Stem Cells International最新文献_第6页

Retracted: Effects of Fibulin-5 Gene Silencing on Proliferation and Apoptosis of IgG4-ROD Lacrimal Gland Fibroblasts 撤回：Fibulin-5基因沉默对IgG4-ROD泪腺成纤维细胞增殖和凋亡的影响

IF 4.3 3区医学 Q2 CELL & TISSUE ENGINEERING

Stem Cells International

Pub Date : 2023-12-20 DOI: 10.1155/2023/9856916

Stem Cells International

引用次数: 0

Combination Therapy with Platelet-Rich Plasma and Epidermal Neural Crest Stem Cells Increases Treatment Efficacy in Vascular Dementia 富血小板血浆和表皮神经干细胞联合疗法可提高血管性痴呆症的疗效

IF 4.3 3区医学 Q2 CELL & TISSUE ENGINEERING

Stem Cells International

Pub Date : 2023-12-18 DOI: 10.1155/2023/3784843

Somayeh Akbari, Masoud Haghani, Mojtaba Ghobadi, Etrat Hooshmandi, Afshin Borhani Haghighi, Mohammad Saied Salehi, Sareh Pandamooz, Negar Azarpira, Afsoon Afshari, Shahrbanoo Zabihi, Marzieh Nemati, Mahnaz Bayat

This study aimed to evaluate the efficacy and treatment mechanism of platelet-rich plasma (PRP) and neural crest-derived epidermal stem cells (ESCs) in their administration alone and combination in vascular dementia (VaD) model by two-vessel occlusion (2VO). Methods. Sixty-six rats were divided into six groups: the control, sham, 2VO + vehicle, 2VO + PRP, 2VO + ESC, and 2VO + ESC + PRP. The treated groups received 1 million cells on days 4, 14, and 21 with or without 500 µl PRP (twice a week) after 2VO. The memory performance and anxiety were evaluated by behavioral tests including open field, passive avoidance, and Morris water maze. The basal-synaptic transmission (BST) and long-term potentiation (LTP) were assessed through field-potential recordings of the CA1. The mRNA expression levels of IGF-1, TGF-β1, PSD-95, and GSk-3β were measured in the rat hippocampus by quantitative reverse transcription polymerase chain reaction. Results. The results demonstrated impaired learning, memory, and synaptic plasticity in the 2VO rats, along with a significant decrease in the expression of IGF-1, TGF-β1, PSD-95, and upregulation of GSK-3β. Treatment with ESC alone and ESC + PRP showed similar improvements in spatial memory and LTP induction, with associated upregulation of PSD-95 and downregulation of GSK-3β. However, only the ESC + PRP group showed recovery in BST. Furthermore, combination therapy was more effective than PRP monotherapy for LTP and memory. Conclusions. The transplantation of ESC showed better effects than PRP alone, and combination therapy increased the treatment efficacy with the recovery of BST. This finding may be a clue for the combination therapy of ESC and PRP for VaD.

本研究旨在评估富血小板血浆（PRP）和神经嵴衍生表皮干细胞（ESCs）单独或联合应用对双血管闭塞（2VO）血管性痴呆（VaD）模型的疗效和治疗机制。研究方法66只大鼠被分为六组：对照组、假阳性组、2VO+载体组、2VO+PRP组、2VO+ESC组和2VO+ESC+PRP组。治疗组在 2VO 后的第 4、14 和 21 天接受 100 万个细胞治疗，同时接受或不接受 500 µl PRP（每周两次）。通过行为测试（包括开阔地、被动回避和莫里斯水迷宫）评估记忆表现和焦虑。通过对CA1的场电位记录评估了基础突触传递（BST）和长期电位（LTP）。通过定量反转录聚合酶链反应测定了大鼠海马中 IGF-1、TGF-β1、PSD-95 和 GSk-3β 的 mRNA 表达水平。结果显示结果表明，2VO大鼠的学习、记忆和突触可塑性受损，IGF-1、TGF-β1、PSD-95的表达显著下降，GSK-3β上调。单独使用 ESC 和 ESC + PRP 治疗在空间记忆和 LTP 诱导方面有相似的改善，同时 PSD-95 上调，GSK-3β 下调。然而，只有 ESC + PRP 组的 BST 有所恢复。此外，在 LTP 和记忆方面，联合疗法比 PRP 单药疗法更有效。结论移植 ESC 比单用 PRP 效果更好，联合疗法提高了疗效，BST 也有所恢复。这一发现可能是ESC和PRP联合治疗VaD的线索。

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引用次数: 0

Advances and Challenges in Cancer Stem Cells for Onco-Therapeutics 肿瘤干细胞治疗的进展和挑战

IF 4.3 3区医学 Q2 CELL & TISSUE ENGINEERING

Stem Cells International

Pub Date : 2023-12-06 DOI: 10.1155/2023/8722803

Sulaiman Mohammed Alnasser

Six decades have passed since the foundational recognition of the primary properties of the stem cells. Research on stem cells has since remained at the forefront of efforts to combat a spectrum of diseases, most notably cancer. Despite remarkable progress in medical science, a definitive cure for cancer has remained elusive, spurring the pursuit of diverse therapeutic strategies, among which stem cell therapy is a particularly promising avenue. Moreover, the utilization of cancer stem cells as a therapeutic source holds immense potential for addressing intractable diseases. The strategy of targeting cancer stem cells is beset with challenges, including immune rejection and disease relapse. Additionally, the capacity to inadvertently generate cancer stem cells upon transplantation underscores the critical need to eliminate these cells to ensure the efficacy of cell-based therapies. This paper underscores the pivotal role of cancer stem cells in onco-therapeutics and their potential to aid in early cancer diagnosis. With the proliferation of tissue banks and their collection of malignant tissue types, a renewable source of medications to combat cancer is on the horizon. While cancer stem cell-based therapy presents sophisticated and significant challenges, it offers unprecedented opportunities to extend human life. Continued technological advancements in stem cell therapy promise to provide new insights and refine approaches for cancer treatment, ushering in a new era of hope and innovation in the fight against this formidable disease.

从对干细胞的基本特性的认识到现在已经过去了60年。从那以后，对干细胞的研究一直处于对抗一系列疾病的前沿，尤其是癌症。尽管医学科学取得了显著的进步，但最终治愈癌症的方法仍然难以捉摸，这促使人们追求各种治疗策略，其中干细胞治疗是一个特别有前途的途径。此外，利用癌症干细胞作为治疗来源，在治疗难治性疾病方面具有巨大的潜力。靶向肿瘤干细胞的策略面临着包括免疫排斥和疾病复发在内的挑战。此外，移植时无意中产生癌症干细胞的能力强调了消除这些细胞以确保细胞治疗效果的迫切需要。本文强调了肿瘤干细胞在肿瘤治疗中的关键作用及其在早期癌症诊断中的潜力。随着组织库的增加和恶性组织类型的收集，对抗癌症的可再生药物来源即将出现。虽然基于癌症干细胞的治疗提出了复杂而重大的挑战，但它为延长人类生命提供了前所未有的机会。干细胞治疗的持续技术进步有望为癌症治疗提供新的见解和改进的方法，在与这一可怕疾病的斗争中迎来一个充满希望和创新的新时代。

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引用次数: 0

Human Umbilical Cord Perivascular Cells Prevent Tumor Growth in a Melanoma Tumor-Bearing Mouse Model and Modulate Breast Cancer and Melanoma Cells in a Cell Line-Dependent Manner In Vitro 人脐带血管周围细胞在黑色素瘤荷瘤小鼠模型中阻止肿瘤生长，并在体外以细胞系依赖的方式调节乳腺癌和黑色素瘤细胞

IF 4.3 3区医学 Q2 CELL & TISSUE ENGINEERING

Stem Cells International

Pub Date : 2023-11-30 DOI: 10.1155/2023/5568206

Lianet Lopez, Hannah Shuster-Hyman, Eden Marco, Hasna Khan, Avishai Gasner, Aleksandra Uzelac, Brandon Wyse, Poonam Mander, Mugundhine Sangaralingam, Joseph Fish, Ariel Gorodensky, Samar Mouazz, Amanda Kauffman, Denis Gallagher, Andrée Gauthier-Fisher, Clifford L. Librach

First trimester (FTM) and term human umbilical cord perivascular cells are promising mesenchymal stromal cell candidates to mitigate side effects of oncotherapy, but their safety for cancer patients remains to be determined. This study was designed to determine if human umbilical cord perivascular cells modulate tumor growth when injected systemically in a tumor-bearing mouse model. Immunodeficient mice-bearing palpable subcutaneous SK-MEL-28 human melanoma tumors were randomized to receive a tail vein injection of three human umbilical cord perivascular cell lines resuspended in hank’s buffer saline solution (vehicle) or vehicle only, as a control. Fibroblast cells were included as a cell control in some experiments. Tumor size was monitored weekly and weighed at 3-weeks postinjection. Cell fate and tumor cell proliferation, apoptosis, vascularization as well as tumor-associated immune cells were assessed using immunostaining and flow cytometry. Serum tumor necrosis factor alpha and C-reactive protein levels were measured using enzyme-linked immunosorbent assays. Transwell coculture models were used to study the paracrine effects of multiple lines of human umbilical cord cells on human melanoma cell lines as well as breast cancer cell lines. Systemic administration of FTM and term human umbilical cord perivascular cells, but not fibroblast cells, prevented melanoma tumor growth in a tumor-bearing animal model by modulating tumor cell proliferation and systemic inflammatory mechanisms. Cancer cell- and donor-dependent paracrine effects on cancer cell growth were observed in vitro. Our preclinical studies thus suggest that, with regards to its effects on tumor growth, systemic administration of FTM and term human umbilical cord perivascular cells may be a safe cell therapy to address the side effects of cancer.

妊娠早期(FTM)和足月人脐带血管周围细胞是有希望减轻肿瘤治疗副作用的间充质间质细胞候选物，但其对癌症患者的安全性仍有待确定。本研究旨在确定在荷瘤小鼠模型中全身注射人脐带血管周围细胞是否能调节肿瘤生长。携带可触皮下SK-MEL-28人黑色素瘤的免疫缺陷小鼠随机接受尾静脉注射，三种人脐带血管周围细胞系重悬在汉克缓冲盐水溶液(对照)中或仅用对照，作为对照。在一些实验中，成纤维细胞被作为细胞对照。每周监测肿瘤大小，注射后3周称重。使用免疫染色和流式细胞术评估细胞命运和肿瘤细胞增殖、凋亡、血管化以及肿瘤相关免疫细胞。采用酶联免疫吸附法测定血清肿瘤坏死因子α和c反应蛋白水平。采用Transwell共培养模型，研究多系人脐带细胞对人黑色素瘤细胞系和乳腺癌细胞系的旁分泌作用。在荷瘤动物模型中，全身给药FTM和足月人脐带血管周围细胞，而不是成纤维细胞，通过调节肿瘤细胞增殖和全身炎症机制，阻止了黑色素瘤肿瘤的生长。体外观察癌细胞依赖性和供体依赖性旁分泌对癌细胞生长的影响。因此，我们的临床前研究表明，就其对肿瘤生长的影响而言，全身给药FTM和长期的人脐带血管周围细胞可能是一种安全的细胞疗法，可以解决癌症的副作用。

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引用次数: 0

Unveiling Cellular Traits of Osteosarcoma Cancer Stem Cells via Bulk and Single-Cell RNA-Sequencing Analysis 通过大量和单细胞rna测序分析揭示骨肉瘤癌症干细胞的细胞特性

IF 4.3 3区医学 Q2 CELL & TISSUE ENGINEERING

Stem Cells International

Pub Date : 2023-11-22 DOI: 10.1155/2023/2923728

Zhen Zhao, Shun Niu, Zhixiang Yu, Hongtao Zhang, Lizhuo Liang, Kui Xu, Chuan Dong, Hua Long

Osteosarcoma (OS) is a prototypical sarcoma, predominantly affecting adolescents. The hallmark of cancer stem cell (CSC) behavior pervades OS, invariably signifying an unfavorable prognosis. However, the intricacies underlying OS metastasis remain incompletely comprehended. As the frontiers of the scientific investigation push forward, encompassing both bulk sequencing and single-cell sequencing (scRNA), the domain of bioinformatics finds multifaceted utility. In this study, we combined scRNA and bulk sequencing with the clinical metadata to excavate the latent molecular substrates governing metastatic propensities within OS. Our scRNA analysis indicated that cell-stemness-related pathways might play vital roles in OS metastasis. Subsequently, an autonomous reservoir of bulk sequencing data set was subjected to weighted gene co-expression network analysis (WGCNA) to identify 10 gene clusters. After analyzing the clinical data, we were able to identify two hub genes, HDAC2 and HSPA4, which are strongly linked to the cancer cell stemness. Moreover, we performed transwell assays to validate the regulation of metastatic behaviors by miR-1-3p, HDAC2, and HSPA4 in OS cells. Significantly, our study was fortified by immunohistochemistry (IHC) analyses performed on tumor tissues acquired from OS patients, thereby accentuating the clinical import of our experimental endeavor. Notably, we unveiled the suppressive influence of miR-1-3p on both HDAC2 and HSPA4, with miRTarBase substantiating lower expression in tumor tissue relative to the normative cohort. Insights gleaned from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) program (https://ocg.cancer.gov/programs/target) further augmented the clinical significance of the identified hub genes. In conclusion, our findings highlight the significant role of cell junctions in governing OS stemness and metastasis, underscored by the integration of single-cell sequencing and bulk-sequencing analyses. Moreover, our foundational experiments identified three hub molecules closely associated with the metastatic behaviors. Our findings provide novel insights into the clinical treatment and fundamental understanding of OS.

骨肉瘤(OS)是一种典型的肉瘤，主要影响青少年。肿瘤干细胞(CSC)行为的标志遍及OS，总是预示着不良预后。然而，OS转移背后的复杂性仍未被完全理解。随着科学研究的前沿不断推进，包括大量测序和单细胞测序(scRNA)，生物信息学领域发现了多方面的用途。在这项研究中，我们将scRNA和批量测序与临床元数据相结合，以挖掘控制OS转移倾向的潜在分子底物。我们的scRNA分析表明，细胞干细胞相关通路可能在肿瘤转移中发挥重要作用。随后，对大量自主测序数据集进行加权基因共表达网络分析(WGCNA)，以识别10个基因簇。通过对临床数据的分析，我们确定了两个中心基因，HDAC2和HSPA4，它们与癌细胞的干细胞性密切相关。此外，我们进行了transwell实验来验证miR-1-3p、HDAC2和HSPA4在OS细胞中对转移行为的调节。值得注意的是，我们的研究通过对OS患者获得的肿瘤组织进行免疫组织化学(IHC)分析而得到加强，从而强调了我们实验努力的临床意义。值得注意的是，我们揭示了miR-1-3p对HDAC2和HSPA4的抑制作用，与标准队列相比，miRTarBase在肿瘤组织中的表达较低。从产生有效治疗的治疗应用研究(TARGET)项目(https://ocg.cancer.gov/programs/target)中收集的见解进一步增强了已确定的中心基因的临床意义。总之，我们的研究结果强调了细胞连接在控制OS干细胞性和转移中的重要作用，这一点通过单细胞测序和批量测序分析的整合得到了强调。此外，我们的基础实验确定了与转移行为密切相关的三个中心分子。我们的发现为临床治疗和对OS的基本理解提供了新的见解。

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引用次数: 0

Mechanisms and Optimization Strategies of Paracrine Exosomes from Mesenchymal Stem Cells in Ischemic Heart Disease. 缺血性心脏病中间充质干细胞旁分泌外泌体的机制和优化策略。

IF 4.3 3区医学 Q2 CELL & TISSUE ENGINEERING

Stem Cells International

Pub Date : 2023-11-22 eCollection Date: 2023-01-01 DOI: 10.1155/2023/6500831

Xiaorong Yin, Lizhi Lin, Fang Fang, Bin Zhang, Cheng Shen

The morbidity and mortality of myocardial infarction (MI) are increasing worldwide. Mesenchymal stem cells (MSCs) are multipotent stem cells with self-renewal and differentiation capabilities that are essential in tissue healing and regenerative medicine. However, the low implantation and survival rates of transplanted cells hinder the widespread clinical use of stem cells. Exosomes are naturally occurring nanovesicles that are secreted by cells and promote the repair of cardiac function by transporting noncoding RNA and protein. In recent years, MSC-derived exosomes have been promising cell-free treatment tools for improving cardiac function and reversing cardiac remodeling. This review describes the biological properties and therapeutic potential of exosomes and summarizes some engineering approaches for exosomes optimization to enhance the targeting and therapeutic efficacy of exosomes in MI.

心肌梗死(MI)的发病率和死亡率在世界范围内呈上升趋势。间充质干细胞(MSCs)是具有自我更新和分化能力的多能干细胞，在组织愈合和再生医学中至关重要。然而，移植细胞的低着床率和存活率阻碍了干细胞的广泛临床应用。外泌体是由细胞分泌的天然纳米囊泡，通过转运非编码RNA和蛋白质促进心脏功能的修复。近年来，msc衍生的外泌体已成为改善心脏功能和逆转心脏重塑的无细胞治疗工具。本文综述了外泌体的生物学特性和治疗潜力，并总结了一些优化外泌体的工程方法，以提高外泌体在心肌梗死中的靶向性和治疗效果。

引用次数: 0

Photobiomodulation Can Enhance Stem Cell Viability in Cochlea with Auditory Neuropathy but Does Not Restore Hearing. 光生物调节可增强听神经病变耳蜗干细胞活力，但不能恢复听力。

IF 4.3 3区医学 Q2 CELL & TISSUE ENGINEERING

Stem Cells International

Pub Date : 2023-11-15 eCollection Date: 2023-01-01 DOI: 10.1155/2023/6845571

So-Young Chang, Eunjeong Kim, Nathaniel T Carpena, Jae-Hun Lee, Doo Hee Kim, Min Young Lee

Sensorineural hearing loss is very difficult to treat. Currently, one of the techniques used for hearing rehabilitation is a cochlear implant that can transform sound into electrical signals instead of inner ear hair cells. However, the prognosis remains very poor if sufficient auditory nerve cells are not secured. In this study, the effect of mouse embryonic stem cells (mESC) and photobiomodulation (PBM) combined treatment on auditory function and auditory nerve cells in a secondary neuropathy animal model was investigated. To confirm the engraftment of stem cells in vitro, cochlear explants were treated with kanamycin (KM) to mimic nerve damage and then cocultured with GFP-mESC. GFP-mESCs were observed to have attached and integrated into the explanted samples. An animal model for secondary neurodegeneration was achieved by KM treatment and was treated by a combination therapy of GFP-mESC and NIR-PBM at 8 weeks of KM treatment. Hearing recovery by functional testing using auditory brain stem response (ABR) and eABR was measured as well as morphological changes and epifluorescence analysis were conducted after 2 weeks of combination therapy. KM treatment elevated the hearing threshold at 70-80 dB and even after the combination treatment with GFP-mESC and PBM was applied, the auditory function was not restored. In addition, the stem cells transplanted into cochlea has exponentially increased due to PBM treatment although did not produce any malignancy. This study confirmed that the combined treatment with mESC and PBM could not improve hearing or increase the response of the auditory nerve. Nevertheless, it is noteworthy in this study that the cells are distributed in most cochlear tissues and the proliferation of stem cells was very active in animals irradiated with PBM compared to other groups wherein the stem cells had disappeared immediately after transplantation or existed for only a short period of time.

感觉神经性听力损失很难治疗。目前，用于听力康复的技术之一是人工耳蜗，它可以将声音转换为电信号，而不是内耳毛细胞。然而，如果没有足够的听神经细胞，预后仍然很差。本研究探讨了小鼠胚胎干细胞(mESC)和光生物调节(PBM)联合治疗对继发性神经病变动物模型听觉功能和听神经细胞的影响。为了证实干细胞的体外移植，我们用卡那霉素(KM)处理耳蜗外植体，模拟神经损伤，然后与GFP-mESC共培养。观察到GFP-mESCs已附着并整合到外植体样品中。通过KM治疗获得继发性神经变性动物模型，并在KM治疗8周时采用GFP-mESC和NIR-PBM联合治疗。联合治疗2周后，采用听觉脑干反应(ABR)和听觉脑干反应(eABR)功能测试测定听力恢复情况，并进行形态学变化和荧光分析。KM治疗可使听力阈值升高70-80 dB，即使采用GFP-mESC和PBM联合治疗，听觉功能也未恢复。此外，由于PBM治疗，移植到耳蜗的干细胞呈指数增长，尽管没有产生任何恶性肿瘤。本研究证实mESC和PBM联合治疗不能改善听力，也不能增加听神经的反应。然而，值得注意的是，在本研究中，细胞分布在大多数耳蜗组织中，与干细胞在移植后立即消失或仅存在很短时间的其他组相比，PBM照射动物的干细胞增殖非常活跃。

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引用次数: 0

Umbilical Cord Mesenchymal Stem Cells Overexpressing Heme Oxygenase-1 Promotes Symptoms Recovery in Cystitis Rats by Alleviating Neuroinflammation 过表达血红素加氧酶-1的脐带间充质干细胞通过减轻神经炎症促进膀胱炎大鼠症状恢复

3区医学 Q2 CELL & TISSUE ENGINEERING

Stem Cells International

Pub Date : 2023-11-14 DOI: 10.1155/2023/8887091

Qiongqiong Gao, Zhentao Gao, Minzhi Su, Yong Huang, Chi Zhang, Cuiping Li, Hailun Zhan, Bolong Liu, Xiangfu Zhou

Interstitial cystitis/bladder pain syndrome (IC/BPS) seriously reduces the patient’s quality of life, yet current therapies only provide partial relief. In the spinal dorsal horn (SDH), neuroinflammation plays a pivotal role in the development of IC. Injection of human umbilical cord mesenchymal stem cells (hUMSCs) to reduce inflammation is an effective strategy, and heme oxygenase-1 (HO-1) exhibits anti-nociceptive effect in neuroinflammatory pain. This study aimed to test the therapeutic effects of hUMSCs overexpressing HO-1 on cyclophosphamide-induced cystitis rat model. Cystitis rats were transplanted with altered cells and then assessed for 3 weeks. A series of behavioral measurements would be trial including suprapubic mechanical allodynia, depressive-like behaviors, micturition frequency, and short-term memory function. Additionally, western blot, immunofluorescence staining, and ELISA kit test for anti-inflammation effect. HUMSCs were capable of being transduced to overexpress HO-1. Injection of hUMSCs overexpressing HO-1 was more effective than hUMSCs alone in alleviating behavioral symptoms in rats. Furthermore, hUMSCs overexpressing HO-1 inhibited the activation of glial and TLR4/p65/NLRP3 pathway, decreased the levels of pro-inflammatory cytokines in the SDH region. Surprisingly, it markedly increased anti-inflammatory cytokine IL-10, reduced MDA content, and protected GSH concentrations in local environment. Our results suggest that injecting hUMSCs overexpressing HO-1 intrathecally can significantly promote functional outcomes in cystitis rats by reducing neuroinflammation, at least, partly through downregulating TLR4/p65/NLRP3 signaling pathway in the SDH region. This cell therapy affords a new strategy for IC/BPS treatment.

间质性膀胱炎/膀胱疼痛综合征(IC/BPS)严重降低患者的生活质量，但目前的治疗只能提供部分缓解。在脊髓背角(SDH)中，神经炎症在IC的发展中起着关键作用。注射人脐带间充质干细胞(hUMSCs)减少炎症是一种有效的策略，血红素加氧酶-1 (HO-1)在神经炎症性疼痛中具有抗伤害性作用。本研究旨在检测过表达HO-1的hUMSCs对环磷酰胺性膀胱炎大鼠模型的治疗作用。膀胱炎大鼠移植改变后的细胞，然后评估3周。包括耻骨上机械性异常性痛、抑郁样行为、排尿频率和短期记忆功能等一系列行为指标。western blot、免疫荧光染色、ELISA试剂盒检测抗炎效果。HUMSCs能够被转导至过表达HO-1。在缓解大鼠行为症状方面，注射过表达HO-1的hUMSCs比单独注射hUMSCs更有效。此外，过表达HO-1的hUMSCs抑制了胶质通路和TLR4/p65/NLRP3通路的激活，降低了SDH区域的促炎细胞因子水平。令人惊讶的是，它显著增加抗炎细胞因子IL-10，降低MDA含量，并保护局部环境中GSH浓度。我们的研究结果表明，鞘内注射过表达HO-1的hUMSCs可以通过减少神经炎症显著改善膀胱炎大鼠的功能结局，至少部分是通过下调SDH区域的TLR4/p65/NLRP3信号通路。这种细胞疗法为IC/BPS的治疗提供了一种新的策略。

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引用次数: 0

CRISPR/Cas9 Genome Editing in LGMD2A/R1 Patient-Derived Induced Pluripotent Stem and Skeletal Muscle Progenitor Cells CRISPR/Cas9基因组编辑在LGMD2A/R1患者来源的诱导多能干细胞和骨骼肌祖细胞中的应用

3区医学 Q2 CELL & TISSUE ENGINEERING

Stem Cells International

Pub Date : 2023-11-09 DOI: 10.1155/2023/9246825

Lampros Mavrommatis, Abdul Zaben, Urs Kindler, Marie-Cécile Kienitz, Julienne Dietz, Hyun-Woo Jeong, Pierre Böhme, Beate Brand-Saberi, Matthias Vorgerd, Holm Zaehres

Large numbers of Calpain 3 (CAPN3) mutations cause recessive forms of limb-girdle muscular dystrophy (LGMD2A/LGMDR1) with selective atrophy of the proximal limb muscles. We have generated induced pluripotent stem cells (iPSC) from a patient with two mutations in exon 3 and exon 4 at the calpain 3 locus (W130C, 550delA). Two different strategies to rescue these mutations are devised: (i) on the level of LGMD2A-iPSC, we combined CRISPR/Cas9 genome targeting with a FACS and Tet transactivator-based biallelic selection strategy, which resulted in a new functional chimeric exon 3-4 without the two CAPN3 mutations. (ii) On the level of LGMD2A-iPSC-derived CD82+/Pax7+ myogenic progenitor cells, we demonstrate CRISPR/Cas9 mediated rescue of the highly prevalent exon 4 CAPN3 mutation. The first strategy specifically provides isogenic LGMD2A corrected iPSC for disease modelling, and the second strategy can be further elaborated for potential translational approaches.

大量的Calpain 3 (CAPN3)突变导致隐性的肢带性肌营养不良(LGMD2A/LGMDR1)，伴有近端肢体肌肉的选择性萎缩。我们从一个calpain3位点(W130C, 550delA)外显子3和外显子4有两个突变的患者身上获得了诱导多能干细胞(iPSC)。设计了两种不同的策略来挽救这些突变:(i)在LGMD2A-iPSC水平上，我们将CRISPR/Cas9基因组靶向与基于FACS和Tet转录激活子的双等位基因选择策略结合起来，产生了一个新的功能嵌合外显子3-4，没有两个CAPN3突变。(ii)在lgmd2a - ipsc衍生的CD82+/Pax7+肌源性祖细胞水平上，我们证明了CRISPR/Cas9介导的高度普遍的外显子4 CAPN3突变的修复。第一种策略专门为疾病建模提供了等基因LGMD2A校正的iPSC，第二种策略可以进一步阐述潜在的翻译方法。

引用次数: 0

Adipose-Derived Mesenchymal Stem Cell Facilitate Hematopoietic Stem Cell Proliferation via the Jagged-1/Notch-1/Hes Signaling Pathway 脂肪源性间充质干细胞通过Jagged-1/Notch-1/Hes信号通路促进造血干细胞增殖

3区医学 Q2 CELL & TISSUE ENGINEERING

Stem Cells International

Pub Date : 2023-11-09 DOI: 10.1155/2023/1068405

Hongbo Wang, Xiaojuan Bi, Rongyao Zhang, Hailong Yuan, Jianli Xu, Kaile Zhang, Songqing Qi, Xue Zhang, Ming Jiang

Background. Poor graft function (PGF) is a life-threatening complication following hematopoietic stem cell transplantation (HSCT). Current therapies, such as CD34+ cell infusion, have shown limited effectiveness. Conversely, mesenchymal stem cells (MSCs) show potential in addressing PGF. Adipose-derived mesenchymal stem cells (ADSCs) effectively support long-term hematopoietic stem cell proliferation. Therefore, this study aimed to investigate the mechanisms underlying the long-term hematopoietic support provided by ADSCs. Methods. ADSCs were isolated from mice and subsequently identified. In vitro experiments involved coculturing ADSCs as feeders with Lin-Sca-1+c-kit+ (LSK) cells from mice for 2 and 5 weeks. The number of LSK cells was quantified after coculture. Scanning electron microscopy was utilized to observe the interaction between ADSCs and LSK cells. Hes-1 expression was assessed using western blot and real-time quantitative PCR. An γ-secretase inhibitor (GSI) was used to confirm the involvement of the Jagged-1/Notch-1/Hes-1 pathway in LSK cell expansion. Additionally, Jagged-1 was knocked down in ADSCs to demonstrate its significance in ADSC-mediated hematopoietic support. In vivo experiments were conducted to study the hematopoietic support provided by ADSCs through the infusion of LSK, LSK + fibroblasts, and LSK + ADSCs, respectively. Mouse survival, platelet count, leukocyte count, and hemoglobin levels were monitored. Results. ADSCs showed high-Jagged-1 expression and promoted LSK cell proliferation. There was a direct interaction between ADSCs and LSK cells. After coculture, Hes-1 expression increased in LSK cells. Moreover, GSI-reduced LSK cell proliferation and Hes-1 expression. Knockdown of Jagged-1 attenuated ADSCs-mediated promotion of LSK cell proliferation. Furthermore, ADSCs facilitated hematopoietic recovery and promoted the survival of NOD/SCID mice. Conclusion. The hematopoietic support provided by ADSCs both in vivo and in vitro may be mediated, at least in part, through the Jagged-1/Notch-1 signaling pathway. These findings provide valuable insights into the mechanisms underlying ADSCs-mediated hematopoietic support and may have implications for improving the treatment of PGF following HSCT.

背景。移植功能差(PGF)是造血干细胞移植(HSCT)后危及生命的并发症。目前的治疗方法，如CD34+细胞输注，已经显示出有限的效果。相反，间充质干细胞(MSCs)显示出解决PGF的潜力。脂肪来源的间充质干细胞(ADSCs)有效地支持长期造血干细胞增殖。因此，本研究旨在探讨ADSCs提供长期造血支持的机制。方法。从小鼠中分离ADSCs并随后进行鉴定。体外实验将ADSCs与小鼠的Lin-Sca-1+c-kit+ (LSK)细胞共培养2周和5周。共培养后定量LSK细胞数量。利用扫描电镜观察ADSCs与LSK细胞的相互作用。采用western blot和实时定量PCR检测Hes-1的表达。用γ-分泌酶抑制剂(GSI)证实Jagged-1/Notch-1/Hes-1通路参与LSK细胞扩增。此外，Jagged-1在adsc中被敲除，以证明其在adsc介导的造血支持中的重要性。通过体内实验分别研究了LSK、LSK +成纤维细胞和LSK + ADSCs对ADSCs的造血支持作用。监测小鼠存活率、血小板计数、白细胞计数和血红蛋白水平。结果。ADSCs高表达jagged -1，促进LSK细胞增殖。ADSCs与LSK细胞之间存在直接相互作用。共培养后，hes1在LSK细胞中的表达增加。此外，gsi降低了LSK细胞的增殖和hes1的表达。Jagged-1的敲除减弱了adscs介导的LSK细胞增殖促进。此外，ADSCs促进造血功能恢复，促进NOD/SCID小鼠的存活。结论。ADSCs在体内和体外提供的造血支持可能至少部分是通过Jagged-1/Notch-1信号通路介导的。这些发现为adscs介导的造血支持机制提供了有价值的见解，并可能对改善HSCT后PGF的治疗具有启示意义。

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引用次数: 0