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Embryonic macrophages support endocrine commitment during human pancreatic differentiation 胚胎巨噬细胞支持人类胰腺分化过程中的内分泌承诺
IF 23.9 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2024-10-14 DOI: 10.1016/j.stem.2024.09.011
Adriana Migliorini, Sabrina Ge, Michael H. Atkins, Amanda Oakie, Rangarajan Sambathkumar, Gregory Kent, Haiyang Huang, Angel Sing, Conan Chua, Adam J. Gehring, Gordon M. Keller, Faiyaz Notta, Maria Cristina Nostro
Organogenesis is a complex process that relies on a dynamic interplay between extrinsic factors originating from the microenvironment and tissue-specific intrinsic factors. For pancreatic endocrine cells, the local niche consists of acinar and ductal cells as well as neuronal, immune, endothelial, and stromal cells. Hematopoietic cells have been detected in human pancreas as early as 6 post-conception weeks, but whether they play a role during human endocrinogenesis remains unknown. To investigate this, we performed single-nucleus RNA sequencing (snRNA-seq) of the second-trimester human pancreas and identified a wide range of hematopoietic cells, including two distinct subsets of tissue-resident macrophages. Leveraging this discovery, we developed a co-culture system of human embryonic stem cell-derived endocrine-macrophage organoids to model their interaction in vitro. Here, we show that macrophages support the differentiation and viability of endocrine cells in vitro and enhance tissue engraftment, highlighting their potential role in tissue engineering strategies for diabetes.
器官生成是一个复杂的过程,有赖于微环境中外在因素和组织特异性内在因素之间的动态相互作用。对于胰腺内分泌细胞来说,局部龛位包括胰腺尖细胞和导管细胞以及神经元、免疫细胞、内皮细胞和基质细胞。早在受孕后 6 周,人类胰腺中就检测到了造血细胞,但它们是否在人类内分泌生成过程中发挥作用仍是未知数。为了研究这个问题,我们对第二胎人类胰腺进行了单核 RNA 测序(snRNA-seq),发现了多种造血细胞,包括两个不同的组织驻留巨噬细胞亚群。利用这一发现,我们开发了人类胚胎干细胞衍生的内分泌-巨噬细胞器官组织共培养系统,以模拟它们在体外的相互作用。在这里,我们展示了巨噬细胞支持内分泌细胞在体外的分化和存活,并增强组织移植,突出了它们在糖尿病组织工程策略中的潜在作用。
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引用次数: 0
Effective regulatory responses to predatory stem cell markets in Australia and Canada 澳大利亚和加拿大针对掠夺性干细胞市场的有效监管对策
IF 23.9 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2024-10-03 DOI: 10.1016/j.stem.2024.09.007
Laertis Ikonomou, Megan Munsie, Carl Power, Douglas Sipp, Leigh Turner, John E.J. Rasko
The rapid proliferation of businesses engaged in direct-to-consumer advertising of unproven stem cell interventions has raised troubling questions about whether government bodies can regulate this health market effectively. Recent developments in Australia and Canada suggest that such fears are unfounded and that targeted regulatory action can have meaningful effects.
从事未经证实的干细胞干预措施的直接面向消费者广告的企业迅速激增,引发了政府机构能否有效监管这一健康市场的令人不安的问题。澳大利亚和加拿大最近的事态发展表明,这种担心是没有根据的,有针对性的监管行动可以产生有意义的效果。
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引用次数: 0
Let’s get functional: Drug sensitivity profiling to enable precision sarcoma medicine 让我们发挥功能:通过药物敏感性分析实现肉瘤精准医疗
IF 23.9 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2024-10-03 DOI: 10.1016/j.stem.2024.09.006
Claudia R. Ball, Stefan Fröhling
Drug sensitivity profiling in patient-derived tumor models offers new hope for improving outcomes in cancers lacking effective therapies. Al Shihabi et al.1 demonstrate that short-term cultures from bone and soft tissue sarcomas enable clinically meaningful screening of multiple drugs and combinations, marking a significant advance in personalized care for these high-risk diseases.
患者衍生肿瘤模型的药物敏感性分析为改善缺乏有效疗法的癌症的治疗效果带来了新希望。Al Shihabi 等人1 证明,骨和软组织肉瘤的短期培养物能够对多种药物和组合进行有临床意义的筛选,标志着这些高风险疾病的个性化治疗取得了重大进展。
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引用次数: 0
Common and uncommon findings in marmoset and human trophoblast stem cells 狨猴和人类滋养层干细胞的常见和不常见发现
IF 23.9 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2024-10-03 DOI: 10.1016/j.stem.2024.07.008
Hiroaki Okae, Shun Shibata, Takahiro Arima
In this issue of Cell Stem Cell, Siriwardena et al. analyze peri- and post-implantation marmoset trophoblast development in detail and establish marmoset trophoblast stem cell (TSC) lines from pluripotent stem cells (PSCs). Comparative analysis of marmoset and human TSCs provides insights into species-specific implantation and placentation strategies.
在本期《细胞干细胞》(Cell Stem Cell)杂志上,Siriwardena等人详细分析了狨猴滋养细胞植入前后的发育过程,并从多能干细胞(PSCs)中建立了狨猴滋养细胞干细胞(TSC)系。对狨猴滋养层干细胞和人类滋养层干细胞的比较分析为了解物种特异性植入和胎盘植入策略提供了见解。
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引用次数: 0
Charles “Chuck” K.F. Chan (1975–2024) 陈国辉(1975-2024)
IF 23.9 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2024-10-03 DOI: 10.1016/j.stem.2024.09.005
Thomas H. Ambrosi, Michael T. Longaker
No Abstract
无摘要
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引用次数: 0
Early human development and stem cell-based human embryo models 人类早期发育和基于干细胞的人类胚胎模型
IF 23.9 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2024-10-03 DOI: 10.1016/j.stem.2024.09.002
Marta N. Shahbazi, Vincent Pasque
The use of stem cells to model the early human embryo promises to transform our understanding of developmental biology and human reproduction. In this review, we present our current knowledge of the first 2 weeks of human embryo development. We first focus on the distinct cell lineages of the embryo and the derivation of stem cell lines. We then discuss the intercellular crosstalk that guides early embryo development and how this crosstalk is recapitulated in vitro to generate stem cell-based embryo models. We highlight advances in this fast-developing field, discuss current limitations, and provide a vision for the future.
利用干细胞建立人类早期胚胎模型有望改变我们对发育生物学和人类生殖的认识。在这篇综述中,我们将介绍人类胚胎发育头两周的现有知识。我们首先关注胚胎的不同细胞系和干细胞系的衍生。然后,我们讨论了指导早期胚胎发育的细胞间串联,以及如何在体外重现这种串联以生成基于干细胞的胚胎模型。我们将重点介绍这一快速发展领域的进展,讨论当前的局限性,并展望未来。
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引用次数: 0
Selective translation of nuclear mitochondrial respiratory proteins reprograms succinate metabolism in AML development and chemoresistance 核线粒体呼吸蛋白的选择性翻译重塑了琥珀酸代谢在急性髓细胞性白血病发展和化疗抗药性过程中的作用
IF 23.9 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2024-10-01 DOI: 10.1016/j.stem.2024.09.008
Guoqiang Han, Manman Cui, Pengbo Lu, Tiantian Zhang, Rong Yin, Jin Hu, Jihua Chai, Jing Wang, Kexin Gao, Weidong Liu, Shuxin Yao, Ziyan Cao, Yanbing Zheng, Wen Tian, Rongxia Guo, Min Shen, Zheming Liu, Weiming Li, Shanshan Zhao, Xiangpeng Lin, Haojian Zhang
Mitochondrial adaptations dynamically reprogram cellular bioenergetics and metabolism and confer key properties for human cancers. However, the selective regulation of these mitochondrial responses remains largely elusive. Here, inspired by a genetic screening in acute myeloid leukemia (AML), we identify RAS effector RREB1 as a translational regulator and uncover a unique translation control system for nuclear-encoded mitochondrial proteins in human cancers. RREB1 deletion reduces mitochondrial activities and succinate metabolism, thereby damaging leukemia stem cell (LSC) function and AML development. Replenishing complex II subunit SDHD rectifies these deficiencies. Notably, inhibition of complex II re-sensitizes AML cells to venetoclax treatment. Mechanistically, a short RREB1 variant binds to a conserved motif in the 3′ UTRs and cooperates with elongation factor eEF1A1 to enhance protein translation of nuclear-encoded mitochondrial mRNAs. Overall, our findings reveal a unique translation control mechanism for mitochondrial adaptations in AML pathogenesis and provide a potential strategy for targeting this vulnerability of LSCs.
线粒体的适应性动态地重塑了细胞的生物能和新陈代谢,并赋予了人类癌症的关键特性。然而,这些线粒体反应的选择性调控在很大程度上仍然难以捉摸。在这里,受急性髓性白血病(AML)基因筛选的启发,我们发现 RAS 效应子 RREB1 是一种翻译调节因子,并揭示了人类癌症中核编码线粒体蛋白的独特翻译控制系统。RREB1 缺失会降低线粒体活性和琥珀酸代谢,从而损害白血病干细胞(LSC)功能和急性髓细胞性白血病的发展。补充复合体 II 亚基 SDHD 可以纠正这些缺陷。值得注意的是,抑制复合体II可使AML细胞对venetoclax治疗重新敏感。从机理上讲,短RREB1变体与3′UTR中的保守基团结合,并与延伸因子eEF1A1合作,增强核编码线粒体mRNA的蛋白质翻译。总之,我们的研究结果揭示了线粒体适应性在急性髓细胞性白血病发病机制中的独特翻译控制机制,并为靶向 LSCs 的这一脆弱性提供了潜在的策略。
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引用次数: 0
A human organoid drug screen identifies α2-adrenergic receptor signaling as a therapeutic target for cartilage regeneration 人体类器官药物筛选确定α2-肾上腺素能受体信号传导是软骨再生的治疗靶点
IF 23.9 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2024-09-30 DOI: 10.1016/j.stem.2024.09.001
Xiaocui Wei, Jingyang Qiu, Ruijun Lai, Tiantian Wei, Zhijie Lin, Shijiang Huang, Yuanjun Jiang, Zhanpeng Kuang, Hao Zeng, Yan Gong, Xiaoling Xie, Jun Yang, Yue Zhang, Sheng Zhang, Zhipeng Zou, Xuefei Gao, Xiaochun Bai
Directed differentiation of stem cells toward chondrogenesis in vitro and in situ to regenerate cartilage suffers from off-target differentiation and hypertrophic tendency. Here, we generated a cartilaginous organoid system from human expanded pluripotent stem cells (hEPSCs) carrying a COL2A1mCherry and COL10A1eGFP double reporter, enabling real-time monitoring of chondrogenesis and hypertrophy. After screening 2,040 FDA-approved drugs, we found that α-adrenergic receptor (α-AR) antagonists, especially phentolamine, stimulated chondrogenesis but repressed hypertrophy, while α2-AR agonists reduced chondrogenesis and induced hypertrophy. Phentolamine prevented cartilage degeneration in hEPSC cartilaginous organoid and human cartilage explant models and stimulated microfracture-activated endogenous skeletal stem cells toward hyaline-like cartilage regeneration without fibrotic degeneration in situ. Mechanistically, α2-AR signaling induced hypertrophic degeneration via cyclic guanosine monophosphate (cGMP)-dependent secretory leukocyte protease inhibitor (SLPI) production. SLPI-deleted cartilaginous organoid was degeneration resistant, facilitating large cartilage defect healing. Ultimately, targeting α2-AR/SLPI was a promising and clinically feasible strategy to regenerate cartilage via promoting chondrogenesis and repressing hypertrophy.
在体外和原位引导干细胞向软骨生成方向分化以再生软骨时,会出现脱靶分化和肥大倾向。在这里,我们用携带COL2A1mCherry和COL10A1eGFP双报告基因的人类扩增多能干细胞(hEPSCs)生成了软骨类器官系统,从而实现了对软骨生成和肥大的实时监测。在筛选了 2,040 种美国 FDA 批准的药物后,我们发现α-肾上腺素能受体(α-AR)拮抗剂,尤其是酚妥拉明,能刺激软骨生成,但抑制肥大,而α2-AR 激动剂能减少软骨生成,诱导肥大。酚妥拉明能防止hEPSC软骨类器官模型和人体软骨外植体模型中的软骨退化,并刺激微骨折激活的内源性骨骼干细胞实现透明样软骨再生,而不会出现原位纤维化退化。从机理上讲,α2-AR 信号通过环磷酸鸟苷(cGMP)依赖性分泌型白细胞蛋白酶抑制剂(SLPI)的产生诱导肥大变性。SLPI缺失的软骨类器官具有抗变性能力,有利于大面积软骨缺损的愈合。最终,以α2-AR/SLPI为靶点,通过促进软骨生成和抑制肥大来实现软骨再生,是一种前景广阔、临床可行的策略。
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引用次数: 0
Epitope prime editing shields hematopoietic cells from CD123 immunotherapy for acute myeloid leukemia 表位素编辑可保护造血细胞免受治疗急性髓性白血病的 CD123 免疫疗法的影响
IF 23.9 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2024-09-30 DOI: 10.1016/j.stem.2024.09.003
Rui-Jin Ji, Guo-Hua Cao, Wei-Qiang Zhao, Mu-Yao Wang, Pan Gao, Yi-Zhou Zhang, Xue-Bin Wang, Hou-Yuan Qiu, Di-Di Chen, Xiao-Han Tong, Min Duan, Hao Yin, Ying Zhang
Acute myeloid leukemia (AML) is a malignant cancer characterized by abnormal differentiation of hematopoietic stem and progenitor cells (HSPCs). While chimeric antigen receptor T (CAR-T) cell immunotherapies target AML cells, they often induce severe on-target/off-tumor toxicity by attacking normal cells expressing the same antigen. Here, we used base editors (BEs) and a prime editor (PE) to modify the epitope of CD123 on HSPCs, protecting healthy cells from CAR-T-induced cytotoxicity while maintaining their normal function. Although BE effectively edits epitopes, complex bystander products are a concern. To enhance precision, we optimized prime editing, increasing the editing efficiency from 5.9% to 78.9% in HSPCs. Epitope-modified cells were resistant to CAR-T lysis while retaining normal differentiation and function. Furthermore, BE- or PE-edited HSPCs infused into humanized mice endowed myeloid lineages with selective resistance to CAR-T immunotherapy, demonstrating a proof-of-concept strategy for treating relapsed AML.
急性髓性白血病(AML)是一种以造血干细胞和祖细胞(HSPC)异常分化为特征的恶性肿瘤。虽然嵌合抗原受体T(CAR-T)细胞免疫疗法以急性髓性白血病细胞为靶点,但它们往往会攻击表达相同抗原的正常细胞,从而诱发严重的靶上/瘤外毒性。在这里,我们使用碱基编辑器(BE)和质粒编辑器(PE)修改了HSPC上CD123的表位,保护健康细胞免受CAR-T诱导的细胞毒性,同时保持它们的正常功能。尽管BE能有效编辑表位,但复杂的旁观者产物也是一个问题。为了提高精确度,我们对素体编辑进行了优化,将 HSPCs 中的编辑效率从 5.9% 提高到 78.9%。表位修饰的细胞对 CAR-T 的裂解具有抵抗力,同时还能保持正常的分化和功能。此外,BE或PE编辑的HSPCs注入人源化小鼠体内后,髓系细胞对CAR-T免疫疗法具有选择性抵抗力,证明了治疗复发急性髓细胞性白血病的概念验证策略。
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引用次数: 0
Multiplex CRISPR/Cas9-Based Genome Editing in Human Hematopoietic Stem Cells Models Clonal Hematopoiesis and Myeloid Neoplasia 基于多重 CRISPR/Cas9 基因组编辑的人类造血干细胞克隆性造血和骨髓性肿瘤模型
IF 23.9 1区 医学 Q1 CELL & TISSUE ENGINEERING Pub Date : 2024-09-24 DOI: 10.1016/j.stem.2024.09.012
Zuzana Tothova, John M. Krill-Burger, Katerina D. Popova, Catherine C. Landers, Quinlan L. Sievers, David Yudovich, Roger Belizaire, Jon C. Aster, Elizabeth A. Morgan, Aviad Tsherniak, Benjamin L. Ebert
No Abstract
无摘要
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引用次数: 0
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Cell stem cell
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