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Second generation multiple channeling using platelet-rich plasma enhances cartilage repair through recruitment of endogenous MSCs in bone marrow. 使用富血小板血浆的第二代多通道疗法通过招募骨髓中的内源性间充质干细胞增强软骨修复。
IF 5.4 2区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2024-11-02 DOI: 10.1093/stcltm/szae075
Min Ji Lee, Jian Jiang, Soo Hyun Kim, Chris Hyunchul Jo

In the treatment of cartilage defects, a key factor is the adequate and specific recruitment of endogenous stem cells to the site of injury. However, the limited quantity and capability of endogenous bone marrow stem cells (BM MSCs) often result in the formation of fibrocartilage when using bone marrow stimulation (BMS) procedures. We engineered second-generation platelet-rich plasma (2G PRP) with defibrinogenating and antifibrinolytic agents for injection into the condyle of the right femur, followed by multiple channeling (MCh) 5 days later. This approach aims to enhance repair by promoting the local proliferation and migration of BM MSCs to the full-thickness knee cartilage defect (ftKD). In our in vitro study, 2G PRP increased the number of endogenous BM MSCs and their ability to migrate toward an IL-1β-induced inflammatory condition. This significance was further confirmed by in vivo proliferation results after injection of 2G PRP into the condyle of rats. Fifty-four healthy male Sprague-Dawley rats were divided into 3 groups (ftKD, MCh, 2G MCh) for 3 time points (2 weeks, 4 weeks, 8 weeks). The 2G MCh (2G PRP injection + MCh) groups significantly improved cartilage formation at 4 and 8 weeks compared to the ftKD and MCh groups. The 2G MCh initiated cartilage repair earlier than MCh and significantly enhanced up to 8 weeks. This study demonstrated that 2G PRP increased the number of BM MSCs through the enhancement of proliferation and recruitment into the injured site, thereby improving articular cartilage repair.

在软骨缺损的治疗中,一个关键因素是将内源性干细胞充分而有针对性地招募到损伤部位。然而,由于内源性骨髓干细胞(BM MSCs)的数量和能力有限,在使用骨髓刺激(BMS)程序时,往往会导致纤维软骨的形成。我们在第二代富血小板血浆(2G PRP)中加入了去纤维蛋白原化剂和抗纤维蛋白溶解剂,将其注射到右股骨髁部,5天后再进行多通道注射(MCh)。这种方法旨在通过促进骨髓间充质干细胞向全厚膝关节软骨缺损(ftKD)的局部增殖和迁移来加强修复。在我们的体外研究中,2G PRP 增加了内源性 BM 间充质干细胞的数量及其向 IL-1β 诱导的炎症条件下迁移的能力。向大鼠髁突注射 2G PRP 后的体内增殖结果进一步证实了这一意义。54只健康的雄性Sprague-Dawley大鼠被分为3组(ftKD组、MCh组、2G MCh组),共3个时间点(2周、4周、8周)。与ftKD组和MCh组相比,2G MCh组(2G PRP注射+MCh)在4周和8周时明显改善了软骨的形成。2G MCh 比 MCh 更早启动软骨修复,并在 8 周内明显增强。这项研究表明,2G PRP 可通过促进增殖和招募进入损伤部位来增加 BM 间充质干细胞的数量,从而改善关节软骨修复。
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引用次数: 0
Factor 3 regulates airway engraftment by human bronchial basal cells. 因子 3 调节人类支气管基底细胞的气道移植。
IF 5.4 2区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2024-11-01 DOI: 10.1093/stcltm/szae084
Susan D Reynolds, Cynthia L Hill, Alfahdah Alsudayri, Jacob T Stack, Kimberly M Shontz, Gianni Carraro, Barry R Stripp, Tendy Chiang

Cystic fibrosis transmembrane conductance regulator (CFTR) gene editing and transplantation of CFTR-gene corrected airway basal cells has the potential to cure CF lung disease. Although mouse studies established that cell transplantation was feasible, the engraftment rate was typically low and frequently less than the estimated therapeutic threshold. The purpose of this study was to identify genes and culture conditions that regulate the therapeutic potential of human bronchial basal cells. Factor 3 (F3, Tissue Factor 1) is a component of the extrinsic coagulation pathway and activates a cascade of proteases that convert fibrinogen to fibrin. Based on reports that F3 was necessary for human basal cell survival and adhesion in vitro, the present study evaluated F3 as a potential determinant of therapeutic fitness. The gene expression profile of F3 mRNA-positive human bronchial basal cells was evaluated by scRNAseq and the impact of the lung environment on F3 expression was modeled by varying in vitro culture conditions. F3 necessity for adhesion, proliferation, and differentiation was determined by CRISPR/Cas9 knockout (KO) of the F3 gene. Finally, the impact of F3 manipulation on engraftment was determined by orthotropic co-transplantation of wild-type and F3-KO cells into the airways of immunocompromised mice. In contrast with the hypothesis that F3 increases the therapeutic fitness of basal cells, F3 expression decreased engraftment. These studies guide the ongoing development of cellular therapies by showing that in vitro assessments may not predict therapeutic potential and that the lung milieu influences the functional properties of transplanted bronchial basal cells.

囊性纤维化跨膜传导调节器(CFTR)基因编辑和移植经 CFTR 基因校正的气道基底细胞有可能治愈 CF 肺病。虽然小鼠研究证实细胞移植是可行的,但移植率通常很低,经常低于估计的治疗阈值。本研究的目的是找出调节人类支气管基底细胞治疗潜力的基因和培养条件。因子 3(F3,组织因子 1)是外凝血途径的一个组成部分,能激活一连串蛋白酶,将纤维蛋白原转化为纤维蛋白。据报道,F3 是人类基底细胞在体外存活和粘附的必要条件,因此本研究将 F3 作为决定治疗效果的潜在因素进行评估。通过 scRNAseq 评估了 F3 mRNA 阳性的人支气管基底细胞的基因表达谱,并通过改变体外培养条件模拟了肺部环境对 F3 表达的影响。通过 CRISPR/Cas9 敲除(KO)F3 基因,确定了 F3 对粘附、增殖和分化的必要性。最后,通过将野生型和 F3-KO 细胞正交联合移植到免疫缺陷小鼠的气道中,确定了 F3 操作对移植的影响。与F3能提高基础细胞治疗能力的假设相反,F3的表达降低了移植效果。这些研究表明,体外评估可能无法预测治疗潜力,而肺部环境会影响移植支气管基底细胞的功能特性,从而为正在进行的细胞疗法开发提供指导。
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引用次数: 0
Safety and feasibility of umbilical cord blood transplantation in children with neuronal ceroid lipofuscinosis: a retrospective study. 神经细胞类脂膜炎患儿脐带血移植的安全性和可行性:一项回顾性研究。
IF 5.4 2区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2024-10-29 DOI: 10.1093/stcltm/szae080
Andrea Bauchat, Veronika Polishchuk, Vanessa A Fabrizio, Jennifer E Brondon, Kristin M Page, Timothy A Driscoll, Paul L Martin, Kris M Mahadeo, Joanne Kurtzberg, Vinod K Prasad

Ceroid lipofuscinosis neuronal (CLN) encompasses rare inherited neurodegenerative disorders that present in childhood with clinical features including epilepsy, psychomotor delay, progressive vision loss, and premature death. Published experience utilizing umbilical cord blood transplant (UCBT) for these disorders is limited. This retrospective analysis includes patients with CLN (2, 3, and 5) who underwent UCBT from 2012 to 2020. All subjects (n = 8) received standard-of-care myeloablative conditioning. Four also enrolled in clinical trial NCT02254863 and received intrathecal DUOC-01 cells posttransplant. Median age at UCBT was 5.9 years. All subjects achieved neutrophil engraftment with >95% donor chimerism at a median of 28.5 days. Sinusoidal obstructive syndrome was not observed. Severe acute graft-versus-host disease occurred in 12.5%. Other complications included autoimmune hemolytic anemia (25%) and viral reactivation/infection (62.5%). No transplant-related mortality was observed. Two CLN2 patients died, 1 from progressive disease and 1 from unknown cause at days +362 and +937, respectively. With median follow-up of 8 years, overall survival at 100 days and 24 months was 100% and 88%, respectively. Three of 4 CLN3 subjects stabilized Hamburg motor and language scores. While UCBT appears safe and feasible in these patients, given the variable expression and natural history, extended follow-up and further studies are needed to elucidate the potential impact of UCBT on clinical outcomes.

类脂质神经病(CLN)是一种罕见的遗传性神经退行性疾病,在儿童期发病,临床特征包括癫痫、精神运动发育迟缓、进行性视力丧失和过早死亡。已发表的利用脐带血移植(UCBT)治疗这些疾病的经验非常有限。本回顾性分析包括2012年至2020年期间接受脐带血移植的CLN(2、3和5)患者。所有受试者(n = 8)均接受了标准护理的骨髓溶解调理。其中四人还参加了 NCT02254863 临床试验,并在移植后接受了鞘内 DUOC-01 细胞治疗。UCBT时的中位年龄为5.9岁。所有受试者在中位28.5天时都实现了中性粒细胞移植,供体嵌合率大于95%。未观察到窦道阻塞综合征。12.5%的受试者出现了严重的急性移植物抗宿主疾病。其他并发症包括自身免疫性溶血性贫血(25%)和病毒再激活/感染(62.5%)。未观察到与移植相关的死亡率。两名CLN2患者分别在+362天和+937天因疾病进展和不明原因死亡。中位随访时间为 8 年,100 天和 24 个月的总存活率分别为 100% 和 88%。4 名 CLN3 受试者中有 3 人的汉堡运动和语言评分趋于稳定。虽然 UCBT 在这些患者中似乎是安全可行的,但鉴于其表现和自然病史的多变性,还需要延长随访时间并开展进一步研究,以阐明 UCBT 对临床结果的潜在影响。
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引用次数: 0
Development and intra-renal delivery of renal progenitor organoids for effective integration in vivo. 开发肾脏祖细胞器官组织并在肾脏内输送,以实现体内有效整合。
IF 5.4 2区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2024-10-28 DOI: 10.1093/stcltm/szae078
Diana Lim, Ickhee Kim, Qianqian Song, Ji Hyun Kim, Anthony Atala, John D Jackson, James J Yoo

Renal progenitor organoids have been proposed as a source of tissue for kidney regeneration; however, their clinical translatability has not been demonstrated due to an inability to mass-produce comprehensive renal progenitor organoids and the lack of an effective intra-renal delivery platform that facilitates rapid integration into functionally meaningful sites. This study addresses these shortcomings. Human-induced pluripotent stem cells were differentiated into renal progenitor cells using an established protocol and aggregated using a novel assembly method to produce high yields of organoids. Organoids were encapsulated in collagen-based scaffolds for in vitro study and in vivo implantation into mouse renal cortex. In vitro, the organoids demonstrated sustained cell viability and renal structure maturation over time. In vivo delivered organoids showed rapid integration into host renal parenchyma while showing tubular and glomerular-like structure development and maturity markers. This proof-of-concept study presents many promising results, providing a system of renal organoid formation and delivery that may support the development of clinically translatable therapies and the advancement of in vitro renal organoid studies.

肾脏祖细胞器官组织已被提出作为肾脏再生的组织来源;然而,由于无法大规模生产全面的肾脏祖细胞器官组织,以及缺乏有效的肾脏内输送平台以促进快速整合到有功能意义的部位,它们的临床可转化性尚未得到证实。本研究弥补了这些不足。采用既定方案将人类诱导多能干细胞分化成肾脏祖细胞,并采用新颖的组装方法将其聚集,以生产高产量的器官组织。有机体被封装在胶原基支架中,用于体外研究和体内植入小鼠肾皮质。在体外,随着时间的推移,器官组织显示出持续的细胞活力和肾脏结构成熟。体内输送的类器官显示出与宿主肾实质的快速整合,同时显示出肾小管和肾小球样结构的发育和成熟标志。这项概念验证研究提出了许多有前景的结果,提供了一个肾脏类器官形成和输送系统,可支持开发可临床转化的疗法和推进体外肾脏类器官研究。
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引用次数: 0
Correction to: Abstract 11: Multicomponent Cord Blood Bank Program, Beyond Transplantation. 更正:摘要 11:多成分脐带血库计划,超越移植。
IF 5.4 2区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2024-10-24 DOI: 10.1093/stcltm/szae082
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引用次数: 0
Effects of microgravity on human iPSC-derived neural organoids on the International Space Station. 微重力对国际空间站上人类 iPSC 衍生神经器官组织的影响。
IF 5.4 2区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2024-10-23 DOI: 10.1093/stcltm/szae070
Davide Marotta, Laraib Ijaz, Lilianne Barbar, Madhura Nijsure, Jason Stein, Nicolette Pirjanian, Ilya Kruglikov, Twyman Clements, Jana Stoudemire, Paula Grisanti, Scott A Noggle, Jeanne F Loring, Valentina Fossati

Research conducted on the International Space Station (ISS) in low-Earth orbit (LEO) has shown the effects of microgravity on multiple organs. To investigate the effects of microgravity on the central nervous system, we developed a unique organoid strategy for modeling specific regions of the brain that are affected by neurodegenerative diseases. We generated 3-dimensional human neural organoids from induced pluripotent stem cells (iPSCs) derived from individuals affected by primary progressive multiple sclerosis (PPMS) or Parkinson's disease (PD) and non-symptomatic controls, by differentiating them toward cortical and dopaminergic fates, respectively, and combined them with isogenic microglia. The organoids were cultured for a month using a novel sealed cryovial culture method on the International Space Station (ISS) and a parallel set that remained on Earth. Live samples were returned to Earth for analysis by RNA expression and histology and were attached to culture dishes to enable neurite outgrowth. Our results show that both cortical and dopaminergic organoids cultured in LEO had lower levels of genes associated with cell proliferation and higher levels of maturation-associated genes, suggesting that the cells matured more quickly in LEO. This study is continuing with several more missions in order to understand the mechanisms underlying accelerated maturation and to investigate other neurological diseases. Our goal is to make use of the opportunity to study neural cells in LEO to better understand and treat neurodegenerative disease on Earth and to help ameliorate potentially adverse neurological effects of space travel.

在低地轨道国际空间站(ISS)上进行的研究显示了微重力对多个器官的影响。为了研究微重力对中枢神经系统的影响,我们开发了一种独特的类器官策略,用于模拟受神经退行性疾病影响的大脑特定区域。我们从诱导多能干细胞(iPSCs)中生成了三维人类神经类器官,这些干细胞来自原发性进行性多发性硬化症(PPMS)或帕金森病(PD)患者以及无症状对照组,分别向皮质和多巴胺能命运分化,并与同源小胶质细胞结合。在国际空间站(ISS)上使用一种新型密封低温培养方法对这些有机体进行了为期一个月的培养,同时还在地球上进行了平行培养。活体样本被送回地球进行 RNA 表达和组织学分析,并附着在培养皿上以实现神经元的生长。我们的研究结果表明,在低地轨道培养的皮质和多巴胺能器官组织中,与细胞增殖相关的基因水平较低,而与成熟相关的基因水平较高,这表明细胞在低地轨道成熟得更快。这项研究还在继续进行多项任务,以了解加速成熟的机制,并研究其他神经系统疾病。我们的目标是利用在低地轨道研究神经细胞的机会,更好地了解和治疗地球上的神经退行性疾病,并帮助改善太空旅行对神经系统的潜在不利影响。
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引用次数: 0
Mesenchymal stromal cells-derived small extracellular vesicles protect against UV-induced photoaging via regulating pregnancy zone protein. 间充质基质细胞衍生的小细胞外囊泡通过调节孕区蛋白防止紫外线引起的光老化。
IF 5.4 2区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2024-10-19 DOI: 10.1093/stcltm/szae069
Zixuan Sun, Tangrong Wang, Xiaomei Hou, Wenhuan Bai, Jiali Li, Yu Li, Jiaxin Zhang, Yuzhou Zheng, Zhijing Wu, Peipei Wu, Lirong Yan, Hui Qian

Ultraviolet (UV) radiation is the primary extrinsic factor in skin aging, contributing to skin photoaging, actinic keratosis (AK), and even squamous cell carcinoma (SCC). Currently, the beneficial role of mesenchymal stromal cell-derived small extracellular vesicles (MSC-sEVs) in cutaneous wound healing has been widely reported, but the field of photoaging remains to be explored. Our results suggested that human umbilical cord MSC-derived sEVs (hucMSC-sEVs) intervention could effectively alleviate skin photoaging phenotypes in vivo and in vitro, including ameliorating UV-induced histopathological changes in the skin and inhibiting oxidative stress and collagen degradation in dermal fibroblasts (DFs). Mechanistically, pretreatment with hucMSC-sEVs reversed UVA-induced down-regulation of pregnancy zone protein (PZP) in DFs, and achieved photoprotection by inhibiting matrix metalloproteinase-1 (MMP-1) expression and reducing DNA damage. Clinically, a significant decrease in PZP in AK and SCC in situ samples was observed, while a rebound appeared in the invasive SCC samples. Collectively, our findings reveal the effective role of hucMSC-sEVs in regulating PZP to combat photoaging and provide new pre-clinical evidence for the potential development of hucMSC-sEVs as an effective skin photoprotective agent.

紫外线(UV)辐射是皮肤老化的主要外在因素,可导致皮肤光老化、光化性角化病(AK)甚至鳞状细胞癌(SCC)。目前,间充质基质细胞衍生的细胞外小泡(MSC-sEVs)在皮肤伤口愈合中的有益作用已被广泛报道,但在光老化领域仍有待探索。我们的研究结果表明,人脐带间充质干细胞衍生小泡(hucMSC-sEVs)干预可有效缓解体内和体外皮肤光老化表型,包括改善紫外线诱导的皮肤组织病理学变化,抑制氧化应激和真皮成纤维细胞(DFs)胶原降解。从机理上讲,使用 hucMSC-sEVs 预处理可逆转 UVA 诱导的真皮成纤维细胞妊娠区蛋白(PZP)下调,并通过抑制基质金属蛋白酶-1(MMP-1)表达和减少 DNA 损伤实现光保护。临床观察发现,AK 和 SCC 原位样本中的 PZP 明显减少,而侵袭性 SCC 样本中的 PZP 则出现反弹。总之,我们的研究结果揭示了hucMSC-sEVs在调节PZP以对抗光老化方面的有效作用,并为hucMSC-sEVs作为一种有效的皮肤光保护剂的潜在开发提供了新的临床前证据。
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引用次数: 0
Exploring P2X7 receptor antagonism as a therapeutic target for neuroprotection in an hiPSC motor neuron model. 探索在 hiPSC 运动神经元模型中将 P2X7 受体拮抗作为神经保护的治疗靶点。
IF 5.4 2区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2024-10-17 DOI: 10.1093/stcltm/szae074
Alexandra E Johns, Arens Taga, Andriana Charalampopoulou, Sarah K Gross, Khalil Rust, Brett A McCray, Jeremy M Sullivan, Nicholas J Maragakis

ATP is present in negligible concentrations in the interstitium of healthy tissues but accumulates to significantly higher concentrations in an inflammatory microenvironment. ATP binds to 2 categories of purine receptors on the surface of cells, the ionotropic P2X receptors and metabotropic P2Y receptors. Included in the family of ionotropic purine receptors is P2X7 (P2X7R), a non-specific cation channel with unique functional and structural properties that suggest it has distinct roles in pathological conditions marked by increased extracellular ATP. The role of P2X7R has previously been explored in microglia and astrocytes within the context of neuroinflammation, however the presence of P2X7R on human motor neurons and its potential role in neurodegenerative diseases has not been the focus of the current literature. We leveraged the use of human iPSC-derived spinal motor neurons (hiPSC-MN) as well as human and rodent tissue to demonstrate the expression of P2X7R on motor neurons. We extend this observation to demonstrate that these receptors are functionally active on hiPSC-MN and that ATP can directly induce death via P2X7R activation in a dose dependent manner. Finally, using a highly specific P2X7R blocker, we demonstrate how modulation of P2X7R activation on motor neurons is neuroprotective and could provide a unique pharmacologic target for ATP-induced MN death that is distinct from the role of ATP as a modulator of neuroinflammation.

ATP 在健康组织间质中的浓度可忽略不计,但在炎症微环境中会蓄积到明显更高的浓度。ATP 与细胞表面的两类嘌呤受体结合,即离子型 P2X 受体和代谢型 P2Y 受体。离子型嘌呤受体家族中包括 P2X7(P2X7R),它是一种非特异性阳离子通道,具有独特的功能和结构特性,表明它在细胞外 ATP 增高的病理条件下具有独特的作用。P2X7R 的作用以前曾在神经炎症的背景下在小胶质细胞和星形胶质细胞中进行过探讨,但 P2X7R 在人类运动神经元中的存在及其在神经退行性疾病中的潜在作用还不是目前文献研究的重点。我们利用人类 iPSC 衍生的脊髓运动神经元(hiPSC-MN)以及人类和啮齿动物组织证明了 P2X7R 在运动神经元上的表达。我们扩展了这一观察结果,证明这些受体在 hiPSC-MN 上具有功能活性,并且 ATP 可以通过 P2X7R 激活以剂量依赖性方式直接诱导死亡。最后,我们利用一种高度特异性的 P2X7R 阻断剂,证明了调节运动神经元上的 P2X7R 激活如何具有神经保护作用,并为 ATP 诱导的 MN 死亡提供了一个独特的药理学靶点,它不同于 ATP 作为神经炎症调节剂的作用。
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引用次数: 0
eIF6 modulates skin wound healing by upregulating keratin 6B. eIF6 通过上调角蛋白 6B 调节皮肤伤口愈合。
IF 5.4 2区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2024-10-15 DOI: 10.1093/stcltm/szae064
Xiaoyan Wang, Guangchao Xu, Fangyingnan Zhang, Yating Wei, Jiawen Deng, Lan Mu, Jinqing He, Dehua He, Meifang Yin, Ilaria Dal Pra, Xiaofang Liu, Weichao Cai, Linjing Yang, Chunmao Han, Guangtao Huang, Jun Wu

Eukaryotic translation initiation factor 6 (eIF6) plays a crucial role in 60S ribosome biogenesis and protein translation, as well as in hypertrophic scar formation, but its potential role in epithelialization is still poorly understood. Herein, we found that eIF6 negatively correlated with the wound healing process. Mice with genetically knockdown eIF6 (eIF6+/-) showed faster re-epithelization as shown by the longer tongue of the newly formed epidermis. Furthermore, eIF6 ablation accelerated the wound healing process by targeting basal keratinocytes in the eIF6 keratinocyte-conditional knockout (eIF6f/+; Krt5-Cre+) mice. Mechanistically, keratin 6B, an important wound-activated protein, was significantly upregulated in eIF6f/+; Krt5-Cre+ mice skin as proved by RNA-seq, western immunoblots, and immunofluorescence staining. Moreover, an elevated level of KRT6B and accelerated proliferative capacity were also observed in stable knockdown eIF6 HaCaT cells. Taken together, eIF6 downregulation could accelerate epithelialization by upregulating KRT6B expression and promoting keratinocyte proliferation. Our results for the first time indicate that eIF6 might be a novel target to regulate re-epithelialization.

真核生物翻译起始因子 6(eIF6)在 60S 核糖体生物发生和蛋白质翻译以及增生性疤痕形成过程中起着至关重要的作用,但其在上皮化过程中的潜在作用仍鲜为人知。在这里,我们发现 eIF6 与伤口愈合过程呈负相关。基因敲除 eIF6(eIF6+/-)的小鼠表现出更快的再上皮化,这表现在新形成的表皮舌头更长。此外,eIF6角质形成细胞条件性敲除(eIF6f/+;Krt5-Cre+)小鼠通过靶向基底角质形成细胞消融加速了伤口愈合过程。RNA-seq、Western 免疫印迹和免疫荧光染色证明,在 eIF6f/+; Krt5-Cre+ 小鼠皮肤中,重要的伤口激活蛋白角蛋白 6B 被显著上调。此外,在稳定敲除 eIF6 的 HaCaT 细胞中也观察到 KRT6B 水平升高和增殖能力加快。综上所述,下调 eIF6 可通过上调 KRT6B 的表达和促进角质形成细胞的增殖来加速上皮化。我们的研究结果首次表明,eIF6 可能是调控上皮再形成的一个新靶点。
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引用次数: 0
Safety and tolerability of a Muse cell-based product in neonatal hypoxic-ischemic encephalopathy with therapeutic hypothermia (SHIELD trial). 基于 Muse 细胞的产品在新生儿缺氧缺血性脑病治疗性低温中的安全性和耐受性(SHIELD 试验)。
IF 5.4 2区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2024-10-14 DOI: 10.1093/stcltm/szae071
Yoshiaki Sato, Shinobu Shimizu, Kazuto Ueda, Toshihiko Suzuki, Sakiko Suzuki, Ryosuke Miura, Masahiko Ando, Kennosuke Tsuda, Osuke Iwata, Yukako Muramatsu, Hiroyuki Kidokoro, Akihiro Hirakawa, Masahiro Hayakawa

Hypoxic-ischemic encephalopathy (HIE), associated with high mortality and neurological sequelae, lacks established treatment except therapeutic hypothermia. Clinical-grade multilineage-differentiating stress-enduring (Muse) cells (CL2020) demonstrated safety and efficacy in nonclinical HIE rat models, thereby leading to an investigator-initiated clinical trial to evaluate CL2020 safety and tolerability in neonatal HIE as a single-center open-label dose-escalation study with 9 neonates with moderate-to-severe HIE who received therapeutic hypothermia. Each patient received a single intravenous injection of CL2020 cells between 5 and 14 days of age. The low-dose (3 patients) and high-dose (6 patients) groups received 1.5 × 106 and 1.5 × 107 cells/dose, respectively. The occurrence of any adverse event within 12 weeks following CL2020 administration was the primary endpoint of this trial. No significant changes in physiological signs including heart rate, blood pressure, and oxygen saturation were observed during or after administration. The only adverse event that may be related to cell administration was a mild γ-glutamyltransferase level elevation in one neonate, which spontaneously resolved without any treatment. All patients enrolled in the trial survived, and normal developmental quotients (≥ 85) in all 3 domains of the Kyoto Scale of Psychological Development 2001 were observed in 67% of the patients in this trial. CL2020 administration was demonstrated to be safe and tolerable for neonates with HIE. Considering the small number of patients, a randomized controlled confirmatory study is warranted to verify these preliminary findings and evaluate the efficacy of this therapy.

缺氧缺血性脑病(HIE)与高死亡率和神经系统后遗症有关,除治疗性低温外,缺乏成熟的治疗方法。临床级多线粒体分化应激耐受(Muse)细胞(CL2020)在非临床HIE大鼠模型中表现出安全性和有效性,因此研究人员发起了一项临床试验,评估CL2020在新生儿HIE中的安全性和耐受性,这是一项单中心开放标签剂量递增研究,9名患有中重度HIE的新生儿接受了治疗性低温。每位患者都在出生后 5 到 14 天之间接受了一次 CL2020 细胞静脉注射。低剂量组(3 名患者)和高剂量组(6 名患者)分别接受了 1.5 × 106 和 1.5 × 107 个细胞/剂量。CL2020用药后12周内发生任何不良事件是本试验的主要终点。用药期间或用药后,心率、血压和血氧饱和度等生理指标均未出现明显变化。唯一可能与细胞给药有关的不良反应是一名新生儿出现轻微的γ-谷氨酰转移酶水平升高,无需任何治疗即可自行缓解。所有参加试验的患者都存活了下来,67%的患者在 2001 年京都心理发展量表的所有 3 个领域中都观察到了正常的发展商数(≥ 85)。试验证明,CL2020 对患有 HIE 的新生儿是安全和可耐受的。考虑到患者人数较少,有必要进行随机对照确证研究,以验证这些初步发现并评估该疗法的疗效。
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Stem Cells Translational Medicine
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