Yolk sac cell atlas reveals multiorgan functions during human early development.
Yolk sac cell atlas reveals multiorgan functions during human early development.
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DOI：
10.1126/science.add7564
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发表时间：
2023-08-18
期刊：
影响因子：
--
通讯作者：
Haniffa M
中科院分区：
文献类型：
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作者：
Goh I;Botting RA;Rose A;Webb S;Engelbert J;Gitton Y;Stephenson E;Quiroga Londoño M;Mather M;Mende N;Imaz-Rosshandler I;Yang L;Horsfall D;Basurto-Lozada D;Chipampe NJ;Rook V;Lee JTH;Ton ML;Keitley D;Mazin P;Vijayabaskar MS;Hannah R;Gambardella L;Green K;Ballereau S;Inoue M;Tuck E;Lorenzi V;Kwakwa K;Alsinet C;Olabi B;Miah M;Admane C;Popescu DM;Acres M;Dixon D;Ness T;Coulthard R;Lisgo S;Henderson DJ;Dann E;Suo C;Kinston SJ;Park JE;Polanski K;Marioni J;van Dongen S;Meyer KB;de Bruijn M;Palis J;Behjati S;Laurenti E;Wilson NK;Vento-Tormo R;Chédotal A;Bayraktar O;Roberts I;Jardine L;Göttgens B;Teichmann SA;Haniffa M
胚胎外卵黄囊（YS）确保向发育中的胚胎输送营养支持和氧气，但在人类中仍然不明确。因此，我们通过整合单细胞蛋白质和基因表达数据，收集了受孕后 3-8 周的人类 YS 的综合多组学参考。除了其作为造血部位的公认作用外，我们还强调其在代谢、凝血、血管发育和造血调节中的作用。我们重建了来自造血内皮的 YS 造血干/祖细胞的出现和衰退，并揭示了 YS 特异性的加速巨噬细胞产生的途径，从而为器官发育提供种子。随着胚胎内器官的发育，YS 的多器官功能被取代，随着妊娠的进行，影响重要功能的多方面传递。卵黄囊（YS）产生第一个血液和免疫细胞，并为发育中的胚胎提供营养和代谢支持。我们目前对其功能的理解源自模型系统的关键研究，而人类研究的见解是有限的。单细胞基因组学技术以前所未有的分辨率促进了对人类发育组织的研究。通过对特定组织进行集中、时间分辨的分析，多个器官的血液和免疫细胞图谱得到了极大的增强。为了表征人类 YS 的功能，我们对 YS 和配对的胚胎肝脏进行了单细胞 RNA 测序 (scRNA-seq) 以及转录组和表位的细胞索引 (CITE-seq)。与外部数据集整合后，我们的参考包含来自 10 个样本的 169,798 个细胞，涵盖受孕后 4-8 周 (PCW) 或卡内基阶段 (CS) 10-23。一系列 2D 和 3D 成像技术提供了空间背景和验证。我们将两种造血诱导多能干细胞 (iPSC) 培养方案的产品与我们的参考进行了比较。我们确定 YS 代谢和营养支持起源于内胚层，内胚层产生凝血蛋白和造血生长因子（促红细胞生成素 (EPO) 和血小板生成素 (THPO)）。尽管代谢和凝血蛋白的产生在人类、小鼠和兔子之间是保守的，但 EPO 和 THPO 的产生仅在人类和兔子中观察到。我们重建了从 YS 造血内皮细胞到早期造血干细胞和祖细胞 (HSPC) 的轨迹。利用早期和最终造血的转录组学特征，我们将 YS HSPC 解析为偏向髓系的早期 HSPC，以及偏向淋巴和巨核细胞的最终 HSPC。在 CS14 之前，当造血细胞首次从主动脉-性腺-中肾 (AGM) 区域出现时，人类胚胎肝脏在宏观上仍保持苍白。追踪血红蛋白亚型使我们得出结论，最初的红细胞生成受到 YS 限制。相比之下，在小鼠中，Hb 亚型表明 AGM 前有两波红细胞生成，包括肉眼可见的红色胚胎肝脏的成熟。在 CS14 之前，单核细胞不存在，巨噬细胞通过前巨噬细胞状态源自 HPSC。 CS14后，单核细胞出现，并重建了第二个单核细胞依赖性分化轨迹。 CS14 后出现了一个罕见的 TREM2+ 巨噬细胞子集，具有类似小胶质细胞的转录组特征。针对巨噬细胞产生进行优化的 iPSC 系统概括了巨噬细胞分化的两种途径，但没有产生在发育组织中观察到的巨噬细胞（包括 TREM2+ 巨噬细胞）的多样性。我们的研究阐明了人类发育的一个以前模糊的阶段，其中重要功能是由作为短暂胚胎外器官的 YS 提供的。我们全面的单细胞图谱是研究早期生命特有的细胞分化途径并将其用于组织工程和细胞治疗的宝贵资源。我们将 scRNA-seq 和 CITE-seq 与 2D 和 3D 成像技术相结合，描述了发育中的人类 YS 的功能。我们的研究结果揭示了 YS 对代谢和营养支持以及早期造血的贡献。我们描述了早期造血过程中的骨髓偏向、不同的骨髓分化轨迹、初始红细胞生成的进化分歧以及 YS 对组织巨噬细胞发育的贡献。
The extraembryonic yolk sac (YS) ensures delivery of nutritional support and oxygen to the developing embryo but remains ill-defined in humans. We therefore assembled a comprehensive multiomic reference of human YS from 3-8 post-conception weeks by integrating single-cell protein and gene expression data. Beyond its recognized role as a site of hematopoiesis, we highlight roles in metabolism, coagulation, vascular development, and hematopoietic regulation. We reconstructed the emergence and decline of YS hematopoietic stem/progenitor cells from hemogenic endothelium and revealed a YS-specific accelerated route to macrophage production that seeds developing organs. The multiorgan functions of YS are superseded as intraembryonic organs develop, effecting a multifaceted relay of vital functions as pregnancy proceeds. The yolk sac (YS) generates the first blood and immune cells and provides nutritional and metabolic support to the developing embryo. Our current understanding of its functions derives from pivotal studies in model systems and insights from human studies are limited. Single-cell genomics technologies have facilitated the interrogation of human developmental tissues at unprecedented resolution. Atlases of blood and immune cells from multiple organs have been greatly enhanced by focused, time-resolved analyses of specific tissues. To characterize the functions of human YS, we performed single-cell RNA sequencing (scRNA-seq) and cellular indexing of transcriptomes and epitopes (CITE-seq) on YS and paired embryonic liver. After integration with external datasets, our reference comprised 169,798 cells from 10 samples spanning 4-8 post-conception weeks (PCW) or Carnegie stages (CS) 10-23. A repertoire of 2D and 3D imaging techniques provided spatial context and validation. We compared the products of two hematopoietic inducible pluripotent stem cell (iPSC) culture protocols against our reference. We determined that YS metabolic and nutritional support originates in the endoderm and that endoderm produces coagulation proteins and hematopoietic growth factors (erythropoietin (EPO) and thrombopoietin (THPO)). Although metabolic and coagulation protein production was conserved between humans, mice, and rabbits, EPO and THPO production was observed in humans and rabbits only. We reconstructed trajectories from YS hemogenic endothelium to early hematopoietic stem and progenitor cells (HSPCs). Using transcriptomic signatures of early and definitive hematopoiesis, we parsed YS HSPCs into myeloid-biased early HSPCs, and lymphoid and megakaryocyte-biased definitive HSPCs. Human embryonic liver remained macroscopically pale prior to CS14, when hematopoietic cells first emerge from the aorta–gonad–mesonephros (AGM) region. Tracking hemoglobin subtypes led us to conclude that initial erythropoiesis is YS-restricted. In mice by contrast, Hb subtypes suggested two waves of pre-AGM erythropoiesis, including maturation in the macroscopically red embryonic liver. Before CS14, monocytes were absent and macrophages originated from HPSCs via a pre-macrophage cell state. After CS14, monocytes emerged and a second, monocyte-dependent differentiation trajectory was reconstructed. A rare subset of TREM2+ macrophages, with a microglia-like transcriptomic signature, was present after CS14. The iPSC system optimized for macrophage production recapitulated the two routes to macrophage differentiation but did not generate the diversity of macrophages (including TREM2+ macrophages) observed in developing tissues. Our study illuminates a previously obscure phase of human development, where vital functions are delivered by the YS acting as a transient extraembryonic organ. Our comprehensive single cell atlas represents a valuable resource for studying the cellular differentiation pathways unique to early life and leveraging these for tissue engineering and cellular therapy. We characterized functions of the developing human YS, combining scRNA-seq and CITE-seq, with 2D and 3D imaging techniques. Our findings revealed YS contributions to metabolic and nutritional support, and early hematopoiesis. We characterized myeloid bias in early hematopoiesis, distinct myeloid differentiation trajectories, evolutionary divergence in initial erythropoiesis, and YS contributions to developing tissue macrophages.
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DOI：
10.1126/science.abl5197
发表时间：
2022-05-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Domínguez Conde C;Xu C;Jarvis LB;Rainbow DB;Wells SB;Gomes T;Howlett SK;Suchanek O;Polanski K;King HW;Mamanova L;Huang N;Szabo PA;Richardson L;Bolt L;Fasouli ES;Mahbubani KT;Prete M;Tuck L;Richoz N;Tuong ZK;Campos L;Mousa HS;Needham EJ;Pritchard S;Li T;Elmentaite R;Park J;Rahmani E;Chen D;Menon DK;Bayraktar OA;James LK;Meyer KB;Yosef N;Clatworthy MR;Sims PA;Farber DL;Saeb-Parsy K;Jones JL;Teichmann SA
通讯作者：
Teichmann SA
影响因子：
25
作者：
Eze UC;Bhaduri A;Haeussler M;Nowakowski TJ;Kriegstein AR
通讯作者：
Kriegstein AR
影响因子：
46.9
作者：
Dann, Emma;Henderson, Neil C.;Marioni, John C.
通讯作者：
Marioni, John C.
影响因子：
9.8
作者：
Canu G;Ruhrberg C
通讯作者：
Ruhrberg C
影响因子：
14.8
作者：
Efremova, Mirjana;Vento-Tormo, Miquel;Vento-Tormo, Roser
通讯作者：
Vento-Tormo, Roser