-19 大流行第一波期间入院后 28 天内危重病发展的预测因素:我们开展了一项前瞻性队列研究,研究对象包括伊斯坦布尔一家三级医院在 2020 年 3 月 12 日至 5 月 12 日期间收治的 477 名 PCR 阳性 COVID-19 患者:最常见的症状是咳嗽、呼吸困难和疲劳。45例(9.4%;95% CI=7.0%-12.4%)患者出现危重症。在多变量分析中,年龄(危险比(HR)=1.05,PP=0.02)、降钙素原≥0.25 µg/L(HR=2.12,P=0.03)和乳酸脱氢酶(LDH)≥350 U/L(HR=2.04,P=0.03)与危重症的发生独立相关。世界卫生组织(WHO)对入院时临床改善情况的序数量表是预测危重症的最强指标(HR=4.15,pp=0.02)。模型的 C 指数为 0.92:结论:年龄、合并症数量、WHO量表、LDH和降钙素原均与危重症的发生独立相关。随着第一波大流行的推进,COVID-19 导致的死亡率似乎在下降。
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引用次数: 0
Comparison of Biological Properties and Clinical Application of Mesenchymal Stem Cells from the Mesoderm and Ectoderm. 中胚层与外胚层间充质干细胞生物学特性及临床应用比较。
IF 4.3 3区 医学 Q2 CELL & TISSUE ENGINEERING Pub Date : 2023-06-10 eCollection Date: 2023-01-01 DOI: 10.1155/2023/4547875
Zhenning Wang, Meng Huang, Yu Zhang, Xiaoxia Jiang, Lulu Xu

Since the discovery of mesenchymal stem cells (MSCs) in the 1970s, they have been widely used in the treatment of a variety of diseases because of their wide sources, strong differentiation potential, rapid expansion in vitro, low immunogenicity, and so on. At present, most of the related research is on mesoderm-derived MSCs (M-MSCs) such as bone marrow MSCs and adipose-derived MSCs. As a type of MSC, ectoderm-derived MSCs (E-MSCs) have a stronger potential for self-renewal, multidirectional differentiation, and immunomodulation and have more advantages than M-MSCs in some specific conditions. This paper analyzes the relevant research development of E-MSCs compared with that of M-MSCs; summarizes the extraction, discrimination and culture, biological characteristics, and clinical application of E-MSCs; and discusses the application prospects of E-MSCs. This summary provides a theoretical basis for the better application of MSCs from both ectoderm and mesoderm in the future.

自20世纪70年代发现间充质干细胞以来,由于其来源广泛、分化潜能强、体外扩增快、免疫原性低等特点,已被广泛应用于多种疾病的治疗。作为一种MSC,外胚层来源的MSC(E-MSCs)具有更强的自我更新、多向分化和免疫调节潜力,在某些特定条件下比M-MSCs更有优势。本文分析了E-MSC与M-MSC的相关研究进展;综述了E-MSCs的提取、鉴别培养、生物学特性及临床应用;并对E-MSC的应用前景进行了探讨。本综述为今后外胚层和中胚层间充质干细胞的更好应用提供了理论依据。
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引用次数: 1
MiR-125b-5p/STAT3 Axis Regulates Drug Resistance in Osteosarcoma Cells by Acting on ABC Transporters. MiR-125b-5p/STAT3 轴通过作用于 ABC 转运体调节骨肉瘤细胞的耐药性
IF 4.3 3区 医学 Q2 CELL & TISSUE ENGINEERING Pub Date : 2023-04-29 eCollection Date: 2023-01-01 DOI: 10.1155/2023/9997676
Yang Yang, Yueyuan Chen, Jiajia Liu, Bo Zhang, Linlin Yang, Jianhua Xue, Zexu Zhang, Lili Qin, Rongpeng Bian

Background: The poor prognosis of the highly malignant tumor osteosarcoma stems from its drug resistance and therefore exploring its resistance mechanisms will help us identify more effective treatment options. However, the effects of miR-125b-5p on drug resistance in osteosarcoma cells are still unclear.

Methods: To study the effects of miR-125b-5p on drug resistance in osteosarcoma cells. Osteosarcoma-resistant miR-125b-5p was obtained from the databases GeneCards and g:Profiler. CCK8, western blot, and transwell were applied for the detection of the miR-125b-5p effects on proliferation, migration, invasion, apoptosis, and drug resistance in osteosarcoma. Bioinformatics is aimed at demonstrating the targeting factor miR-125b-5p, performing protein interaction enrichment analysis by Metascape, and finally validating by binding sites.

Results: Upregulation of miR-125b-5p restrains proliferation, migration, and invasion of osteosarcoma and promotes apoptosis. In addition, miR-125b-5p can restore drug sensitivity in drug-resistant osteosarcoma. miR-125-5p restrains the signal transducer and inhibits the transcription 3 (STAT3) expression activator via targeting its 3'-UTR. STAT3 affects drug-resistant osteosarcoma to regulate the ABC transporter.

Conclusion: miR-125b-5p/STAT3 axis mediates the drug resistance of osteosarcoma by acting on ABC transporter.

背景:高度恶性肿瘤骨肉瘤的不良预后源于其耐药性,因此探索其耐药机制将有助于我们找到更有效的治疗方案。然而,miR-125b-5p 对骨肉瘤细胞耐药性的影响尚不清楚:方法:研究 miR-125b-5p 对骨肉瘤细胞耐药性的影响。从数据库 GeneCards 和 g:Profiler 中获取骨肉瘤耐药 miR-125b-5p。应用 CCK8、Western 印迹和 transwell 检测 miR-125b-5p 对骨肉瘤细胞增殖、迁移、侵袭、凋亡和耐药性的影响。生物信息学的目的是证明miR-125b-5p的靶向因子,利用Metascape进行蛋白质相互作用富集分析,最后通过结合位点进行验证:结果:miR-125b-5p 的上调可抑制骨肉瘤的增殖、迁移和侵袭,并促进其凋亡。此外,miR-125b-5p 还能恢复耐药骨肉瘤的药物敏感性。miR-125-5p 通过靶向 3'-UTR 抑制信号转导抑制转录 3(STAT3)表达激活因子。结论:miR-125b-5p/STAT3轴通过作用于ABC转运体介导骨肉瘤的耐药性。
{"title":"MiR-125b-5p/STAT3 Axis Regulates Drug Resistance in Osteosarcoma Cells by Acting on ABC Transporters.","authors":"Yang Yang, Yueyuan Chen, Jiajia Liu, Bo Zhang, Linlin Yang, Jianhua Xue, Zexu Zhang, Lili Qin, Rongpeng Bian","doi":"10.1155/2023/9997676","DOIUrl":"10.1155/2023/9997676","url":null,"abstract":"<p><strong>Background: </strong>The poor prognosis of the highly malignant tumor osteosarcoma stems from its drug resistance and therefore exploring its resistance mechanisms will help us identify more effective treatment options. However, the effects of miR-125b-5p on drug resistance in osteosarcoma cells are still unclear.</p><p><strong>Methods: </strong>To study the effects of miR-125b-5p on drug resistance in osteosarcoma cells. Osteosarcoma-resistant miR-125b-5p was obtained from the databases GeneCards and g:Profiler. CCK8, western blot, and transwell were applied for the detection of the miR-125b-5p effects on proliferation, migration, invasion, apoptosis, and drug resistance in osteosarcoma. Bioinformatics is aimed at demonstrating the targeting factor miR-125b-5p, performing protein interaction enrichment analysis by Metascape, and finally validating by binding sites.</p><p><strong>Results: </strong>Upregulation of miR-125b-5p restrains proliferation, migration, and invasion of osteosarcoma and promotes apoptosis. In addition, miR-125b-5p can restore drug sensitivity in drug-resistant osteosarcoma. miR-125-5p restrains the signal transducer and inhibits the transcription 3 (STAT3) expression activator via targeting its 3'-UTR. STAT3 affects drug-resistant osteosarcoma to regulate the ABC transporter.</p><p><strong>Conclusion: </strong>miR-125b-5p/STAT3 axis mediates the drug resistance of osteosarcoma by acting on ABC transporter.</p>","PeriodicalId":21962,"journal":{"name":"Stem Cells International","volume":"2023 ","pages":"9997676"},"PeriodicalIF":4.3,"publicationDate":"2023-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10163973/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9813282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Construction of an Excellent 7 mRNAsi-Related Gene Model Based on Cancer Stem Cells for Predicting Survival Outcome of Cervical Cancer 基于肿瘤干细胞构建预测宫颈癌存活结果的7 mrnasi相关基因模型
IF 4.3 3区 医学 Q2 CELL & TISSUE ENGINEERING Pub Date : 2023-04-26 DOI: 10.1155/2023/8383058
Yang Liu, Lin Yang, Hao Liang, Jianhua Zeng, Yuanyuan Hua, Huancheng Wu
Background. Cervical cancer (CC) is one of the most frequent female malignancy. Cancer stem cells (CSCs) positively affect survival outcomes in cancer patients, but in cervical cancer, the mechanism of tumor stem cells is still uncertain. Methods. RNA-seq data and related clinical follow-up of patients suffering from CC were from TCGA. Consensus clustering screened prognostic mRNAsi-related genes and identified molecular subtypes for CC. Based on the overlapping differentially expressed genes (DEGs) in subtypes, we employed LASSO and multivariate Cox regression to screen prognostic-related genes and established the RiskScore system. The patients were grouped by RiskScore, the prognosis was analyzed by the Kaplan-Meier (K-M) curve among the various groups, and the precision of the RiskScore was assessed by the ROC curve. Finally, the potential worth of RiskScore in immunotherapy/chemotherapy response was assessed by evaluating TIDE scores and chemotherapy drug IC 50 values. Results. We noticed that patients with low mRNAsi had a shorter survival and then identified three molecular subtypes (C1-3), with the C1 having the worst prognosis and the lowest mRNAsi. Finally, we identified 7 prognostic-related genes (SPRY4, PPP1R14A, MT1A, DES, SEZ6L2, SLC22A3, and CXCL8) via LASSO and Cox regression analysis. We established a 7-gene model defined RiskScore to predict the prognosis of CC patients. K-M curve indicated that low RiskScore patients had improved prognosis, and ROC curves indicated that RiskScore could precisely direct the prognostic evaluation for those suffering from the cancer. This was also confirmed in the GSE44001 and GSE52903 external cohorts. Patients were more sensitive to immunotherapy if with low RiskScore, and RiskScore exhibited precise assessment ability in predicting response to immunological therapy in CC patients. Conclusion. CC stemness is associated with patient prognosis, and the RiskScore constructed based on stemness characteristics is an independent prognostic index, which is expected to be a guide for immunotherapy, providing a new idea for CC clinical practice.
背景。宫颈癌(CC)是最常见的女性恶性肿瘤之一。肿瘤干细胞(Cancer stem cells, CSCs)积极影响癌症患者的生存结局,但在宫颈癌中,肿瘤干细胞的作用机制仍不确定。方法。CC患者的RNA-seq数据及相关临床随访均来自TCGA。共识聚类筛选预后mrnasi相关基因并鉴定CC分子亚型,基于亚型中差异表达基因(DEGs)的重叠,采用LASSO和多变量Cox回归筛选预后相关基因并建立RiskScore系统。采用RiskScore对患者进行分组,各组间采用Kaplan-Meier (K-M)曲线分析预后,采用ROC曲线评价RiskScore的准确性。最后,通过评估TIDE评分和化疗药物IC 50值来评估RiskScore在免疫治疗/化疗反应中的潜在价值。结果。我们注意到低mRNAsi患者的生存期较短,然后确定了三种分子亚型(C1-3),其中C1预后最差,mRNAsi最低。最后,我们通过LASSO和Cox回归分析确定了7个预后相关基因(SPRY4、PPP1R14A、MT1A、DES、SEZ6L2、SLC22A3和CXCL8)。我们建立了一个定义为RiskScore的7基因模型来预测CC患者的预后。K-M曲线提示低RiskScore患者预后较好,ROC曲线提示RiskScore可以准确指导癌症患者的预后评价。这在GSE44001和GSE52903外部队列中也得到了证实。RiskScore低的患者对免疫治疗更敏感,RiskScore在预测CC患者免疫治疗反应方面表现出精确的评估能力。结论。CC干性与患者预后相关,基于干性特征构建的RiskScore是一个独立的预后指标,有望为免疫治疗提供指导,为CC临床实践提供新的思路。
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引用次数: 0
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Stem Cells International
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