Experimental hematology最新文献_第9页

3031 – DEFINING THE MESODERMAL ORIGINS OF THE HUMAN HEMATOPOIETIC PROGRAMS USING PLURIPOTENT STEM CELLS 3031 -使用多能干细胞确定人类造血程序的中胚层起源

IF 2.1 4区医学 Q2 HEMATOLOGY

Experimental hematology

Pub Date : 2025-11-01 DOI: 10.1016/j.exphem.2025.104972

Quynh Nguyen , Vladimir Manchev , Greg Kent , Donghe Yang , Jamie Kwan , Brenda Cohen , Marion Kennedy , Ian Fernandes , Paraish Misra , Mark Gagliardi , Gordon Keller

The generation of human pluripotent stem cell (hPSC)-derived hematopoietic progenitors for specific therapeutic applications is dependent on the accurate specification of the appropriate hematopoietic program in the dish. Using developmental biology-guided approaches, differentiation protocols have been established, generating the equivalent of the yolk sac (YS) primitive and EMP/LMPP programs as well as an ‘intraembryonic’ definitive program. Recent significant advances include the successful generation of hematopoietic stem cells (HSCs) from the definitive program and the discovery of a YS multipotent progenitor (YS MPP) population specified by the EMP/LMPP program. However, the low frequencies of these cells in the differentiation cultures limit their downstream therapeutic applications. As hematopoietic fates are specified early at the mesoderm induction stage, the inefficient generation of a particular hematopoietic cell type likely stems from the failure to specify the appropriate mesoderm subset. To address this, we have identified a novel set of markers that effectively resolve the heterogeneity within the hematopoietic mesoderm populations, in turn establishing a new model of the embryonic hematopoietic development. Specifically, cell sorting studies revealed that the fates of primitive and YS MPP programs, and, likely, of definitive HSC-independent MPP and HSC programs, are specified from distinct mesoderm populations. These subsets of mesoderm differ in their signaling requirements, kinetics of development, and developmental potential. Collectively, these findings established a novel, comprehensive developmental map of the human hematopoietic system, enabling the precise specification of distinct hematopoietic programs and, in turn, the generation of the otherwise inaccessible hematopoietic progenitors essential for the development of future cell therapies.

人类多能干细胞（hPSC）衍生的造血祖细胞用于特定的治疗应用依赖于在培养皿中适当的造血程序的准确规格。利用发育生物学指导的方法，已经建立了分化方案，产生相当于卵黄囊（YS）原始程序和EMP/LMPP程序以及“胚胎内”最终程序。最近的重大进展包括从最终计划中成功产生造血干细胞（hsc），以及发现EMP/LMPP计划指定的YS多能祖细胞（YS MPP）群体。然而，这些细胞在分化培养中的低频率限制了它们的下游治疗应用。由于造血命运早在中胚层诱导阶段就已确定，特定造血细胞类型的低效产生可能源于未能确定适当的中胚层亚群。为了解决这个问题，我们确定了一组新的标记，有效地解决了造血中胚层群体内的异质性，从而建立了胚胎造血发育的新模型。具体来说，细胞分选研究表明，原始和YS MPP程序的命运，以及最终的HSC独立MPP和HSC程序，都是从不同的中胚层群体中指定的。这些中胚层亚群在它们的信号需求、发育动力学和发育潜力方面有所不同。总的来说，这些发现建立了一个全新的、全面的人类造血系统发育图，能够精确地描述不同的造血程序，反过来，产生对未来细胞疗法的发展至关重要的造血祖细胞。

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引用次数: 0

1013 – EMBRYONIC MACROPHAGES SHAPE THE STEM CELL NICHE. 胚胎巨噬细胞形成干细胞生态位。

IF 2.1 4区医学 Q2 HEMATOLOGY

Experimental hematology

Pub Date : 2025-11-01 DOI: 10.1016/j.exphem.2025.104893

Claudia Waskow

This presentation will explore the role of embryonic versus adult macrophages in establishing the hematopoietic stem cell niche. It will also discuss the impact of the developmental origin of macrophages on both immune cell homeostasis and overall immune function.

本报告将探讨胚胎巨噬细胞与成人巨噬细胞在建立造血干细胞生态位中的作用。它还将讨论巨噬细胞的发育起源对免疫细胞稳态和整体免疫功能的影响。

引用次数: 0

IFC Editorial Board IFC编委会

IF 2.1 4区医学 Q2 HEMATOLOGY

Experimental hematology

Pub Date : 2025-11-01 DOI: 10.1016/S0301-472X(25)00560-0

引用次数: 0

2020 – PROCR+ ENDOTHELIAL PROGENITOR CELLS ORCHESTRATE HEMATOPOIETIC STEM CELL FUNCTION VIA MESENCHYMAL STEM CELL-MEDIATED REGULATORY CROSSTALK 2020 - procr +内皮祖细胞通过间充质干细胞介导的调节串扰协调造血干细胞功能

IF 2.1 4区医学 Q2 HEMATOLOGY

Experimental hematology

Pub Date : 2025-11-01 DOI: 10.1016/j.exphem.2025.104933

Chang Xu, Xue Lv, Shangda Yang, Yanling Lv, Tao Cheng, Hui Cheng

The hematopoietic stem cell (HSC) microenvironment comprises heterogeneous niches within the bone marrow (BM). Although the BM vascular endothelium is known to regulate HSC homeostasis, the specific roles of distinct endothelial cell (EC) subpopulations remain unclear. Here, we identified a subpopulation of Procr-expressing ECs with progenitor-like properties. Following irradiation-induced injury, Procr⁺ ECs in BM exhibited approximately 10-fold expansion, driving vascular regeneration. Procr deficiency in ECs impaired vascular regeneration, disrupted mesenchymal stem cell (MSC) differentiation into adipogenic/osteogenic lineage, and ultimately compromised hematopoiesis by reducing HSC self-renewal capacity and skewing differentiation toward the myeloid lineage. Mechanistically, Procr promoted Dll4 expression in ECs by facilitating Foxc2 nuclear translocation, thereby sustaining the Dll4-Notch3 signaling axis essential for MSC–EC crosstalk. Notably, pharmacologic activation of Notch signaling rescued the hematopoietic and microenvironmental defects induced by EC-specific Procr knockout. Our work defines Procr⁺ ECs as pivotal niche orchestrators, revealing a therapeutic target for hematopoietic homeostasis maintenance.

造血干细胞（HSC）微环境包括骨髓（BM）内的异质生态位。虽然已知BM血管内皮调节HSC稳态，但不同内皮细胞（EC）亚群的具体作用尚不清楚。在这里，我们鉴定了具有祖细胞样特性的表达procr的ECs亚群。在辐照损伤后，BM中的Procr + ECs表现出大约10倍的扩张，推动血管再生。内皮细胞Procr缺乏会损害血管再生，破坏间充质干细胞（MSC）向脂肪/成骨谱系的分化，并最终通过降低HSC自我更新能力和向髓系分化而损害造血功能。在机制上，Procr通过促进Foxc2核易位促进了Dll4在ec中的表达，从而维持了MSC-EC串扰所必需的Dll4- notch3信号轴。值得注意的是，Notch信号的药理激活挽救了ec特异性Procr敲除引起的造血和微环境缺陷。我们的研究将Procr + ECs定义为关键的生态位协调者，揭示了维持造血稳态的治疗靶点。

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引用次数: 0

2008 – IDENTIFICATION OF NOVEL CNS NICHE-SPECIFIC IMMUNE REGULATION AND GROWTH FACTOR SIGNALING IN INFANT KMT2A-REARRANGED B-ALL 2008 -在婴儿kmt2a重排b-all中发现新的中枢神经系统小众特异性免疫调节和生长因子信号

IF 2.1 4区医学 Q2 HEMATOLOGY

Experimental hematology

Pub Date : 2025-11-01 DOI: 10.1016/j.exphem.2025.104921

Katrin Ottersbach , Alasdair Duguid , Camille Malouf , Tom Leah , Leslie Nitsche , Neil Barrett , Owen Smith , Chris Halsey

Infant B-cell acute lymphoblastic leukemia (B-ALL) with KMT2A rearrangements is a rare and aggressive disease with poor outcomes. This young patient group also suffers from particularly high rates of central nervous system (CNS) involvement, which significantly contributes to the dismal prognosis, and the treatment of which causes severe neurotoxicity. There is limited understanding of how leukemia cells can infiltrate and survive in the nutrient-poor CNS niche and how they interact with the local immune system. This has hindered the development of effective therapies, especially as current immunotherapies have reduced efficacy in the CNS environment. Using an immunocompetent KMT2A-AFF1+ infant B-ALL murine model previously developed in our laboratory, we have carried out extensive transcriptomic studies, followed by functional validation, to identify unique adaptations of leukemia cells within the CNS niche. We observed that the CNS microenvironment selects for a more quiescent and potentially more therapy-resistant leukemic-propagating cell population that can cause systemic relapse. We also describe suppressed T-cell and macrophage activity in the CNS, suggesting niche-specific immune escape mechanisms that carry important implications for current immunotherapy efforts. Additionally, we uncover PI3K pathway activation as a key driver of CNS leukemia propagation, with miR-93 emerging as a potential upstream regulator. We confirm miR-93 upregulation in patient samples, suggesting its suitability as a novel biomarker for CNS involvement. Critically, miR-93 knockdown impairs CNS leukemia engraftment, highlighting its niche-specific role in leukemia biology. These data highlight novel CNS niche-specific leukemia adaptations, immune regulation, and growth factor signaling pathways, which may pave the way for targeted CNS-specific interventions for infant B-ALL.

伴有KMT2A重排的婴儿b细胞急性淋巴细胞白血病（B-ALL）是一种罕见的侵袭性疾病，预后较差。这一年轻患者群体还患有中枢神经系统（CNS）受累率特别高，这显著导致预后不佳，其治疗会导致严重的神经毒性。人们对白血病细胞如何在营养贫乏的中枢神经系统中浸润和存活以及它们如何与局部免疫系统相互作用的了解有限。这阻碍了有效疗法的发展，特别是目前的免疫疗法在中枢神经系统环境中的疗效降低。利用我们实验室先前开发的免疫活性KMT2A-AFF1+婴儿B-ALL小鼠模型，我们进行了广泛的转录组学研究，随后进行了功能验证，以确定白血病细胞在中枢神经系统生态位中的独特适应性。我们观察到，中枢神经系统微环境选择了更安静的、可能更耐药的白血病增殖细胞群，这些细胞群可能导致全身复发。我们还描述了中枢神经系统中被抑制的t细胞和巨噬细胞活性，这表明小生境特异性免疫逃逸机制对当前的免疫治疗工作具有重要意义。此外，我们发现PI3K通路激活是中枢神经系统白血病传播的关键驱动因素，miR-93成为潜在的上游调节因子。我们证实了患者样本中miR-93的上调，表明其作为中枢神经系统参与的一种新的生物标志物的适用性。关键的是，miR-93敲低会损害CNS白血病的植入，突出其在白血病生物学中的利基特异性作用。这些数据强调了新的中枢神经系统利基特异性白血病适应、免疫调节和生长因子信号通路，这可能为靶向中枢神经系统特异性干预婴儿B-ALL铺平道路。

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引用次数: 0

2004 – RETROTRANSPOSONS ARE CO-OPTED TO ACTIVATE HEMATOPOIETIC STEM CELLS AND ERYTHROPOIESIS DURING HEMATOPOIETIC STRESS 2004 -在造血应激过程中，逆转录转座子被用来激活造血干细胞和红细胞生成

IF 2.1 4区医学 Q2 HEMATOLOGY

Experimental hematology

Pub Date : 2025-11-01 DOI: 10.1016/j.exphem.2025.104917

Julia Phan , Brandon Chen , Zhiyu Zhao , Alpaslan Tasdogan , Sean Morrison

Hematopoietic stem cells (HSCs) reside in a quiescent state within the bone marrow under steady-state conditions. During hematopoietic stresses, HSCs are activated to increase production of blood cells in extramedullary tissues. One such stress is pregnancy, when HSC activation increases erythropoiesis to prevent anemia; however, our understanding of the mechanisms is limited.

We found that retrotransposon transcription increased during pregnancy and after serial bleeding. Reverse transcription of retrotransposons can lead to cyclic GMP-AMP synthase- stimulator of interferon genes (cGAS-STING) signaling pathway activation. During pregnancy, treating mice with reverse transcriptase inhibitors, which would prevent cGAS-STING activation by retrotransposons, and STING or cGAS deficiency reduced HSC cell division, numbers of HSCs and erythroid progenitors in spleens, and red blood cell counts. cGAS-STING signaling promotes interferon (IFN) expression. HSCs from the spleens of pregnant mice had increased IFN expression and IFN gene signature, which was largely blocked by STING deficiency and type I IFN receptor deficiency. Deficiency for type I IFN receptor reduced the numbers of HSCs and erythroid progenitors in the spleen during pregnancy. HSCs from humans also had increased retrotransposon transcription during pregnancy and increased IFN gene signature. Reverse transcriptase inhibitor use in humans attenuated changes in IFN gene signature and was associated with anemia during pregnancy.

Our data suggest retrotransposons activate HSCs and erythropoiesis during hematopoietic stresses through cGAS-STING-IFN signaling, increasing HSC cell division and splenic erythropoiesis. This may provide an explanation for why mammals, unlike some other species, did not eliminate active retrotransposons from their genomes during evolution.

在稳态条件下，造血干细胞（hsc）在骨髓内处于静止状态。在造血应激过程中，造血干细胞被激活以增加髓外组织中血细胞的产生。其中一个压力是怀孕，当HSC激活增加红细胞生成以预防贫血；然而，我们对其机制的理解是有限的。我们发现逆转录转座子转录在怀孕期间和连续出血后增加。逆转录转座子的逆转录可导致环状GMP-AMP合成酶-干扰素基因刺激因子（cGAS-STING）信号通路的激活。在怀孕期间，用逆转录酶抑制剂（可以阻止逆转录转座子激活cGAS-STING）治疗小鼠，STING或cGAS缺乏会减少HSC细胞分裂、脾脏中HSC和红系祖细胞的数量以及红细胞计数。cGAS-STING信号传导促进干扰素（IFN）的表达。妊娠小鼠脾脏造血干细胞中IFN表达增加，IFN基因标记增加，这在很大程度上被STING缺乏和I型IFN受体缺乏阻断。I型IFN受体缺乏导致妊娠期间脾脏造血干细胞和红系祖细胞数量减少。人类造血干细胞在怀孕期间也有逆转录转座子转录增加和IFN基因标记增加。在人类中使用逆转录酶抑制剂可减弱IFN基因特征的变化，并与妊娠期间的贫血有关。我们的数据表明，在造血压力下，逆转录转座子通过cGAS-STING-IFN信号激活HSC和红细胞生成，增加HSC细胞分裂和脾红细胞生成。这也许可以解释为什么哺乳动物在进化过程中不像其他物种那样从基因组中消除活跃的反转录转座子。

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引用次数: 0

1020 – TARGETING THE EBF1-ITGB8 AXIS IN THE BONE MARROW NICHE AS A PROMISING THERAPEUTIC APPROACH FOR MYELOFIBROSIS 1020 -靶向骨髓生态位中的ebf1-itgb8轴作为治疗骨髓纤维化的一种有前景的方法

IF 2.1 4区医学 Q2 HEMATOLOGY

Experimental hematology

Pub Date : 2025-11-01 DOI: 10.1016/j.exphem.2025.104900

Marta Derecka , Melodie Doute , Lyudmila Tsurkan , Rashid Mehmood , Nicholas Morchel , Lahiri Konada , Jayaram Sakthi , Jia-Hua Qu , Lei Han , Te Ling , Amha Atakilit , Bridget Marcellino , Ronald Hoffman , John Crispino , Dean Sheppard , Jeremy Crawfor

Fibrotic remodeling of the bone marrow (BM) niche is a characteristic feature of myelofibrosis (MF) that contributes to disease progression. In MF, mesenchymal stromal cells (MSCs) produce excessive amounts of inflammatory cytokines and extracellular matrix, leading to BM fibrosis and impaired blood production, extramedullary hematopoiesis, and fatal BM failure. Although the genetic events that initiate MF in hematopoietic cells are well defined, our understanding of the mechanisms responsible for BM fibrosis remains incomplete. Here, we show that transcription factor EBF1 is a key regulator of the fibrotic gene program in mouse and human MSCs. EBF1 is upregulated in pre-fibrotic MSCs, and mice with MSC-specific deletion of Ebf1 exhibit reduced BM fibrosis, decreased expansion of myeloid cells, and splenomegaly when transplanted with MPL^W515L expressing cells. Moreover, we identify ITGB8 as an EBF1-regulated gene with therapeutic potential. MF mice treated with ITGB8-neutralizing antibodies or with MSC-specific Itgb8 deletion show reduced disease burden, as indicated by decreased marrow fibrosis, significantly reduced frequencies of MPL mutant cells, and lower inflammation in the BM. Our data indicate that targeting the EBF1-ITGB8 axis in the MF niche may have therapeutic benefits.

骨髓（BM）生态位的纤维化重塑是骨髓纤维化（MF）的一个特征，有助于疾病进展。在MF中，间充质间质细胞（MSCs）产生过量的炎症细胞因子和细胞外基质，导致BM纤维化和血液生成、髓外造血功能受损，以及致命的BM衰竭。虽然在造血细胞中启动MF的遗传事件已经被很好地定义，但我们对骨髓纤维化机制的理解仍然不完整。在这里，我们发现转录因子EBF1是小鼠和人间充质干细胞中纤维化基因程序的关键调节因子。EBF1在纤维化前MSCs中上调，MSCs特异性缺失EBF1的小鼠在移植表达MPLW515L的细胞时表现出BM纤维化减少、髓系细胞扩增减少和脾肿大。此外，我们发现ITGB8是一个具有治疗潜力的ebf1调控基因。用Itgb8中和抗体或msc特异性Itgb8缺失治疗的MF小鼠显示出疾病负担减轻，这表明骨髓纤维化减少，MPL突变细胞的频率显著降低，BM中的炎症降低。我们的数据表明，靶向MF生态位中的EBF1-ITGB8轴可能具有治疗益处。

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引用次数: 0

1018 – EARLY LIFE B CELL MEMORY IS ARCHIVED IN THE MOUSE B-1 CELL COMPARTMENT AND DRIVES CHRONIC LYMPHOCYTIC LEUKEMIA-LIKE DISEASE 1018 -早期b细胞记忆被保存在小鼠b -1细胞室中，并驱动慢性淋巴细胞白血病样疾病

IF 2.1 4区医学 Q2 HEMATOLOGY

Experimental hematology

Pub Date : 2025-11-01 DOI: 10.1016/j.exphem.2025.104898

Joan Yuan, Niklas Segren

The adult B cell pool is a developmental mosaic comprising short-lived naïve B cells and long-lived memory B cells. Using genetic time-stamping, we previously showed that B cells generated early in life contributed substantially to the adult mouse immune system. In this study, we found that anatomically distinct early life origin (ELO) B cell subsets share a memory-like molecular signature. Notably, B-1 cells exhibited an enrichment for the PD-L2/CD80 double-positive (DP) immunophenotype associated with highly differentiated B cell memory. Indeed, microbial antigen exposure in neonates expanded distinct specificities within the DP B-1 cell compartment, identifying the latter as a reservoir of early life IgM memory. Human B cell chronic lymphocytic leukemia (CLL) is a disease marked by the accumulation of memory-like B cells. By applying time-stamping to a mouse model for unmutated CLL (U-CLL), we demonstrated that leukemic expansion is driven by DP B-1 cell clones that first emerged before postnatal day 10. Importantly, ELO B-1 cells represented the subset in healthy mice that most closely resembled the molecular profile of human U-CLL. Collectively, these results provide evidence of functional convergence between mouse B-1 cells and IgM memory, which serves as a cross-species reference point for understanding the origins of U-CLL pathology.

成体B细胞池是由短寿命naïve B细胞和长寿命记忆B细胞组成的发育嵌合体。利用遗传时间戳，我们先前表明，在生命早期产生的B细胞对成年小鼠的免疫系统有重大贡献。在这项研究中，我们发现解剖学上不同的早期生命起源（ELO） B细胞亚群具有类似记忆的分子特征。值得注意的是，B-1细胞表现出与高度分化的B细胞记忆相关的PD-L2/CD80双阳性（DP）免疫表型的富集。事实上，在新生儿中暴露微生物抗原扩大了DP B-1细胞区室内的明显特异性，确定后者是早期生命IgM记忆的储存库。人B细胞慢性淋巴细胞白血病（CLL）是一种以记忆样B细胞积累为特征的疾病。通过将时间戳应用于未突变CLL （U-CLL）小鼠模型，我们证明了白血病扩张是由出生后10天之前首次出现的DP B-1细胞克隆驱动的。重要的是，ELO B-1细胞代表了健康小鼠中最接近人类U-CLL分子谱的亚群。总之，这些结果为小鼠B-1细胞和IgM记忆之间的功能趋同提供了证据，这可以作为理解U-CLL病理起源的跨物种参考点。

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引用次数: 0

1002 – MITOCHONDRIA REGULATE THE CELL FATE DECISIONS OF MEGAKARYOCYTE-ERYTHROID PROGENITORS 线粒体调节巨核红细胞祖细胞的命运决定

IF 2.1 4区医学 Q2 HEMATOLOGY

Experimental hematology

Pub Date : 2025-11-01 DOI: 10.1016/j.exphem.2025.104882

Hozumi Motohashi

Recent studies highlight the critical role of mitochondria in hematopoiesis, especially in stem cell function and erythroid maturation. To explore mitochondrial contributions to cell lineage commitment in hematopoietic progenitors, we utilized Cars2 mutant mice, an ideal model for this purpose. CARS2, a mitochondrial isoform of cysteinyl-tRNA synthetase, has cysteine persulfide synthase (CPERS) activity. Our new mouse model, with reduced CPERS activity, showed that the Cars2 mutation led to mitochondrial inhibition and anemia by suppressing erythroid commitment in megakaryocyte-erythroid progenitors (MEPs). This suppression was reproduced using mitochondrial electron transport chain inhibitors. We identified two distinct MEP populations based on the mitochondrial content: mitochondria-rich MEPs favored erythroid differentiation, whereas the mitochondria-poor MEPs favored megakaryocyte differentiation. These findings reveal critical contributions of mitochondria to MEP lineage selection, acting as a “mitochondrial navigation” for lineage commitment.

最近的研究强调了线粒体在造血过程中的关键作用，特别是在干细胞功能和红细胞成熟方面。为了探索线粒体对造血祖细胞谱系承诺的贡献，我们使用了Cars2突变小鼠，这是一种理想的模型。CARS2是半胱氨酸- trna合成酶的线粒体同工型，具有半胱氨酸过硫合成酶（CPERS）活性。我们的新小鼠模型，CPERS活性降低，表明Cars2突变通过抑制巨核细胞-红细胞祖细胞（MEPs）的红细胞承诺导致线粒体抑制和贫血。使用线粒体电子传递链抑制剂可以重现这种抑制。我们根据线粒体含量确定了两种不同的MEP群体：线粒体丰富的MEP倾向于红细胞分化，而线粒体贫乏的MEP倾向于巨核细胞分化。这些发现揭示了线粒体对MEP谱系选择的重要贡献，作为谱系承诺的“线粒体导航”。

引用次数: 0

3022 – COMPARING IN VITRO HUMAN PLURIPOTENT STEM CELL MODELS TO ASSESS HEMATOPOIETIC DEVELOPMENT 3022 -比较体外人多能干细胞模型来评估造血发育

IF 2.1 4区医学 Q2 HEMATOLOGY

Experimental hematology

Pub Date : 2025-11-01 DOI: 10.1016/j.exphem.2025.104963

Liza Dijkhuis , Meritxell Vinyoles , Edurne Solabarrieta , Simon Rouschop , Helena Kooi , Clara Bueno , Eszter Varga , Emile Van den Akker , Pablo Menendez , Arthur Flohr Svendsen , Cristina Pina , Gerald de Haan

Generating human hematopoietic stem cells (HSC) from pluripotent stem cell (PSC)-derived in vitro models is of great interest. Success would increase HSC availability for clinical purposes and expand detailed understanding of blood development. Efforts from multiple laboratories have shown that blood progenitors, and indeed HSCs, can be generated from PSC sources. However, protocols diverge substantially and have not been compared systematically.

In this study, we contrasted two models of developmental blood formation based on human PSC. Specifically, we compared a spontaneouly forming, low cytokine-input embryoid body (EB)-based system and a controlled spatial-temporal accurate gastruloid model. We characterized both models based on immunophenotypic subpopulations of hemogenic endothelium (HE, read as CD31+CD34+ cells), specification of HSC/progenitors (HSPC, CD34+CD43+), and mature hematopoietic cells (CD43+CD45+). We traced the expression of key developmental hematopoietic markers (GATA2, RUNX1, MECOM, and HLF) and performed global transcriptomics, including at the single-cell level. The data showed the emergence of HE and HSPC in both models, albeit with different abundances. In current versions of the protocols, relative HSPC output is lower from gastruloids, potentially reflecting balanced production of other, nonhematopoietic cell types and/or the stepwise reconstitution of primitive, predefinitive, and definitive hematopoiesis. Ongoing transcriptomic and functional analyses specifically interrogate the nature of the progenitors they formed and their neighboring cells.

These analyses will shed light on the parameters that influence commitment at the different hematopoietic waves, thus facilitating understanding and emulation of human hematopoietic development and ultimately increasing robust HSC sources for stem cell transplantations.

从多能干细胞（PSC）衍生的体外模型中生成人类造血干细胞（HSC）是一个非常有趣的问题。成功将增加临床用途的造血干细胞的可用性，并扩大对血液发育的详细了解。多个实验室的研究表明，造血祖细胞和造血干细胞可以从PSC来源生成。然而，不同的协议差异很大，还没有进行系统的比较。在这项研究中，我们对比了两种基于人类PSC的发育性血液形成模型。具体来说，我们比较了一个自发形成的、低细胞因子输入的基于胚胎体（EB）的系统和一个受控的时空精确的胃原体模型。我们基于造血内皮（HE，称为CD31+CD34+细胞）的免疫表型亚群，HSC/祖细胞（HSPC, CD34+CD43+）和成熟造血细胞（CD43+CD45+）的特异性来表征这两种模型。我们追踪了关键发育造血标志物（GATA2, RUNX1， MECOM和HLF）的表达，并进行了全球转录组学，包括在单细胞水平。数据显示，尽管丰度不同，但在两种模型中都出现了HE和HSPC。在当前版本的方案中，原肠样细胞的相对HSPC输出较低，这可能反映了其他非造血细胞类型和/或原始、预先和最终造血的逐步重建的平衡生产。正在进行的转录组学和功能分析特别询问了它们形成的祖细胞及其邻近细胞的性质。这些分析将揭示影响不同造血波的参数，从而促进对人类造血发育的理解和模拟，并最终为干细胞移植增加可靠的造血干细胞来源。

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引用次数: 0