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Ligament injury in adult zebrafish triggers ECM remodeling and cell dedifferentiation for scar-free regeneration. 成年斑马鱼的韧带损伤触发ECM重塑和细胞去分化以实现无瘢痕再生。
IF 6.4 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-09-19 DOI: 10.1038/s41536-023-00329-9
Troy Anderson, Julia Mo, Ernesto Gagarin, Desmarie Sherwood, Maria Blumenkrantz, Eric Mao, Gianna Leon, Hailey Levitz, Hung-Jhen Chen, Kuo-Chang Tseng, Peter Fabian, J Gage Crump, Joanna Smeeton

After traumatic injury, healing of mammalian ligaments is typically associated with fibrotic scarring as opposed to scar-free regeneration. In contrast, here we show that the ligament supporting the jaw joint of adult zebrafish is capable of rapid and complete scar-free healing. Following surgical transection of the jaw joint ligament, we observe breakdown of ligament tissue adjacent to the cut sites, expansion of mesenchymal tissue within the wound site, and then remodeling of extracellular matrix (ECM) to a normal ligament morphology. Lineage tracing of mature ligamentocytes following transection shows that they dedifferentiate, undergo cell cycle re-entry, and contribute to the regenerated ligament. Single-cell RNA sequencing of the regenerating ligament reveals dynamic expression of ECM genes in neural-crest-derived mesenchymal cells, as well as diverse immune cells expressing the endopeptidase-encoding gene legumain. Analysis of legumain mutant zebrafish shows a requirement for early ECM remodeling and efficient ligament regeneration. Our study establishes a new model of adult scar-free ligament regeneration and highlights roles of immune-mesenchyme cross-talk in ECM remodeling that initiates regeneration.

创伤后,哺乳动物韧带的愈合通常与纤维化瘢痕形成有关,而不是无瘢痕再生。相比之下,我们在这里表明,支撑成年斑马鱼下颌关节的韧带能够快速完全无疤痕愈合。手术切断下颌关节韧带后,我们观察到切口附近的韧带组织断裂,伤口内间充质组织扩张,然后细胞外基质(ECM)重塑为正常的韧带形态。切断后成熟韧带细胞的谱系追踪显示,它们去分化,经历细胞周期重新进入,并有助于再生韧带。再生韧带的单细胞RNA测序揭示了ECM基因在神经嵴衍生的间充质细胞以及表达内肽酶编码基因legumain的多种免疫细胞中的动态表达。对legumain突变斑马鱼的分析表明,需要早期ECM重塑和有效的韧带再生。我们的研究建立了一种新的成人无瘢痕韧带再生模型,并强调了免疫性间充质串扰在启动再生的ECM重塑中的作用。
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引用次数: 0
Local BMP2 hydrogel therapy for robust bone regeneration in a porcine model of Legg-Calvé-Perthes disease. 局部BMP2水凝胶治疗Legg-Calvé-Perthes病猪模型中强健的骨再生。
IF 7.2 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-09-14 DOI: 10.1038/s41536-023-00322-2
Chi Ma, Min Sung Park, Felipe Alves do Monte, Vishal Gokani, Olumide O Aruwajoye, Yinshi Ren, Xiaohua Liu, Harry K W Kim

Legg-Calvé-Perthes disease is juvenile idiopathic osteonecrosis of the femoral head (ONFH) that has no effective clinical treatment. Previously, local injection of bone morphogenetic protein-2 (BMP2) for ONFH treatment showed a heterogeneous bone repair and a high incidence of heterotopic ossification (HO) due to the BMP2 leakage. Here, we developed a BMP2-hydrogel treatment via a transphyseal bone wash and subsequential injection of BMP2-loaded hydrogel. In vitro studies showed that a hydrogel of gelatin-heparin-tyramine retained the BMP2 for four weeks. The injection of the hydrogel can efficiently prevent leakage. With the bone wash, the injected hydrogel had a broad distribution in the head. In vivo studies on pigs revealed that the BMP2-hydrogel treatment produced a homogeneous bone regeneration without HO. It preserved the subchondral contour and restored the subchondral endochondral ossification, although it increased growth plate fusions. In summary, the study demonstrated a promising BMP2-hydrogel treatment for ONFH treatment, especially for teenagers.

Legg-Calvé-Perthes病是一种幼年特发性股骨头坏死(ONFH),目前尚无有效的临床治疗方法。先前,局部注射骨形态发生蛋白-2(BMP2)用于ONFH治疗显示出异质性骨修复和由于BMP2渗漏导致的异位骨化(HO)的高发生率。在这里,我们开发了一种BMP2水凝胶治疗方法,通过经骨关节冲洗和随后注射负载BMP2的水凝胶。体外研究表明,明胶-肝素-酪胺的水凝胶将BMP2保留了四周。水凝胶的注射可以有效地防止渗漏。通过骨清洗,注射的水凝胶在头部有广泛的分布。对猪的体内研究表明,BMP2水凝胶处理在没有HO的情况下产生了均匀的骨再生。它保留了软骨下轮廓并恢复了软骨下软骨内骨化,尽管它增加了生长板融合。总之,该研究证明了BMP2水凝胶治疗ONFH的前景,尤其是对青少年。
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引用次数: 1
Topically-applied collagen-binding serum albumin-fused interleukin-4 modulates wound microenvironment in non-healing wounds. 局部应用胶原结合血清白蛋白融合白细胞介素-4调节未愈合伤口的伤口微环境。
IF 7.2 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-09-11 DOI: 10.1038/s41536-023-00326-y
Abigail L Lauterbach, Rachel P Wallace, Aaron T Alpar, Kirsten C Refvik, Joseph W Reda, Ako Ishihara, Taryn N Beckman, Anna J Slezak, Yukari Mizukami, Aslan Mansurov, Suzana Gomes, Jun Ishihara, Jeffrey A Hubbell

Non-healing wounds have a negative impact on quality of life and account for many cases of amputation and even early death among patients. Diabetic patients are the predominate population affected by these non-healing wounds. Despite the significant clinical demand, treatment with biologics has not broadly impacted clinical care. Interleukin-4 (IL-4) is a potent modulator of the immune system, capable of skewing macrophages towards a pro-regeneration phenotype (M2) and promoting angiogenesis, but can be toxic after frequent administration and is limited by its short half-life and low bioavailability. Here, we demonstrate the design and characterization of an engineered recombinant interleukin-4 construct. We utilize this collagen-binding, serum albumin-fused IL-4 variant (CBD-SA-IL-4) delivered in a hyaluronic acid (HA)-based gel for localized application of IL-4 to dermal wounds in a type 2 diabetic mouse model known for poor healing as proof-of-concept for improved tissue repair. Our studies indicate that CBD-SA-IL-4 is retained within the wound and can modulate the wound microenvironment through induction of M2 macrophages and angiogenesis. CBD-SA-IL-4 treatment significantly accelerated wound healing compared to native IL-4 and HA vehicle treatment without inducing systemic side effects. This CBD-SA-IL-4 construct can address the underlying immune dysfunction present in the non-healing wound, leading to more effective tissue healing in the clinic.

不愈合的伤口对生活质量有负面影响,导致许多患者截肢甚至早逝。糖尿病患者是受这些不愈合伤口影响的主要人群。尽管临床需求巨大,但生物制剂治疗并没有广泛影响临床护理。白细胞介素-4(IL-4)是免疫系统的有效调节剂,能够使巨噬细胞向促再生表型(M2)倾斜并促进血管生成,但在频繁给药后可能有毒,并且受到其半衰期短和生物利用度低的限制。在此,我们展示了一种工程化重组白细胞介素-4构建体的设计和表征。我们利用这种在透明质酸(HA)基凝胶中递送的胶原结合、血清白蛋白融合的IL-4变体(CBD-SA-IL-4),将IL-4局部应用于2型糖尿病小鼠模型的真皮伤口,该模型以愈合不良而闻名,作为改善组织修复的概念证明。我们的研究表明,CBD-SA-IL-4保留在伤口内,可以通过诱导M2巨噬细胞和血管生成来调节伤口微环境。与天然IL-4和HA载体治疗相比,CBD-SA-IL-4治疗显著加速伤口愈合,而不会诱导全身副作用。这种CBD-SA-IL-4构建体可以解决未愈合伤口中存在的潜在免疫功能障碍,从而在临床上实现更有效的组织愈合。
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引用次数: 0
Opposing roles for TGFβ- and BMP-signaling during nascent alveolar differentiation in the developing human lung. tgf - β-和bmp -信号在人肺发育初期肺泡分化中的对立作用
IF 7.2 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-09-09 DOI: 10.1038/s41536-023-00325-z
Tristan Frum, Peggy P Hsu, Renee F C Hein, Ansley S Conchola, Charles J Zhang, Olivia R Utter, Abhinav Anand, Yi Zhang, Sydney G Clark, Ian Glass, Jonathan Z Sexton, Jason R Spence

Alveolar type 2 (AT2) cells function as stem cells in the adult lung and aid in repair after injury. The current study aimed to understand the signaling events that control differentiation of this therapeutically relevant cell type during human development. Using lung explant and organoid models, we identified opposing effects of TGFβ- and BMP-signaling, where inhibition of TGFβ- and activation of BMP-signaling in the context of high WNT- and FGF-signaling efficiently differentiated early lung progenitors into AT2-like cells in vitro. AT2-like cells differentiated in this manner exhibit surfactant processing and secretion capabilities, and long-term commitment to a mature AT2 phenotype when expanded in media optimized for primary AT2 culture. Comparing AT2-like cells differentiated with TGFβ-inhibition and BMP-activation to alternative differentiation approaches revealed improved specificity to the AT2 lineage and reduced off-target cell types. These findings reveal opposing roles for TGFβ- and BMP-signaling in AT2 differentiation and provide a new strategy to generate a therapeutically relevant cell type in vitro.

肺泡2型(Alveolar type 2, AT2)细胞在成人肺中具有干细胞的功能,并有助于损伤后的修复。目前的研究旨在了解在人类发育过程中控制这种治疗相关细胞类型分化的信号事件。利用肺外植体和类器官模型,我们发现了tgf - β-和bmp -信号的相反作用,在高WNT-和fgf -信号的背景下,tgf - β-的抑制和bmp -信号的激活在体外有效地将早期肺祖细胞分化为at2样细胞。以这种方式分化的AT2样细胞表现出表面活性剂加工和分泌能力,并且在优化的AT2原代培养培养基中扩增时,长期致力于成熟的AT2表型。将tgf β抑制和bmp活化的AT2样细胞与其他分化方法进行比较,发现对AT2谱系的特异性提高,脱靶细胞类型减少。这些发现揭示了tgf - β-和bmp -信号在AT2分化中的相反作用,并提供了在体外产生治疗相关细胞类型的新策略。
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引用次数: 0
Publisher Correction: A postnatal network of co-hepato/pancreatic stem/progenitors in the biliary trees of pigs and humans. 出版商更正:猪和人类胆道树中共肝/胰腺干/祖细胞的出生后网络。
IF 7.2 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-09-06 DOI: 10.1038/s41536-023-00323-1
Wencheng Zhang, Xicheng Wang, Giacomo Lanzoni, Eliane Wauthier, Sean Simpson, Jennifer Ashley Ezzell, Amanda Allen, Carolyn Suitt, Jonah Krolik, Alexander Jhirad, Juan Dominguez-Bendala, Vincenzo Cardinale, Domenico Alvaro, Diletta Overi, Eugenio Gaudio, Praveen Sethupathy, Guido Carpino, Christopher Adin, Jorge A Piedrahita, Kyle Mathews, Zhiying He, Lola McAdams Reid
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引用次数: 0
Combination human umbilical cord perivascular and endothelial colony forming cell therapy for ischemic cardiac injury. 脐带血管周围细胞与内皮细胞集落形成细胞联合治疗缺血性心脏损伤。
IF 7.2 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-08-25 DOI: 10.1038/s41536-023-00321-3
Farwah Iqbal, Alexander Johnston, Brandon Wyse, Razieh Rabani, Poonam Mander, Banafshe Hoseini, Jun Wu, Ren-Ke Li, Andrée Gauthier-Fisher, Peter Szaraz, Clifford Librach

Cell-based therapeutics are promising interventions to repair ischemic cardiac tissue. However, no single cell type has yet been found to be both specialized and versatile enough to heal the heart. The synergistic effects of two regenerative cell types including endothelial colony forming cells (ECFC) and first-trimester human umbilical cord perivascular cells (FTM HUCPVC) with endothelial cell and pericyte properties respectively, on angiogenic and regenerative properties were tested in a rat model of myocardial infarction (MI), in vitro tube formation and Matrigel plug assay. The combination of FTM HUCPVCs and ECFCs synergistically reduced fibrosis and cardiomyocyte apoptosis, while promoting favorable cardiac remodeling and contractility. These effects were in part mediated by ANGPT2, PDGF-β, and VEGF-C. PDGF-β signaling-dependent synergistic effects on angiogenesis were also observed in vitro and in vivo. FTM HUCPVCs and ECFCs represent a cell combination therapy for promoting and sustaining vascularization following ischemic cardiac injury.

基于细胞的治疗方法是修复缺血心脏组织的有希望的干预措施。然而,目前还没有发现一种细胞类型既特化又万能,足以治愈心脏。采用大鼠心肌梗死(MI)模型、体外成管实验和Matrigel塞实验,研究了内皮集落形成细胞(ECFC)和孕早期脐带血管周围细胞(FTM HUCPVC)对血管生成和再生特性的协同作用。FTM HUCPVCs和ecfc联合使用可协同减少纤维化和心肌细胞凋亡,同时促进有利的心脏重塑和收缩。这些作用部分是由ANGPT2、PDGF-β和VEGF-C介导的。体外和体内也观察到PDGF-β信号依赖性对血管生成的协同作用。FTM HUCPVCs和ecfc代表了一种促进和维持缺血性心脏损伤后血管化的细胞联合疗法。
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引用次数: 1
Ferric citrate and apo-transferrin enable erythroblast maturation with β-globin from hemogenic endothelium. 柠檬酸铁和载铁转铁蛋白通过造血内皮中的β-珠蛋白促进红母细胞成熟。
IF 7.2 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-08-25 DOI: 10.1038/s41536-023-00320-4
Soo-Been Jeon, Hyebin Koh, A-Reum Han, Jieun Kim, Sunghun Lee, Jae-Ho Lee, Seung-Soon Im, Young-Sup Yoon, Jong-Hee Lee, Ji Yoon Lee

Red blood cell (RBC) generation from human pluripotent stem cells (PSCs) offers potential for innovative cell therapy in regenerative medicine as well as developmental studies. Ex vivo erythropoiesis from PSCs is currently limited by the low efficiency of functional RBCs with β-globin expression in culture systems. During induction of β-globin expression, the absence of a physiological microenvironment, such as a bone marrow niche, may impair cell maturation and lineage specification. Here, we describe a simple and reproducible culture system that can be used to generate erythroblasts with β-globin expression. We prepared a two-dimensional defined culture with ferric citrate treatment based on definitive hemogenic endothelium (HE). Floating erythroblasts derived from HE cells were primarily CD45+CD71+CD235a+ cells, and their number increased remarkably upon Fe treatment. Upon maturation, the erythroblasts cultured in the presence of ferric citrate showed high transcriptional levels of β-globin and enrichment of genes associated with heme synthesis and cell cycle regulation, indicating functionality. The rapid maturation of these erythroblasts into RBCs was observed when injected in vivo, suggesting the development of RBCs that were ready to grow. Hence, induction of β-globin expression may be explained by the effects of ferric citrate that promote cell maturation by binding with soluble transferrin and entering the cells.Taken together, upon treatment with Fe, erythroblasts showed advanced maturity with a high transcription of β-globin. These findings can help devise a stable protocol for the generation of clinically applicable RBCs.

人类多能干细胞(PSCs)生成红细胞(RBC)为再生医学和发育研究的创新细胞治疗提供了潜力。目前,由于培养系统中表达β-珠蛋白的功能性红细胞效率低,PSCs的体外红细胞生成受到限制。在诱导β-珠蛋白表达的过程中,缺乏生理微环境,如骨髓生态位,可能会损害细胞成熟和谱系规范。在这里,我们描述了一个简单的和可重复的培养系统,可用于产生红母细胞与β-珠蛋白表达。我们制备了一种基于最终血流生成内皮(HE)的二维定义培养物,柠檬酸铁处理。来源于HE细胞的漂浮红细胞主要为CD45+CD71+CD235a+细胞,铁处理后其数量显著增加。成熟后,在柠檬酸铁环境下培养的红母细胞显示出高水平的β-珠蛋白转录和与血红素合成和细胞周期调节相关的基因富集,表明功能性。在体内注射时,观察到这些红母细胞迅速成熟为红细胞,这表明红细胞的发育已经准备好生长。因此,柠檬酸铁通过与可溶性转铁蛋白结合并进入细胞促进细胞成熟的作用可以解释β-珠蛋白表达的诱导。综上所述,经铁处理后,红母细胞表现出成熟程度较高的β-珠蛋白转录水平。这些发现可以帮助设计一个稳定的方案来产生临床适用的红细胞。
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引用次数: 0
Engineered inhaled nanocatalytic therapy for ischemic cerebrovascular disease by inducing autophagy of abnormal mitochondria. 诱导异常线粒体自噬的工程化吸入纳米催化治疗缺血性脑血管病。
IF 7.2 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-08-11 DOI: 10.1038/s41536-023-00315-1
Deping Wang, Bowen Li, Shuchao Wang, Yingjian Hao, Hua Wang, Wei Sun, Jimin Cao, Xin Zhou, Bin Zheng

Mitochondrial dysfunction and subsequent accumulation of reactive oxygen species (ROS) are key contributors to the pathology of ischemic cerebrovascular disease. Therefore, elimination of ROS and damaged mitochondria is crucial for the effective treatment of this disease. For this purpose, we designed an inhalation nanotherapeutic agent, P/D@Mn/Co3O4, to treat ischemic cerebrovascular disease. Mn/Co3O4 effectively removed excess ROS from cells, reduced acute cellular oxidative stress, and protected neural cells from apoptosis. Furthermore, it depleted the H+ surrounding mitochondria and depolarized the mitochondrial membrane potential, inducing mitophagy and eliminating abnormal mitochondria, thereby avoiding the continuous overproduction of ROS by eliminating the source of ROS regeneration. On intranasal administration, Mn/Co3O4 encapsulated by platelet membranes and 2,3-(dioxy propyl)-trimethylammonium chloride can bypass the blood-brain barrier, enter the brain through the trigeminal and olfactory pathways, and target inflammatory regions to remove ROS and damaged mitochondria from the lesion area. In rat models of stroke and vascular dementia, P/D@Mn/Co3O4 effectively inhibited the symptoms of acute and chronic cerebral ischemia by scavenging ROS and damaged mitochondria in the affected area. Our findings indicate that the nanotherapeutic agent developed in this study can be used for the effective treatment of ischemic cerebrovascular disease.

线粒体功能障碍和随后活性氧(ROS)的积累是缺血性脑血管病病理的关键因素。因此,清除活性氧和受损线粒体对于有效治疗该疾病至关重要。为此,我们设计了一种吸入性纳米治疗剂P/D@Mn/Co3O4,用于治疗缺血性脑血管病。Mn/Co3O4能有效去除细胞中过量的ROS,降低细胞急性氧化应激,保护神经细胞免于凋亡。此外,它耗尽线粒体周围的H+,使线粒体膜电位去极化,诱导线粒体自噬,消除异常线粒体,从而通过消除ROS再生的来源,避免了ROS的持续过量产生。经鼻给药,经血小板膜和2,3-(二氧基丙基)-三甲基氯化铵包被的Mn/Co3O4可以绕过血脑屏障,通过三叉神经和嗅觉途径进入大脑,靶向炎症区域,清除病变区域的ROS和受损线粒体。在脑卒中和血管性痴呆大鼠模型中,P/D@Mn/Co3O4通过清除患处ROS和受损线粒体,有效抑制急慢性脑缺血症状。我们的研究结果表明,本研究开发的纳米治疗剂可用于缺血性脑血管病的有效治疗。
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引用次数: 0
Transgene-free direct conversion of murine fibroblasts into functional muscle stem cells. 无转基因小鼠成纤维细胞直接转化为功能性肌肉干细胞。
IF 7.2 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-08-08 DOI: 10.1038/s41536-023-00317-z
Xhem Qabrati, Inseon Kim, Adhideb Ghosh, Nicola Bundschuh, Falko Noé, Andrew S Palmer, Ori Bar-Nur

Transcription factor-based cellular reprogramming provides an attractive approach to produce desired cell types for regenerative medicine purposes. Such cellular conversions are widely dependent on viral vectors to efficiently deliver and express defined factors in target cells. However, use of viral vectors is associated with unfavorable genomic integrations that can trigger deleterious molecular consequences, rendering this method a potential impediment to clinical applications. Here, we report on a highly efficient transgene-free approach to directly convert mouse fibroblasts into induced myogenic progenitor cells (iMPCs) by overexpression of synthetic MyoD-mRNA in concert with an enhanced small molecule cocktail. First, we performed a candidate compound screen and identified two molecules that enhance fibroblast reprogramming into iMPCs by suppression of the JNK and JAK/STAT pathways. Simultaneously, we developed an optimal transfection protocol to transiently overexpress synthetic MyoD-mRNA in fibroblasts. Combining these two techniques enabled robust and rapid reprogramming of fibroblasts into Pax7 positive iMPCs in as little as 10 days. Nascent transgene-free iMPCs proliferated extensively in vitro, expressed a suite of myogenic stem cell markers, and could differentiate into highly multinucleated and contractile myotubes. Furthermore, using global and single-cell transcriptome assays, we delineated gene expression changes associated with JNK and JAK/STAT pathway inhibition during reprogramming, and identified in iMPCs a Pax7+ stem cell subpopulation resembling satellite cells. Last, transgene-free iMPCs robustly engrafted skeletal muscles of a Duchenne muscular dystrophy mouse model, restoring dystrophin expression in hundreds of myofibers. In summary, this study reports on an improved and clinically safer approach to convert fibroblasts into myogenic stem cells that can efficiently contribute to muscle regeneration in vivo.

基于转录因子的细胞重编程为再生医学目的提供了一种有吸引力的方法来产生所需的细胞类型。这种细胞转化广泛依赖于病毒载体在靶细胞中有效地传递和表达确定的因子。然而,病毒载体的使用与不利的基因组整合相关,可能引发有害的分子后果,使该方法成为临床应用的潜在障碍。在这里,我们报道了一种高效的无转基因方法,通过过度表达合成MyoD-mRNA和增强的小分子鸡尾酒,直接将小鼠成纤维细胞转化为诱导的肌源性祖细胞(iMPCs)。首先,我们进行了候选化合物筛选,并确定了两种通过抑制JNK和JAK/STAT途径增强成纤维细胞重编程为iMPCs的分子。同时,我们开发了一种最佳转染方案,在成纤维细胞中短暂过表达合成MyoD-mRNA。结合这两种技术,可以在短短10天内将成纤维细胞强大而快速地重编程为Pax7阳性iMPCs。新生的无转基因iMPCs在体外广泛增殖,表达一套肌源性干细胞标记物,并能分化成高度多核和可收缩的肌管。此外,利用全局和单细胞转录组分析,我们描述了重编程过程中与JNK和JAK/STAT通路抑制相关的基因表达变化,并在iMPCs中鉴定了一个类似卫星细胞的Pax7+干细胞亚群。最后,无转基因的iMPCs稳健地植入杜氏肌营养不良小鼠模型的骨骼肌,在数百条肌纤维中恢复了肌营养不良蛋白的表达。总之,本研究报告了一种改进的、临床上更安全的将成纤维细胞转化为肌源性干细胞的方法,这种方法可以有效地促进体内肌肉再生。
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引用次数: 2
Author Correction: The bright side of fibroblasts: molecular signature and regenerative cues in major organs. 作者更正:成纤维细胞的光明面:主要器官的分子特征和再生线索。
IF 7.2 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2023-08-07 DOI: 10.1038/s41536-023-00319-x
Rita N Gomes, Filipa Manuel, Diana S Nascimento
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引用次数: 2
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