JOR Spine最新文献_第6页

Intradiscal administration of autologous platelet-rich plasma in patients with Modic type 1 associated low back pain: A prospective pilot study 自体富血小板血浆在莫迪奇 1 型腰痛患者中的椎间盘内给药：前瞻性试点研究

IF 3.7 3区医学 Q1 Medicine

JOR Spine

Pub Date : 2024-03-18 DOI: 10.1002/jsp2.1320

Soya Kawabata, Sota Nagai, Kei Ito, Hiroki Takeda, Daiki Ikeda, Yusuke Kawano, Shinjiro Kaneko, Yukako Shiraishi, Yuichiro Sano, Yoshiharu Ohno, Nobuyuki Fujita

Background

Various treatments for chronic low back pain (LBP) have been reported; among them, platelet-rich plasma (PRP) as a regenerative medicine has attracted much attention. Although Modic type 1 change (MC1) is associated with LBP, no treatment has been established so far. In addition, no studies have administered PRP to intervertebral discs (IVDs) in patients with LBP, targeting MC1 only. Thus, the purpose of this study was to determine the safety and efficacy of PRP administration to the IVDs in patients with MC1 experiencing LBP.

Methods

PRP was injected intradiscally to 10 patients with MC1 experiencing LBP. Patients were followed prospectively for up to 24 weeks after primary administration. Physical condition, laboratory data, and lumbar x-ray images were evaluated for safety assessment. Furthermore, to evaluate the effectiveness of PRP, patient-reported outcomes were considered. In addition, changes in MC1 were assessed using magnetic resonance imaging (MRI).

Results

There were no adverse events in the laboratory data or lumbar X-ray images after administration. The mean visual analog scale, which was 70.0 ± 13.3 before the treatment, significantly decreased 1 week after PRP administration and was 39.0 ± 28.8 at the last observation. Oswestry disability index and Roland Morris disability questionnaire scores promptly improved after treatment, and both improved significantly 24 weeks after PRP administration. Follow-up MRI 24 weeks after treatment showed a significant decrease in the mean high-signal intensity of fat-suppressed T2-weighted imaging from 10.1 to 7.90 mm² compared with that before PRP administration.

Conclusions

The safety and efficacy of PRP administration to the IVDs of patients with MC1 experiencing LBP were identified. Post-treatment MRI suggested improvement in inflammation, speculating that PRP suppressed inflammation and consequently relieved the patient's symptoms. Despite the small number of patients, this treatment is promising for patients with MC1 experiencing LBP. The study protocol has been reviewed and approved by the Certified Committee for Regenerative Medicine and the Japanese Ministry of Health, Labor and Welfare (Japan Registry of Clinical Trials [jRCT] No. jRCTb042210159).

背景已经报道了多种治疗慢性腰背痛（LBP）的方法，其中作为再生医学的富血小板血浆（PRP）备受关注。虽然莫迪奇 1 型改变（MC1）与腰背痛有关，但迄今为止尚未确定治疗方法。此外，也没有任何研究仅针对 MC1 对椎间盘（IVD）注射 PRP。因此，本研究旨在确定对患有 MC1 的椎间盘突出症患者施用 PRP 的安全性和有效性。方法为 10 名腰痛的 MC1 患者在腹腔内注射 PRP。在初次给药后，对患者进行了长达 24 周的前瞻性随访。对患者的身体状况、实验室数据和腰椎 X 光图像进行评估，以进行安全性评估。此外，为了评估 PRP 的有效性，还考虑了患者报告的结果。此外，还使用磁共振成像（MRI）评估了 MC1 的变化。结果用药后，实验室数据和腰椎 X 光图像均未出现不良反应。治疗前的平均视觉模拟量表为（70.0 ± 13.3），注射 PRP 1 周后显著下降，最后一次观察时为（39.0 ± 28.8）。奥斯韦特里残疾指数和罗兰-莫里斯残疾问卷评分在治疗后迅速改善，在注射 PRP 24 周后均有明显改善。治疗 24 周后的磁共振成像随访显示，与使用 PRP 前相比，脂肪抑制 T2 加权成像的平均高信号强度从 10.1 mm2 显著降至 7.90 mm2。结论对腰椎间盘突出症 MC1 患者的 IVD 施用 PRP 具有安全性和有效性。治疗后的磁共振成像显示炎症有所改善，推测 PRP 抑制了炎症，从而缓解了患者的症状。尽管患者人数较少，但这种治疗方法对于患有枸杞多糖症的 MC1 患者来说前景广阔。该研究方案已通过再生医学认证委员会和日本厚生劳动省的审查和批准（日本临床试验登记[jRCT]编号：jRCTb042210159）。

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引用次数: 0

Correction to ‘Recommendations for intervertebral disc notochordal cell investigation: From isolation to characterization’ 对 "椎间盘脊索间细胞调查建议 "的更正：从分离到定性

IF 3.7 3区医学 Q1 Medicine

JOR Spine

Pub Date : 2024-03-04 DOI: 10.1002/jsp2.1317

Williams RJ, Laagland LT, Bach FC, Ward L, Chan W, Tam V, Medzikovic A, Basatvat S, Paillat L, Vedrenne N, Snuggs JW, Poramba-Liyanage DW, Hoyland JA, Chan D, Camus A, Richardson SM, Tryfonidou MA, Le Maitre CL. Recommendations for intervertebral disc notochordal cell investigation: From isolation to characterization. JOR Spine 2023;6:e1272. doi: 10.1002/jsp2.1272

The article cited above omitted an ethical review statement regarding access to human fetal samples used as examples within Figure 2 and prior development of the extractions methodology as recommended:

Ethics Statement

Fetal samples utilised in this study were obtained from full informed consent following medical or surgical pregnancy termination and were approved by the National Research Ethics Committee (UK) (Fetal approval number: 13/NW/0205, Paediatric approval number: 12/NW/0437).

In addition, there was a minor error in the Author Contributions; the correct text is shown below.

Rebecca J. Williams, Lisanne T. Laagland, Frances C. Bach, Lizzy Ward, Shaghayegh Basatvat, Wilson Chan, Joseph W. Snuggs, and Lily Paillat contributed to acquisition of laboratory data (Rebecca J. Williams: Porcine and Rat isolation, numeration studies, characterization, and culture; Lisanne T. Laagland: Canine and porcine isolation and characterization; Frances C. Bach: canine, and porcine isolation; Lizzy Ward: human isolation; Shaghayegh Basatvat: porcine isolation; Wilson Chan: mouse isolation; Joseph W. Snuggs: rat isolation, monolayer culture, and characterization; Lily Paillat: mouse isolation).

We apologize for this error.

Williams RJ、Laagland LT、Bach FC、Ward L、Chan W、Tam V、Medzikovic A、Basatvat S、Paillat L、Vedrenne N、Snuggs JW、Poramba-Liyanage DW、Hoyland JA、Chan D、Camus A、Richardson SM、Tryfonidou MA、Le Maitre CL。椎间盘脊索间细胞研究建议：从分离到表征。JOR Spine 2023;6:e1272. doi: 10.1002/jsp2.1272上述文章遗漏了有关获取图 2 中用作示例的人类胎儿样本的伦理审查声明，以及事先开发提取方法的建议：伦理声明本研究中使用的胎儿样本是在医疗或手术终止妊娠后经完全知情同意获得的，并已获得英国国家研究伦理委员会批准（胎儿批准号：13/NW/0205，儿科批准号：12/NW/0437）。Rebecca J. Williams、Lisanne T. Laagland、Frances C. Bach、Lizzy Ward、Shaghayegh Basatvat、Wilson Chan、Joseph W. Snuggs 和 Lily Paillat 对实验室数据的采集做出了贡献（Rebecca J. Williams：猪和大鼠的分离、编号研究、特征描述和培养；Lisanne T. Laagland：Frances C. Bach：犬和猪分离；Lizzy Ward：人类分离；Shaghayegh Basatvat：猪分离；Wilson Chan：小鼠分离；Joseph W. Snuggs：大鼠分离、单层培养和特征描述；Lily Paillat：小鼠分离。

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引用次数: 0

Comparative analysis of paraspinal muscle imbalance between idiopathic scoliosis and congenital scoliosis from the transcriptome aspect 从转录组角度比较分析特发性脊柱侧弯症和先天性脊柱侧弯症的脊柱旁肌肉失衡问题

IF 3.7 3区医学 Q1 Medicine

JOR Spine

Pub Date : 2024-03-04 DOI: 10.1002/jsp2.1318

Zhen Wang, Junduo Zhao, Haining Tan, Yang Jiao, Xin Chen, Jianxiong Shen

Background

Previous studies have analyzed paraspinal muscle imbalance in idiopathic scoliosis (IS) with methods including imaging, histology and electromyography. However, whether paraspinal muscle imbalance is the cause or the consequence of spinal deformities in IS remains unclear. Comparison of paraspinal muscle imbalance between IS and congenital scoliosis (CS) may shed some light on the causality of paraspinal muscle imbalance and IS. This study aimed to elucidate the generality and individuality of paraspinal muscle imbalance between IS and CS from gene expression.

Methods

Five pairs of surgical-treated IS and CS patients were matched. Bilateral paraspinal muscles at the apex were collected for transcriptome sequencing. Differentially expressed genes (DEGs) between the convexity and concavity in both IS and CS were identified. Comparison of DEGs between IS and CS was conducted to discriminate IS-specific DEGs from DEGs shared by both IS and CS. Bioinformatics analysis was performed. The top 10 hub genes in the protein–protein interaction (PPI) network of IS-specific DEGs were validated by quantitative PCR (qPCR) in 10 pairs of IS and CS patients.

Results

A total of 370 DEGs were identified in IS, whereas 380 DEGs were identified in CS. Comparison of DEGs between IS and CS identified 59 DEGs shared by IS and CS, along with 311 DEGs specific for IS. These IS-specific DEGs were enriched in response to external stimulus and signaling receptor binding in GO terms and calcium signaling pathway in KEGG pathways. The top 10 hub genes in the PPI network of IS-specific DEGs include BDKRB1, PRH1-TAS2R14, CNR2, NPY4R, HTR1E, CXCL3, ICAM1, ALB, ADIPOQ, and GCGR. Among these hub genes, the asymmetrical expression of PRH1-TAS2R14 and ADIPOQ in IS but not CS were validated by qPCR.

Conclusions

Transcriptomic differences in bilateral paraspinal muscles between the convexity and concavity in IS share few similarities with those in CS.

背景以往的研究通过影像学、组织学和肌电图等方法分析了特发性脊柱侧弯症（IS）的脊柱旁肌肉失衡。然而，脊柱旁肌肉失衡是导致特发性脊柱侧弯症脊柱畸形的原因还是结果仍不清楚。比较IS和先天性脊柱侧弯症（CS）的脊柱旁肌肉失衡可能会对脊柱旁肌肉失衡和IS的因果关系有所启发。本研究旨在从基因表达的角度阐明IS和CS脊柱旁肌肉失衡的普遍性和个体性。方法对五对经过手术治疗的 IS 和 CS 患者进行配对。采集双侧脊柱旁顶点肌肉进行转录组测序。确定了IS和CS凸面和凹面之间的差异表达基因（DEGs）。对 IS 和 CS 的 DEGs 进行比较，以区分 IS 特异的 DEGs 和 IS 与 CS 共享的 DEGs。进行了生物信息学分析。在10对IS和CS患者中通过定量PCR（qPCR）验证了IS特异性DEGs的蛋白-蛋白相互作用（PPI）网络中的前10个枢纽基因。结果在 IS 中发现了 370 个 DEGs，而在 CS 中发现了 380 个 DEGs。通过比较 IS 和 CS 的 DEGs，发现 IS 和 CS 共有 59 个 DEGs，IS 特异的 DEGs 有 311 个。这些IS特异的DEGs在GO术语中富集于对外部刺激的反应和信号受体结合，在KEGG通路中富集于钙信号通路。在 IS 特异性 DEGs 的 PPI 网络中，前 10 个枢纽基因包括 BDKRB1、PRH1-TAS2R14、CNR2、NPY4R、HTR1E、CXCL3、ICAM1、ALB、ADIPOQ 和 GCGR。在这些枢纽基因中，通过 qPCR 验证了 PRH1-TAS2R14 和 ADIPOQ 在 IS 中的非对称表达，而在 CS 中则没有。结论 IS 双侧脊柱旁肌肉凸面和凹面的转录组差异与 CS 几乎没有相似之处。

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引用次数: 0

Evaluating the causal effect of atherosclerosis on the risk of intervertebral disc degeneration 评估动脉粥样硬化对椎间盘退化风险的因果影响

IF 3.7 3区医学 Q1 Medicine

JOR Spine

Pub Date : 2024-03-04 DOI: 10.1002/jsp2.1319

Yang-Ting Cai, Xian-Xing Zhong, Ling Mo, Rui-Ze Huang, Qiang Lin, Cai-Jun Liu, Shun-Cong Zhang

Background

Intervertebral disc degeneration (IDD) and atherosclerosis are two common age-related conditions that can cause significant morbidity. While previous studies have suggested an association between the two conditions, the nature of this association remains unclear.

Methods

We used Mendelian randomization (MR) to investigate the causal relationship between IDD and atherosclerosis. We identified genetic variants associated with IDD using summary statistics from a large genome-wide association study (GWAS). These variants were then used as instrumental variables to infer causal relationships with atherosclerosis in summary statistics from a separate GWAS.

Results

Our MR analysis provided evidence for a causal relationship between IDD and atherosclerosis. We found that the genetic predisposition to atherosclerosis was associated with a higher risk of IDD (odds ratio [OR] = 3.55, 95% confidence interval [CI]: 1.07–11.74, p = 0.04). The IVW estimates were consistent with the observational findings and other robust MR methods. Sensitivity analyses suggested that our findings were robust to potential sources of bias.

Conclusions

Our study provides evidence for a causal link between IDD and atherosclerosis, suggesting that interventions targeting atherosclerosis could have potential benefits for reducing the risk of IDD. Further research is needed to explore the underlying mechanisms that link these two conditions and to investigate potential therapeutic interventions.

背景椎间盘退变（IDD）和动脉粥样硬化是两种常见的与年龄有关的疾病，可导致严重的发病率。虽然以前的研究表明这两种疾病之间存在关联，但这种关联的性质仍不清楚。方法我们采用孟德尔随机法（MR）研究 IDD 和动脉粥样硬化之间的因果关系。我们利用大型全基因组关联研究（GWAS）的汇总统计数据确定了与 IDD 相关的遗传变异。然后将这些变异作为工具变量，从另一项全基因组关联研究的汇总统计中推断与动脉粥样硬化的因果关系。结果我们的磁共振分析为 IDD 与动脉粥样硬化之间的因果关系提供了证据。我们发现，动脉粥样硬化的遗传易感性与较高的 IDD 风险相关（比值比 [OR] = 3.55，95% 置信区间 [CI]：1.07-11.74，p = 0.04）。IVW估计值与观察结果和其他稳健的磁共振方法一致。敏感性分析表明，我们的研究结果对潜在的偏倚来源是稳健的。结论我们的研究为 IDD 与动脉粥样硬化之间的因果关系提供了证据，表明针对动脉粥样硬化的干预措施可能对降低 IDD 风险有益。还需要进一步的研究来探索将这两种疾病联系在一起的潜在机制，并调查潜在的治疗干预措施。

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引用次数: 0

The role of the complement system in disc degeneration and Modic changes 补体系统在椎间盘退变和莫迪变化中的作用

IF 3.7 3区医学 Q1 Medicine

JOR Spine

Pub Date : 2024-02-02 DOI: 10.1002/jsp2.1312

Irina Heggli, Graciosa Q. Teixeira, James C. Iatridis, Cornelia Neidlinger-Wilke, Stefan Dudli

Disc degeneration and vertebral endplate bone marrow lesions called Modic changes are prevalent spinal pathologies found in chronic low back pain patients. Their pathomechanisms are complex and not fully understood. Recent studies have revealed that complement system proteins and interactors are dysregulated in disc degeneration and Modic changes. The complement system is part of the innate immune system and plays a critical role in tissue homeostasis. However, its dysregulation has also been associated with various pathological conditions such as rheumatoid arthritis and osteoarthritis. Here, we review the evidence for the involvement of the complement system in intervertebral disc degeneration and Modic changes. We found that only a handful of studies reported on complement factors in Modic changes and disc degeneration. Therefore, the level of evidence for the involvement of the complement system is currently low. Nevertheless, the complement system is tightly intertwined with processes known to occur during disc degeneration and Modic changes, such as increased cell death, autoantibody production, bacterial defense processes, neutrophil activation, and osteoclast formation, indicating a contribution of the complement system to these spinal pathologies. Based on these mechanisms, we propose a model how the complement system could contribute to the vicious cycle of tissue damage and chronic inflammation in disc degeneration and Modic changes. With this review, we aim to highlight a currently understudied but potentially important inflammatory pathomechanism of disc degeneration and Modic changes that may be a novel therapeutic target.

椎间盘退变和椎体终板骨髓病变（称为莫迪克病变）是慢性腰背痛患者普遍存在的脊柱病变。其病理机制复杂，尚未完全明了。最近的研究发现，在椎间盘变性和 Modic 病变中，补体系统蛋白和相互作用因子失调。补体系统是先天性免疫系统的一部分，在组织稳态中发挥着关键作用。然而，它的失调也与类风湿性关节炎和骨关节炎等多种病症有关。在此，我们回顾了补体系统参与椎间盘退变和莫迪变化的证据。我们发现，只有少数研究报告了莫迪奇变化和椎间盘退变中的补体因素。因此，目前关于补体系统参与的证据水平还很低。然而，补体系统与已知的椎间盘退变和莫迪氏病变过程密切相关，如细胞死亡增加、自身抗体产生、细菌防御过程、中性粒细胞活化和破骨细胞形成等，这表明补体系统对这些脊柱病变有一定的作用。基于这些机制，我们提出了一个模型，说明补体系统如何在椎间盘退变和 Modic 病变中促成组织损伤和慢性炎症的恶性循环。通过这篇综述，我们旨在强调椎间盘退变和莫迪氏病变的一个目前未被充分研究但却具有潜在重要性的炎症病理机制，它可能成为一个新的治疗靶点。

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引用次数: 0

Integrated DNA methylation analysis reveals a potential role for PTPRN2 in Marfan syndrome scoliosis DNA 甲基化综合分析揭示了 PTPRN2 在马凡氏综合征脊柱侧凸中的潜在作用。

IF 3.7 3区医学 Q1 Medicine

JOR Spine

Pub Date : 2024-01-29 DOI: 10.1002/jsp2.1304

Zhen-zhong Zheng, Jing-hong Xu, Jia-lin Chen, Bin Jiang, Hong Ma, Lei Li, Ya-wei Li, Yu-liang Dai, Bing Wang

Background

Marfan syndrome (MFS) is a rare genetic disorder caused by mutations in the Fibrillin-1 gene (FBN1) with significant clinical features in the skeletal, cardiopulmonary, and ocular systems. To gain deeper insights into the contribution of epigenetics in the variability of phenotypes observed in MFS, we undertook the first analysis of integrating DNA methylation and gene expression profiles in whole blood from MFS and healthy controls (HCs).

Methods

The Illumina 850K (EPIC) DNA methylation array was used to detect DNA methylation changes on peripheral blood samples of seven patients with MFS and five HCs. Associations between methylation levels and clinical features of MFS were analyzed. Subsequently, we conducted an integrated analysis of the outcomes of the transcriptome data to analyze the correlation between differentially methylated positions (DMPs) and differentially expressed genes (DEGs) and explore the potential role of methylation-regulated DEGs (MeDEGs) in MFS scoliosis. The weighted gene co-expression network analysis was used to find gene modules with the highest correlation coefficient with target MeDEGs to annotate their functions in MFS.

Results

Our study identified 1253 DMPs annotated to 236 genes that were primarily associated with scoliosis, cardiomyopathy, and vital capacity. These conditions are typically associated with reduced lifespan in untreated MFS. We calculated correlations between DMPs and clinical features, such as cobb angle to evaluate scoliosis and FEV1% to assess pulmonary function. Notably, cg20223687 (PTPRN2) exhibited a positive correlation with cobb angle of scoliosis, potentially playing a role in ERKs inactivation.

Conclusions

Taken together, our systems-level approach sheds light on the contribution of epigenetics to MFS and offers a plausible explanation for the complex phenotypes that are linked to reduced lifespan in untreated MFS patients.

背景：马凡综合征（MFS）是由纤连蛋白-1基因（FBN1）突变引起的一种罕见遗传性疾病，在骨骼、心肺和眼部系统具有显著的临床特征。为了深入了解表观遗传学在 MFS 表型变异中的作用，我们首次对 MFS 和健康对照组（HCs）全血的 DNA 甲基化和基因表达谱进行了整合分析：方法：使用Illumina 850K (EPIC) DNA甲基化阵列检测7名MFS患者和5名健康对照者外周血样本的DNA甲基化变化。分析了甲基化水平与 MFS 临床特征之间的关联。随后，我们对转录组数据的结果进行了综合分析，分析了差异甲基化位点（DMPs）与差异表达基因（DEGs）之间的相关性，并探讨了甲基化调控的DEGs（MeDEGs）在MFS脊柱侧凸中的潜在作用。通过加权基因共表达网络分析，找到与目标 MeDEGs 相关系数最高的基因模块，以注释它们在 MFS 中的功能：我们的研究发现了1253个DMPs，注释了236个基因，这些基因主要与脊柱侧弯、心肌病和生命能力有关。这些情况通常与未经治疗的 MFS 的寿命缩短有关。我们计算了 DMP 与临床特征之间的相关性，如评估脊柱侧弯的 cobb 角和评估肺功能的 FEV1%。值得注意的是，cg20223687（PTPRN2）与脊柱侧弯的柯布角呈正相关，可能在ERKs失活中发挥作用：综上所述，我们的系统水平方法揭示了表观遗传学对 MFS 的贡献，并为 MFS 患者未经治疗而寿命缩短的复杂表型提供了合理的解释。

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引用次数: 0

Dynamics of N6-methyladenosine modification during aging and their potential roles in the degeneration of intervertebral disc 老化过程中 N6-甲基腺苷修饰的动态变化及其在椎间盘退化中的潜在作用。

IF 3.7 3区医学 Q1 Medicine

JOR Spine

Pub Date : 2024-01-25 DOI: 10.1002/jsp2.1316

Libangxi Liu, Hong Sun, Yang Zhang, Chang Liu, Yong Zhuang, Miao Liu, Xuezheng Ai, Dan Long, Bo Huang, Changqing Li, Yue Zhou, Shiwu Dong, Chencheng Feng

Background

The N6-methyladenosine (m6A) dynamics in the progression of intervertebral disc (IVD) aging remain largely unknown. This study aimed to explore the distribution and pattern of m⁶A modification in nucleus pulpous (NP) tissues of rats at different ages.

Methods

Histological staining and MRI were performed to evaluate the degeneration of IVD. The expression of m6A modifiers was analyzed using qRT-PCR and western blot. Subsequently, methylated RNA immunoprecipitation next generation sequencing and RNA-seq were conducted to identify differences in m6A methylome and transcriptome of NP tissues.

Results

Compared to 2-month-old rats, we found significant changes in the global m6A level and the expression of Mettl3 and FTO in NP tissues from 20-month-old rats. During the progression of NP aging, there were 1126 persistently differentially m6A peaks within 931 genes, and 51 persistently differentially expressed genes. GO and KEGG analyses showed that these m6A peaks and m6A modified genes were mainly engaged in the biological processes and pathways of intervertebral disc degermation (IDD), such as extracellular matrix metabolism, angiogenesis, inflammatory response, mTOR and AMPK signaling pathways. Meanwhile, conjoint analyses and Venn diagram revealed a total of 405 aging related genes contained significant methylation and expression levels in 20-month-old rats in contrast to 2-month-old and 10-month-old rats. Moreover, it was found that four aging related genes with hypermethylated modification including BUB1, CA12, Adamts1, and Adamts4 depicted differentially expressed at protein level, of which BUB1 and CA12 were decreased, while Adamts1 and Adamts4 were increased during the progression of NP aging.

Conclusion

Collectively, this study elucidated the distribution and pattern of m6A modification during the aging of IVD. Furthermore, the m6A modified genes were involved in the IDD related biological processes and pathways. These findings may provide novel insights into the mechanisms and therapies of IDD from the perspective of aging.

背景：N6-甲基腺苷（m6A）在椎间盘（IVD）老化过程中的动态变化在很大程度上仍是未知的。本研究旨在探讨不同年龄大鼠髓核组织中 m6A 修饰物的分布和模式。采用 qRT-PCR 和 Western 印迹法分析 m6A修饰物的表达。随后，进行了甲基化 RNA 免疫沉淀新一代测序和 RNA-seq 分析，以确定 NP 组织中 m6A 甲基组和转录组的差异：结果：与 2 月龄大鼠相比，我们发现 20 月龄大鼠 NP 组织中 m6A 的整体水平以及 Mettl3 和 FTO 的表达均发生了显著变化。在NP衰老过程中，931个基因中有1126个持续差异m6A峰，51个持续差异表达基因。GO和KEGG分析表明，这些m6A峰和m6A修饰基因主要参与椎间盘退化（IDD）的生物学过程和通路，如细胞外基质代谢、血管生成、炎症反应、mTOR和AMPK信号通路等。同时，联合分析和维恩图显示，20月龄大鼠与2月龄和10月龄大鼠相比，共有405个衰老相关基因含有显著的甲基化和表达水平。此外，研究还发现，BUB1、CA12、Adamts1和Adamts4等4个存在高甲基化修饰的衰老相关基因在蛋白水平上存在差异表达，其中BUB1和CA12在NP衰老过程中表达量减少，而Adamts1和Adamts4在NP衰老过程中表达量增加：总之，本研究阐明了 IVD 衰老过程中 m6A 修饰的分布和模式。此外，m6A修饰基因参与了IDD相关的生物学过程和通路。这些发现可能会从衰老的角度为 IDD 的机制和治疗提供新的见解。

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引用次数: 0

Developmental morphogens direct human induced pluripotent stem cells toward an annulus fibrosus-like cell phenotype 发育形态原引导人类诱导多能干细胞形成环状纤维样细胞表型。

IF 3.7 3区医学 Q1 Medicine

JOR Spine

Pub Date : 2024-01-25 DOI: 10.1002/jsp2.1313

Ana P. Peredo, Tonia K. Tsinman, Edward D. Bonnevie, Xi Jiang, Harvey E. Smith, Sarah E. Gullbrand, Nathaniel A. Dyment, Robert L. Mauck

Introduction

Therapeutic interventions for intervertebral disc herniation remain scarce due to the inability of endogenous annulus fibrosus (AF) cells to respond to injury and drive tissue regeneration. Unlike other orthopedic tissues, such as cartilage, delivery of exogenous cells to the site of annular injury remains underdeveloped, largely due to a lack of an ideal cell source and the invasive nature of cell isolation. Human induced pluripotent stem cells (iPSCs) can be differentiated to specific cell fates using biochemical factors and are, therefore, an invaluable tool for cell therapy approaches. While differentiation protocols have been developed for cartilage and fibrous connective tissues (e.g., tendon), the signals that regulate the induction and differentiation of human iPSCs toward the AF fate remain unknown.

Methods

iPSC-derived sclerotome cells were treated with various combinations of developmental signals including transforming growth factor beta 3 (TGF-β3), connective tissue growth factor (CTGF), platelet derived growth factor BB (PDGF-BB), insulin-like growth factor 1 (IGF-1), or the Hedgehog pathway activator, Purmorphamine, and gene expression changes in major AF-associated ECM genes were assessed. The top performing combination treatments were further validated by using three distinct iPSC lines and by assessing the production of upregulated ECM proteins of interest. To conduct a broader analysis of the transcriptomic shifts elicited by each factor combination, and to compare genetic profiles of treated cells to mature human AF cells, a 96.96 Fluidigm gene expression array was applied, and principal component analysis was employed to identify the transcriptional signatures of each cell population and treatment group in comparison to native AF cells.

Results

TGF-β3, in combination with PDGF-BB, CTGF, or IGF-1, induced an upregulation of key AF ECM genes in iPSC-derived sclerotome cells. In particular, treatment with a combination of TGF-β3 with PDGF-BB for 14 days significantly increased gene expression of collagen II and aggrecan and increased protein deposition of collagen I and elastin compared to other treatment groups. Assessment of genes uniquely highly expressed by AF cells or SCL cells, respectively, revealed a shift toward the genetic profile of AF cells with the addition of TGF-β3 and PDGF-BB for 14 days.

Discussion

These findings represent an initial approach to guide human ind

导言：由于内源性纤维环（AF）细胞无法对损伤做出反应并驱动组织再生，因此治疗椎间盘突出症的干预措施仍然很少。与软骨等其他骨科组织不同，将外源性细胞输送到椎间盘环损伤部位的技术仍不发达，这主要是由于缺乏理想的细胞来源以及细胞分离的侵入性。人类诱导多能干细胞（iPSC）可利用生化因子分化为特定的细胞命运，因此是细胞疗法的宝贵工具。虽然已开发出软骨和纤维结缔组织（如肌腱）的分化方案，但调节软骨和纤维结缔组织分化的信号还不明确、肌腱）的分化方案，但调节人类 iPSCs 向房颤命运诱导和分化的信号仍然未知。方法：用各种发育信号组合处理 iPSC 衍生的硬骨细胞，包括转化生长因子 beta 3（TGF-β3）、结缔组织生长因子（CTGF）、血小板衍生生长因子 BB（PDGF-BB）、胰岛素样生长因子 1（IGF-1）或刺猬通路激活剂 Purmorphamine，并评估主要 AF 相关 ECM 基因的基因表达变化。通过使用三种不同的 iPSC 株系和评估上调的相关 ECM 蛋白的生成情况，进一步验证了表现最佳的组合疗法。为了对每种因子组合引起的转录组变化进行更广泛的分析，并将处理过的细胞的基因图谱与成熟的人类房颤细胞进行比较，应用了96.96 Fluidigm基因表达阵列，并采用主成分分析法确定了每个细胞群和处理组与原生房颤细胞相比的转录特征：结果：TGF-β3 与 PDGF-BB、CTGF 或 IGF-1 结合使用可诱导 iPSC 衍生的硬骨体细胞中的关键 AF ECM 基因上调。特别是，与其他处理组相比，TGF-β3 与 PDGF-BB 联合处理 14 天可显著增加胶原蛋白 II 和凝集素的基因表达，并增加胶原蛋白 I 和弹性蛋白的蛋白质沉积。对AF细胞或SCL细胞分别表达的独特高表达基因的评估显示，在添加TGF-β3和PDGF-BB 14天后，AF细胞的基因特征发生了转变：这些发现代表了一种引导人类诱导多能干细胞向AF样命运转变的初步方法，可用于细胞递送策略。

{"title":"Developmental morphogens direct human induced pluripotent stem cells toward an annulus fibrosus-like cell phenotype","authors":"Ana P. Peredo, Tonia K. Tsinman, Edward D. Bonnevie, Xi Jiang, Harvey E. Smith, Sarah E. Gullbrand, Nathaniel A. Dyment, Robert L. Mauck","doi":"10.1002/jsp2.1313","DOIUrl":"10.1002/jsp2.1313","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>Therapeutic interventions for intervertebral disc herniation remain scarce due to the inability of endogenous annulus fibrosus (AF) cells to respond to injury and drive tissue regeneration. Unlike other orthopedic tissues, such as cartilage, delivery of exogenous cells to the site of annular injury remains underdeveloped, largely due to a lack of an ideal cell source and the invasive nature of cell isolation. Human induced pluripotent stem cells (iPSCs) can be differentiated to specific cell fates using biochemical factors and are, therefore, an invaluable tool for cell therapy approaches. While differentiation protocols have been developed for cartilage and fibrous connective tissues (e.g., tendon), the signals that regulate the induction and differentiation of human iPSCs toward the AF fate remain unknown.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>iPSC-derived sclerotome cells were treated with various combinations of developmental signals including transforming growth factor beta 3 (TGF-β3), connective tissue growth factor (CTGF), platelet derived growth factor BB (PDGF-BB), insulin-like growth factor 1 (IGF-1), or the Hedgehog pathway activator, Purmorphamine, and gene expression changes in major AF-associated ECM genes were assessed. The top performing combination treatments were further validated by using three distinct iPSC lines and by assessing the production of upregulated ECM proteins of interest. To conduct a broader analysis of the transcriptomic shifts elicited by each factor combination, and to compare genetic profiles of treated cells to mature human AF cells, a 96.96 Fluidigm gene expression array was applied, and principal component analysis was employed to identify the transcriptional signatures of each cell population and treatment group in comparison to native AF cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>TGF-β3, in combination with PDGF-BB, CTGF, or IGF-1, induced an upregulation of key AF ECM genes in iPSC-derived sclerotome cells. In particular, treatment with a combination of TGF-β3 with PDGF-BB for 14 days significantly increased gene expression of collagen II and aggrecan and increased protein deposition of collagen I and elastin compared to other treatment groups. Assessment of genes uniquely highly expressed by AF cells or SCL cells, respectively, revealed a shift toward the genetic profile of AF cells with the addition of TGF-β3 and PDGF-BB for 14 days.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Discussion</h3>\u0000 \u0000 <p>These findings represent an initial approach to guide human ind","PeriodicalId":14876,"journal":{"name":"JOR Spine","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10810760/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139569689","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

Transcriptomic profiling reveals key early response genes during GDF6-mediated differentiation of human adipose-derived stem cells to nucleus pulposus cells 转录组分析揭示了 GDF6 介导的人脂肪干细胞向髓核细胞分化过程中的关键早期反应基因

IF 3.7 3区医学 Q1 Medicine

JOR Spine

Pub Date : 2024-01-19 DOI: 10.1002/jsp2.1315

Hamish T. J. Gilbert, Francis E. J. Wignall, Leo Zeef, Judith A. Hoyland, Stephen M. Richardson

Background

Stem cell-based therapies show promise as a means of repairing the degenerate intervertebral disc, with growth factors often used alongside cells to help direct differentiation toward a nucleus pulposus (NP)-like phenotype. We previously demonstrated adipose-derived stem cell (ASC) differentiation with GDF6 as optimal for generating NP-like cells through evaluating end-stage differentiation parameters. Here we conducted a time-resolved transcriptomic characterization of ASCs response to GDF6 stimulation to understand the early drivers of differentiation to NP-like cells.

Methods

Human ASCs were treated with recombinant human GDF6 for 2, 6, and 12 h. RNA sequencing and detailed bioinformatic analysis were used to assess differential gene expression, gene ontology (GO), and transcription factor involvement during early differentiation. Quantitative polymerase chain reaction (qPCR) was used to validate RNA sequencing findings and inhibitors used to interrogate Smad and Erk signaling pathways, as well as identify primary and secondary response genes.

Results

The transcriptomic response of ASCs to GDF6 stimulation was time-resolved and highly structured, with “cell differentiation” “developmental processes,” and “response to stimulus” identified as key biological process GO terms. The transcription factor ERG1 was identified as a key early response gene. Temporal cluster analysis of differentiation genes identified positive regulation NP cell differentiation, as well as inhibition of osteogenesis and adipogenesis. A role for Smad and Erk signaling in the regulation of GDF6-induced early gene expression response was observed and both primary and secondary response genes were identified.

Conclusions

This study identifies a multifactorial early gene response that contributes to lineage commitment, with the identification of a number of potentially useful early markers of differentiation of ASCs to NP cells. This detailed insight into the molecular processes in response to GDF6 stimulation of ASCs is important for the development of an efficient and efficacious cell-based therapy for intervertebral disc degeneration-associated back pain.

背景基于干细胞的疗法有望成为修复退化椎间盘的一种手段，通常与细胞一起使用的生长因子有助于引导细胞向髓核（NP）样表型分化。我们之前通过评估末期分化参数，证明了脂肪源性干细胞（ASC）与GDF6的分化是生成NP样细胞的最佳选择。在此，我们对ASCs对GDF6刺激的反应进行了时间分辨转录组学表征，以了解向NP样细胞分化的早期驱动因素。方法用重组人 GDF6 处理人 ASCs 2、6 和 12 小时。使用 RNA 测序和详细的生物信息学分析来评估早期分化过程中的不同基因表达、基因本体（GO）和转录因子参与情况。定量聚合酶链反应（qPCR）用于验证 RNA 测序结果，抑制剂用于检测 Smad 和 Erk 信号通路，以及鉴定主要和次要反应基因。结果 ASCs 对 GDF6 刺激的转录组反应具有时间分辨性和高度结构性，"细胞分化"、"发育过程 "和 "对刺激的反应 "被确定为关键生物过程 GO 术语。转录因子 ERG1 被确定为关键的早期反应基因。分化基因的时间聚类分析确定了对 NP 细胞分化的正向调控，以及对成骨和成脂的抑制。观察到 Smad 和 Erk 信号在调控 GDF6 诱导的早期基因表达反应中的作用，并确定了一级和二级反应基因。结论本研究发现了一种多因素的早期基因应答，这种应答有助于细胞系的承诺，同时还发现了一些潜在的有用的早期标志物，这些标志物可促进 ASCs 向 NP 细胞的分化。详细了解GDF6刺激ASCs的分子反应过程，对于开发高效、有效的细胞疗法治疗椎间盘变性相关背痛非常重要。

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引用次数: 0

Repetitive strikes loading organ culture model to investigate the biological and biomechanical responses of the intervertebral disc 研究椎间盘的生物和生物力学反应的重复冲击加载器官培养模型

IF 3.7 3区医学 Q1 Medicine

JOR Spine

Pub Date : 2024-01-19 DOI: 10.1002/jsp2.1314

Jiaxiang Zhou, Jianmin Wang, Jianfeng Li, Zhengya Zhu, Zhongyuan He, Junhong Li, Tao Tang, Hongkun Chen, Yukun Du, Zhen Li, Manman Gao, Zhiyu Zhou, Yongming Xi

Background

Disc degeneration is associated with repetitive violent injuries. This study aims to explore the impact of repetitive strikes loading on the biology and biomechanics of intervertebral discs (IVDs) using an organ culture model.

Methods

IVDs from the bovine tail were isolated and cultured in a bioreactor, with exposure to various loading conditions. The control group was subjected to physiological loading, while the model group was exposed to either one strike loading (compression at 38% of IVD height) or repetitive one strike loading (compression at 38% of IVD height). Disc height and dynamic compressive stiffness were measured after overnight swelling and loading. Furthermore, histological morphology, cell viability, and gene expression were analyzed on Day 32. Glycosaminoglycan (GAG) and nitric oxide (NO) release in conditioned medium were also analyzed.

Results

The repetitive one strike group exhibited early disc degeneration, characterized by decreased dynamic compression stiffness, the presence of annulus fibrosus clefts, and degradation of the extracellular matrix. Additionally, this group demonstrated significantly higher levels of cell death (p < 0.05) and glycosaminoglycan (GAG) release (p < 0.05) compared to the control group. Furthermore, upregulation of MMP1, MMP13, and ADAMTS5 was observed in both nucleus pulposus (NP) and annulus fibrosus (AF) tissues of the repetitive one strike group (p < 0.05). The one strike group exhibited annulus fibrosus clefts but showed no gene expression changes compared to the control group.

Conclusions

This study shows that repetitive violent injuries lead to the degeneration of a healthy bovine IVDs, thereby providing new insights into early-stage disc degeneration.

背景椎间盘退化与重复性暴力损伤有关。本研究旨在利用器官培养模型探讨重复性打击负荷对椎间盘（IVD）的生物学和生物力学的影响。方法在生物反应器中分离和培养牛尾椎间盘，并将其置于各种加载条件下。对照组承受生理负荷，而模型组则承受单击负荷（以 IVD 高度的 38% 压缩）或重复单击负荷（以 IVD 高度的 38% 压缩）。经过一夜的膨胀和加载后，对椎间盘高度和动态压缩刚度进行了测量。此外，第 32 天还对组织形态、细胞活力和基因表达进行了分析。此外，还分析了条件培养基中糖胺聚糖（GAG）和一氧化氮（NO）的释放情况。结果重复一击组表现出早期椎间盘退变，其特征是动态压缩硬度下降、出现纤维环裂隙和细胞外基质降解。此外，与对照组相比，该组的细胞死亡水平（p < 0.05）和糖胺聚糖（GAG）释放水平（p < 0.05）明显更高。此外，在重复一击组的髓核（NP）和环状纤维（AF）组织中都观察到了 MMP1、MMP13 和 ADAMTS5 的上调（p < 0.05）。与对照组相比，一击组出现环状纤维裂隙，但基因表达无变化。结论本研究表明，重复性暴力损伤会导致健康牛 IVD 退化，从而为早期椎间盘退化提供了新的见解。

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引用次数: 0

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