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A mineralizing pool of Gli1-expressing progenitors builds the tendon enthesis and demonstrates therapeutic potential 矿化池的gli1表达祖细胞建立肌腱终结和显示治疗潜力
IF 23.9 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2025-09-30 DOI: 10.1016/j.stem.2025.09.010
Fei Fang, Yang Xiao, Elazar Zelzer, Kam W. Leong, Stavros Thomopoulos
(Cell Stem Cell 29, 1669–1684.e1–e6; December 1, 2022)
(Cell Stem Cell 29, 1669-1684.e1-e6; 2022年12月1日)
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引用次数: 0
Targeting lysozyme 2 in endocardium promotes rapid recovery by modulating remote injury signals 靶向溶菌酶2在心内膜通过调节远程损伤信号促进快速恢复
IF 23.9 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2025-09-17 DOI: 10.1016/j.stem.2025.08.015
Chenghao Fan, Shen Song, Yu Han, Dongcheng Cai, Anteng Shi, Fangfang Wan, Jie Feng, Jiajun Zhong, Yifan Xie, Fei Xu, Jiangping Song, Shengshou Hu, Yu Nie, Hui Zhang
Adult mammalian hearts are non-regenerative, and a majority of studies examining repair and potential regeneration post-myocardial infarction (MI) have focused on cardiomyocyte (CM) proliferation and infarcted zones. Here, we observed aberrantly high expression of lysozyme 2 (Lyz2) in injured mouse hearts at both local injury sites and at remote zones, with sustained Lyz2 expression conspicuous in endocardial cells of non-regenerative hearts. Although traditionally conceptualized as a myeloid marker, we demonstrate that LYZ2 functions as an injury-specific, positive regulator of lysosomal degradation capacity that mediates pathogenic degradation of the extracellular matrix. We observed an anti-apoptotic benefit to CMs upon disrupting LYZ2/LYZ function in mice and in a human endomyocardium experimental model. Harnessing these insights, we show that both Lyz2 knockout (KO) and pharmacological inhibition of lysosomal degradation confer rapid functional recovery in injured non-regenerative hearts. Thus, targeting a remote injury response in a non-CM cell type rapidly promotes post-MI recovery of non-regenerative hearts.
成年哺乳动物的心脏是不可再生的,大多数关于心肌梗死(MI)后修复和潜在再生的研究都集中在心肌细胞(CM)增殖和梗死区。在这里,我们观察到溶菌酶2 (Lyz2)在损伤小鼠心脏的局部损伤部位和远处区域异常高表达,在非再生心脏的心内膜细胞中持续表达明显。虽然传统上被认为是髓系标志物,但我们证明LYZ2是一种损伤特异性的、溶酶体降解能力的正调节因子,介导细胞外基质的致病性降解。在小鼠和人心肌内膜实验模型中,我们观察到破坏LYZ2/LYZ功能对CMs具有抗凋亡作用。利用这些见解,我们表明Lyz2敲除(KO)和溶酶体降解的药理抑制都能使受伤的非再生心脏快速功能恢复。因此,靶向非cm细胞类型的远程损伤反应可迅速促进非再生心脏的心肌梗死后恢复。
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引用次数: 0
Spatially patterned kidney assembloids recapitulate progenitor self-assembly and enable high-fidelity in vivo disease modeling 空间模式的肾脏组装体概括了祖细胞的自组装,并实现了高保真的体内疾病建模
IF 23.9 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2025-09-17 DOI: 10.1016/j.stem.2025.08.013
Biao Huang, Pedro Medina, Jincan He, Zipeng Zeng, Sunghyun Kim, Janet Romo, Kari Koppitch, Chennan C. Zhang, Georgina Gyarmati, Yohan Park, Ruslan Bohovyk, Pierre-Emmanuel Yoann N’Guetta, Jinjin Guo, Tianyi Ma, Megan E. Schreiber, Cong Xu, Jessica Pham, Riana K. Parvez, Jackson Su, Mateo W. Xia, Zhongwei Li
Current kidney organoids do not recapitulate the kidney’s complex spatial patterning and function, limiting their applications. The human kidney comprises one million nephrons, derived from nephron progenitor cells, that connect to an arborized ureteric progenitor cell-derived collecting system. Here, we develop spatially organized mouse and human kidney progenitor assembloid (KPA) models in which the nephrons undergo extensive development and fuse to a centrally located collecting system, recapitulating kidney progenitor self-assembly processes observed in vivo. KPAs show dramatically improved cellular complexity and maturity and exhibit several aspects of major kidney functions in vitro and in vivo. Modeling human autosomal dominant polycystic kidney disease (ADPKD) with genome-edited, in vivo-grown human KPAs recapitulated the cystic phenotype and the molecular and cellular hallmarks of the disease and highlighted the crosstalk among cyst epithelium, stroma, and macrophages. The KPA platform opens new avenues for high-fidelity disease modeling and lays a strong foundation for kidney regenerative medicine.
目前的肾脏类器官不能概括肾脏复杂的空间模式和功能,限制了它们的应用。人体肾脏由100万个肾单位组成,这些肾单位来源于肾单位祖细胞,它们连接到一个由输尿管祖细胞衍生的收集系统。在这里,我们建立了空间组织的小鼠和人类肾脏祖细胞组装体(KPA)模型,其中肾单位经历广泛的发育并融合到一个集中的收集系统,再现了在体内观察到的肾脏祖细胞自组装过程。在体外和体内,KPAs显著改善了细胞的复杂性和成熟度,并表现出主要肾脏功能的几个方面。用基因组编辑的、体内培养的人kpa模拟人类常染色体显性多囊肾病(ADPKD),再现了该疾病的囊性表型、分子和细胞特征,并突出了囊肿上皮、间质和巨噬细胞之间的串扰。KPA平台为高保真疾病建模开辟了新的途径,为肾脏再生医学奠定了坚实的基础。
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引用次数: 0
Signaling reprogramming via Stat3 activation unravels high-fidelity human post-implantation embryo modeling 通过Stat3激活的信号重编程揭示了高保真的人类植入后胚胎建模
IF 23.9 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2025-09-16 DOI: 10.1016/j.stem.2025.08.011
Chuanxin Chen, Jinyi Wu, Xinggu Wang, Litao Chang, Kexin Wang, Kaiyi Wu, Mingyue Guo, Huanhuan Li, Fei Sun, Xinxing Jiang, Yanlin Ma, Guangjin Pan, Zhenyu Xiao, José C.R. Silva
Human embryo models hold great promise for advancing medicine, but current systems lack efficiency and fidelity in replicating post-implantation stages. Here, we investigate whether STAT3 activation can reprogram pluripotent stem cells (PSCs) into early fates that self-organize into embryo models. Using a medium enhancing STAT3 activity (SAM), PSCs reprogram within 60 h into hypoblast, trophectoderm, naive epiblast, and extraembryonic mesoderm. Dissociating SAM-treated PSCs at 60–120 h, followed by 3D culture, results in dynamic development of post-implantation embryo-like structures with up to 52.41% ± 8.92% efficiency. Resulting day 6 examples resemble Carnegie stages 5 (CS5) to 7 (CS7) embryos, exhibiting bilaminar disc structure with epiblast and yolk sac, amniotic cavity, mesenchyme, chorionic cavity, and trophoblast. Notably, CS6/7-like examples exhibit gastrulation, including the formation and correct positioning of primitive streak, epithelial-to-mesenchymal transition, mesoderm, and definitive endoderm. The STAT3-mediated embryo model also closely aligns molecularly with CS6/7 embryo references and represents a state-of-the-art platform for advancing human embryogenesis research.
人类胚胎模型在推进医学方面有着巨大的希望,但目前的系统在复制植入后阶段缺乏效率和保真度。在这里,我们研究STAT3激活是否可以重编程多能干细胞(PSCs)进入自组织成胚胎模型的早期命运。使用增强STAT3活性(SAM)的培养基,PSCs在60小时内重编程为下胚层、滋养外胚层、原始外胚层和胚外中胚层。在60-120 h解离经过sam处理的PSCs,然后进行3D培养,可获得植入后胚胎样结构的动态发育,效率高达52.41%±8.92%。第6天的样品类似于卡内基5期(CS5)至7期(CS7)胚胎,表现出双层盘状结构,包括外胚层和卵黄囊、羊膜腔、间充质、绒毛膜腔和滋养细胞。值得注意的是,cs6 /7样样本显示原肠胚形成,包括原始条纹的形成和正确定位、上皮向间质转变、中胚层和终胚层。stat3介导的胚胎模型在分子上也与CS6/7胚胎文献密切一致,代表了推进人类胚胎发生研究的最先进平台。
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引用次数: 0
Safety and tolerability of RPESC-RPE transplantation in patients with dry age-related macular degeneration: Low-dose clinical outcomes 干性年龄相关性黄斑变性患者RPESC-RPE移植的安全性和耐受性:低剂量临床结果
IF 23.9 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2025-09-16 DOI: 10.1016/j.stem.2025.08.012
Rajesh C. Rao, Brigitte L. Arduini, Susan Borden, Dhruv Sareen, Clive Svendsen, Paul Lee, Charles Ryan, Shilpa Kodati, Caroline Nyaiburi, Keith Wolsieffer, Eric Oh, Shuna Park, Glenna Ford, Keith Dionne, Sally Temple, Jeffrey Stern
Retinal pigment epithelium (RPE) cell atrophy in dry age-related macular degeneration (AMD) compromises photoreceptor cell function, leading to vision loss. Stem cell-based RPE replacement therapy aims to reverse disease progression and restore vision. RPESC-RPE-4W, a post-mitotic adult RPE stem cell-derived RPE (RPESC-RPE) progenitor cell product, exhibits consistent safety and efficacy in preclinical studies. The first-in-human clinical trial of RPESC-RPE-4W completed low-dose cohort 1 interventions (NCT04627428). Six subjects received a subretinal suspension of 50,000 RPESC-RPE-4W cells. No significant inflammation, tumor, or product-related serious adverse events were observed. Best-corrected visual acuity in the three worse-seeing group A subjects improved by an average of +21.67 letters from baseline at 12 months. Three better-seeing group B subjects improved by an average of +3.0 letters at 6 months. The positive safety and tolerability outcomes for low-dose cohort 1 enabled dose escalation to mid-dose RPESC-RPE-4W therapy for dry AMD.
干性年龄相关性黄斑变性(AMD)视网膜色素上皮(RPE)细胞萎缩损害感光细胞功能,导致视力丧失。基于干细胞的RPE替代疗法旨在逆转疾病进展并恢复视力。RPESC-RPE- 4w是一种有丝分裂后成人RPE干细胞衍生的RPE (RPESC-RPE)祖细胞产品,在临床前研究中显示出一致的安全性和有效性。RPESC-RPE-4W的首次人体临床试验完成了低剂量队列1干预(NCT04627428)。6名受试者接受了50,000个RPESC-RPE-4W细胞的视网膜下悬浮。未观察到明显的炎症、肿瘤或与产品相关的严重不良事件。三名视力较差的A组受试者的最佳矫正视力在12个月时比基线平均提高了21.67个字母。三个视力较好的B组受试者在6个月时平均提高了+3.0个字母。低剂量队列1的阳性安全性和耐受性结果使剂量增加到中剂量RPESC-RPE-4W治疗干性AMD。
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引用次数: 0
Human adult hippocampal neurogenesis is shaped by neuropsychiatric disorders, demographics, and lifestyle-related factors 成人海马神经发生受神经精神疾病、人口统计学和生活方式相关因素的影响
IF 23.9 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2025-09-15 DOI: 10.1016/j.stem.2025.08.010
Berenice Márquez-Valadez, Marta Gallardo-Caballero, María Llorens-Martín
Adult hippocampal neurogenesis (AHN) regulates hippocampal-dependent functions and is targeted by physiological aging and neurodegenerative conditions. Patients with neuropsychiatric disorders show hippocampal abnormalities that might be related to changes in AHN. Here, we sought to determine whether major depression, schizophrenia, and bipolar disorder threaten the integrity of human AHN and the homeostasis of the dentate gyrus (DG) neurogenic niche—a specialized microenvironment in which new neurons grow. Our results show that the initial and intermediate stages of AHN, as well as distinct components of the niche, are selectively affected in these disorders. Demographics and various lifestyle-related factors (such as the consumption of alcohol and drugs of abuse) modulate both AHN and the cells that compose the niche, not only in patients with these disorders but also in neurologically healthy control individuals. These data might be relevant for the design of future strategies to treat and prevent mental health conditions.
成人海马神经发生(AHN)调节海马依赖功能,是生理衰老和神经退行性疾病的目标。神经精神障碍患者表现出海马异常,这可能与AHN的改变有关。在这里,我们试图确定重度抑郁症、精神分裂症和双相情感障碍是否会威胁人类AHN的完整性和齿状回(DG)神经源性生态位(新神经元生长的特殊微环境)的稳态。我们的研究结果表明,AHN的初始和中期阶段以及生态位的不同组成部分在这些疾病中受到选择性影响。人口统计和各种与生活方式相关的因素(如饮酒和滥用药物)不仅在患有这些疾病的患者中,而且在神经健康对照个体中,都能调节AHN和构成生态位的细胞。这些数据可能与设计未来治疗和预防心理健康状况的策略有关。
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引用次数: 0
Adopting novel alternative methods (NAMs) for biomedical research—What is the right approach? 采用新颖的替代方法(NAMs)进行生物医学研究-什么是正确的方法?
IF 23.9 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2025-09-05 DOI: 10.1016/j.stem.2025.08.014
Clive N. Svendsen

Section snippets

Declaration of interests

C.N.S. serves on the advisory board of Cell Stem Cell.
部分片段利益声明担任Cell Stem Cell的顾问委员会成员。
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引用次数: 0
Modeling the human maternal-fetal interface 人类母胎界面建模
IF 23.9 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2025-09-04 DOI: 10.1016/j.stem.2025.08.004
Vladyslav Bondarenko, Margherita Yayoi Turco
Stem cells and organoids enable the modeling of various aspects of human development in vitro, yet integrating them to study maternal-fetal interactions remains challenging. In this review, we explore the current in vitro models of the endometrium, placenta, and embryo and identify key challenges associated with their integration, including the establishment of morpho-functional complexity, spatiotemporal coordination, and appropriate in vivo benchmarking. We propose an interdisciplinary perspective that emphasizes a shift from “building blocks” to “building interactions.” Altogether, we provide a discussion on the challenges and prospects for advancing mechanistic understanding of intrauterine human development and the maternal-fetal interface.
干细胞和类器官能够在体外模拟人类发育的各个方面,但将它们整合到母胎相互作用的研究中仍然具有挑战性。在这篇综述中,我们探讨了目前子宫内膜、胎盘和胚胎的体外模型,并确定了与它们整合相关的关键挑战,包括形态功能复杂性的建立、时空协调和适当的体内基准。我们提出一个跨学科的观点,强调从“构建模块”到“构建交互”的转变。总之,我们提供了一个讨论的挑战和前景,以促进对子宫内人类发育和母胎界面的机制理解。
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引用次数: 0
Severing the scar supply line: CAR-T in chronic kidney disease 切断疤痕供给线:CAR-T治疗慢性肾脏疾病
IF 23.9 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2025-09-04 DOI: 10.1016/j.stem.2025.08.002
Longwei Liu, Yingxiao Wang
CAR-T cell therapy is rapidly being extended to target various pathophysiological processes beyond cancer. In this issue of Cell Stem Cell, Zhao et al. engineered PDGFRβ-specific CAR-T cells in vivo to selectively target extracellular matrix-producing cells in kidney fibrosis,1 opening new opportunities for treating fibrotic diseases with precision immunotherapy.
CAR-T细胞疗法正在迅速扩展到针对癌症以外的各种病理生理过程。在这一期的《细胞干细胞》中,Zhao等人在体内设计了pdgfr β特异性CAR-T细胞,选择性地靶向肾纤维化的细胞外基质生成细胞,1为精确免疫治疗纤维化疾病开辟了新的机会。
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引用次数: 0
From β soloist to endocrine symphony: Subtype-complete islets conduct glucose harmony 从β独奏家到内分泌交响乐:亚型完全胰岛指挥葡萄糖和谐
IF 23.9 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2025-09-04 DOI: 10.1016/j.stem.2025.08.001
Jia Zhao, Shenghui Liang, Timothy J. Kieffer
While current stem cell differentiation protocols generate β cell-enriched islets that reverse hyperglycemia post-implantation, they can cause hypoglycemia. Meng et al.1 reconstruct endocrine subtype-complete islets, which restore counterregulatory responses and protect against hypoglycemia in diabetic mice, highlighting the importance of endocrine diversity in designing physiologically regulated cell therapies for diabetes.
虽然目前的干细胞分化方案产生富含β细胞的胰岛,可以逆转植入后的高血糖,但它们可能导致低血糖。孟等人重建了内分泌亚型完全胰岛,该胰岛可以恢复糖尿病小鼠的反调节反应并防止低血糖,强调了内分泌多样性在设计生理调节的糖尿病细胞疗法中的重要性。
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引用次数: 0
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Cell stem cell
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