Cui, L. et al. Spatial transcriptomic characterization of a Carnegie stage 7 human embryo. Nat. Cell Biol. 27, 360–369 (2025).
Tyser, R. C. V. et al. Single-cell transcriptomic characterization of a gastrulating human embryo. Nature 600, 285–289 (2021).
Xiao, Z. et al. 3D reconstruction of a gastrulating human embryo. Cell 187, 2855–2874.e2819 (2024).
Luckett, W. P. Origin and differentiation of the yolk sac and extraembryonic mesoderm in presomite human and rhesus monkey embryos. Am. J. Anat. 152, 59–97 (1978).
Palis, J. & Yoder, M. C. Yolk-sac hematopoiesis: the first blood cells of mouse and man. Exp. Hematol. 29, 927–936 (2001).
Ross, C. & Boroviak, T. E. Origin and function of the yolk sac in primate embryogenesis. Nat. Commun. 11, 3760 (2020).
Calvanese, V. & Mikkola, H. K. A. The genesis of human hematopoietic stem cells. Blood 142, 519–532 (2023).
Farrell, J. A. et al. Single-cell reconstruction of developmental trajectories during zebrafish embryogenesis. Science 360, eaar3131 (2018).
Kretzschmar, J., Goodwin, K. & McDole, K. Organizer activity in the mouse embryo. Cells Dev. 184, 204001 (2025).
Bae, S., Reid, C. D. & Kessler, D. S. Siamois and Twin are redundant and essential in formation of the Spemann organizer. Dev. Biol. 352, 367–381 (2011).
Kumar, V., Park, S., Lee, U. & Kim, J. The organizer and its signaling in embryonic development. J. Dev. Biol. 9, 47 (2021).
Martyn, I., Kanno, T. Y., Ruzo, A., Siggia, E. D. & Brivanlou, A. H. Self-organization of a human organizer by combined Wnt and Nodal signalling. Nature 558, 132–135 (2018).
Kinder, S. J. et al. The organizer of the mouse gastrula is composed of a dynamic population of progenitor cells for the axial mesoderm. Development 128, 3623–3634 (2001).
Martinez Arias, A. & Steventon, B. On the nature and function of organizers. Development 145, dev159525 (2018).
Manning, E. & Placzek, M. Organizing activities of axial mesoderm. Curr. Top. Dev. Biol. 157, 83–123 (2024).
Zhu, Q. et al. Decoding anterior-posterior axis emergence among mouse, monkey, and human embryos. Dev. Cell 58, 63–79.e64 (2023).
Ginhoux, F. & Guilliams, M. Tissue-resident macrophage ontogeny and homeostasis. Immunity 44, 439–449 (2016).
Neo, W. H., Lie, A. L. M., Fadlullah, M. Z. H. & Lacaud, G. Contributions of embryonic HSC-independent hematopoiesis to organogenesis and the adult hematopoietic system. Front. Cell Dev. Biol. 9, 631699 (2021).
Palis, J. Hematopoietic stem cell-independent hematopoiesis: emergence of erythroid, megakaryocyte, and myeloid potential in the mammalian embryo. FEBS Lett. 590, 3965–3974 (2016).
Yokomizo, T. et al. Independent origins of fetal liver haematopoietic stem and progenitor cells. Nature 609, 779–784 (2022).
Yokomizo, T. & Suda, T. Development of the hematopoietic system: expanding the concept of hematopoietic stem cell-independent hematopoiesis. Trends Cell Biol. 34, 161–172 (2024).
Dzierzak, E. & Bigas, A. Blood development: hematopoietic stem cell dependence and independence. Cell Stem Cell 22, 639–651 (2018).
Du, J., Li, Z., Gong, Y., Lan, Y. & Liu, B. Integrative cross-species transcriptome analysis reveals earlier occurrence of myelopoiesis in pre-circulation primates compared to mice. Zool. Res. 45, 1276–1286 (2024).
Ditadi, A., Sturgeon, C. M. & Keller, G. A view of human haematopoietic development from the Petri dish. Nat. Rev. Mol. Cell Biol. 18, 56–67 (2017).
Spencer Chapman, M. et al. Lineage tracing of human development through somatic mutations. Nature 595, 85–90 (2021).
Takashina, T. Haemopoiesis in the human yolk sac. J. Anat. 151, 125–135 (1987).
Biben, C. et al. In vivo clonal tracking reveals evidence of haemangioblast and haematomesoblast contribution to yolk sac haematopoiesis. Nat. Commun. 14, 41 (2023).
Lancrin, C. et al. The haemangioblast generates haematopoietic cells through a haemogenic endothelium stage. Nature 457, 892–895 (2009).
Hou, S. et al. New insights into the endothelial origin of hematopoietic system inspired by “TIF” approaches. Blood Sci. 6, e00199 (2024).
Dias, A. et al. A temporal coordination between Nodal and Wnt signalling governs the emergence of the mammalian body plan. Preprint at bioRxiv https://doi.org/10.1101/2025.01.11.632562 (2025).
Wirschell, M. et al. The nexin–dynein regulatory complex subunit DRC1 is essential for motile cilia function in algae and humans. Nat. Genet. 45, 262–268 (2013).
Pijuan-Sala, B. et al. A single-cell molecular map of mouse gastrulation and early organogenesis. Nature 566, 490–495 (2019).
Zhai, J. et al. Primate gastrulation and early organogenesis at single-cell resolution. Nature 612, 732–738 (2022).
Messmer, T. et al. Transcriptional heterogeneity in naive and primed human pluripotent stem cells at single-cell resolution. Cell Rep. 26, 815–824.e814 (2019).
Sampath Kumar, A. et al. Spatiotemporal transcriptomic maps of whole mouse embryos at the onset of organogenesis. Nat. Genet. 55, 1176–1185 (2023).
Bandyopadhyay, S. et al. Mapping the cellular biogeography of human bone marrow niches using single-cell transcriptomics and proteomic imaging. Cell 187, 3120–3140.e3129 (2024).
Bian, Z. et al. Deciphering human macrophage development at single-cell resolution. Nature 582, 571–576 (2020).
Tober, J. et al. The megakaryocyte lineage originates from hemangioblast precursors and is an integral component both of primitive and of definitive hematopoiesis. Blood 109, 1433–1441 (2007).
Cheung, P. et al. Repression of CTSG, ELANE and PRTN3-mediated histone H3 proteolytic cleavage promotes monocyte-to-macrophage differentiation. Nat. Immunol. 22, 711–722 (2021).
Makita, T., Duncan, S. A. & Sucov, H. M. Retinoic acid, hypoxia, and GATA factors cooperatively control the onset of fetal liver erythropoietin expression and erythropoietic differentiation. Dev. Biol. 280, 59–72 (2005).
Chen, H., Li, D. & Bar-Joseph, Z. SCS: cell segmentation for high-resolution spatial transcriptomics. Nat. Methods 20, 1237–1243 (2023).
Byrd, N. et al. Hedgehog is required for murine yolk sac angiogenesis. Development 129, 361–372 (2002).
Petty, A. J. et al. Hedgehog signaling promotes tumor-associated macrophage polarization to suppress intratumoral CD8+ T cell recruitment. J. Clin. Invest. 129, 5151–5162 (2019).
Goh, I. et al. Yolk sac cell atlas reveals multiorgan functions during human early development. Science 381, eadd7564 (2023).
Rossmann, M. P. & Palis, J. Developmental regulation of primitive erythropoiesis. Curr. Opin. Hematol. 31, 71–81 (2024).
Ni, Y. et al. Human yolk sac-derived innate lymphoid-biased multipotent progenitors emerge prior to hematopoietic stem cell formation. Dev. Cell 59, 2626–2642.e2626 (2024).
Xiang, L. et al. A developmental landscape of 3D-cultured human pre-gastrulation embryos. Nature 577, 537–542 (2020).
Zhou, F. et al. Reconstituting the transcriptome and DNA methylome landscapes of human implantation. Nature 572, 660–664 (2019).
Dattani, A. et al. Naive pluripotent stem cell-based models capture FGF-dependent human hypoblast lineage specification. Cell Stem Cell 31, 1058–1071.e1055 (2024).
Hislop, J. et al. Modelling post-implantation human development to yolk sac blood emergence. Nature 626, 367–376 (2024).
Okubo, T. et al. Hypoblast from human pluripotent stem cells regulates epiblast development. Nature 626, 357–366 (2024).
Séguin, C. A., Draper, J. S., Nagy, A. & Rossant, J. Establishment of endoderm progenitors by SOX transcription factor expression in human embryonic stem cells. Cell Stem Cell 3, 182–195 (2008).
Tamaoki, N. et al. Self-organized yolk sac-like organoids allow for scalable generation of multipotent hematopoietic progenitor cells from induced pluripotent stem cells. Cell Rep. Methods 3, 100460 (2023).
Wamaitha, S. E. et al. Gata6 potently initiates reprograming of pluripotent and differentiated cells to extraembryonic endoderm stem cells. Genes Dev. 29, 1239–1255 (2015).
de Jong, J. L. & Zon, L. I. Use of the zebrafish system to study primitive and definitive hematopoiesis. Annu. Rev. Genet. 39, 481–501 (2005).
Hoeffel, G. et al. C-Myb+ erythro-myeloid progenitor-derived fetal monocytes give rise to adult tissue-resident macrophages. Immunity 42, 665–678 (2015).
Lee, C. Z. W., Kozaki, T. & Ginhoux, F. Studying tissue macrophages in vitro: are iPSC-derived cells the answer? Nat. Rev. Immunol. 18, 716–725 (2018).
Chen, A. et al. Spatiotemporal transcriptomic atlas of mouse organogenesis using DNA nanoball-patterned arrays. Cell 185, 1777–1792.e1721 (2022).
Wang, M. et al. High-resolution 3D spatiotemporal transcriptomic maps of developing Drosophila embryos and larvae. Dev. Cell 57, 1271–1283.e1274 (2022).
Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15–21 (2013).
Xia, C. R., Cao, Z. J., Tu, X. M. & Gao, G. Spatial-linked alignment tool (SLAT) for aligning heterogenous slices. Nat. Commun. 14, 7236 (2023).
Hao, Y. et al. Dictionary learning for integrative, multimodal and scalable single-cell analysis. Nat. Biotechnol. 42, 293–304 (2024).
Korsunsky, I. et al. Fast, sensitive and accurate integration of single-cell data with Harmony. Nat. Methods 16, 1289–1296 (2019).
Stuart, T. et al. Comprehensive integration of single-cell data. Cell 177, 1888–1902.e1821 (2019).
Choudhary, S. & Satija, R. Comparison and evaluation of statistical error models for scRNA-seq. Genome Biol. 23, 27 (2022).
Maher, K. et al. Mitigating autocorrelation during spatially resolved transcriptomics data analysis. Preprint at bioRxiv https://doi.org/10.1101/2023.06.30.547258 (2023).
Singhal, V. et al. BANKSY unifies cell typing and tissue domain segmentation for scalable spatial omics data analysis. Nat. Genet. 56, 431–441 (2024).
Dong, K. & Zhang, S. Deciphering spatial domains from spatially resolved transcriptomics with an adaptive graph attention auto-encoder. Nat. Commun. 13, 1739 (2022).
Long, Y. et al. Spatially informed clustering, integration, and deconvolution of spatial transcriptomics with GraphST. Nat. Commun. 14, 1155 (2023).
Wu, T. et al. clusterProfiler 4.0: A universal enrichment tool for interpreting omics data. Innovation 2, 100141 (2021).
Corsini, M. et al. In situ DNA/protein interaction assay to visualize transcriptional factor activation. Methods Protoc. 3, 80 (2020).
Gu, Z., Gu, L., Eils, R., Schlesner, M. & Brors, B. circlize implements and enhances circular visualization in R. Bioinformatics 30, 2811–2812 (2014).
Gulati, G. S. et al. Single-cell transcriptional diversity is a hallmark of developmental potential. Science 367, 405–411 (2020).
Kang, M. et al. Improved reconstruction of single-cell developmental potential with CytoTRACE 2. Nat. Methods 22, 2258–2263 (2025).
Bhattacharya, B. et al. Gene expression in human embryonic stem cell lines: unique molecular signature. Blood 103, 2956–2964 (2004).
Cao, J. et al. The single-cell transcriptional landscape of mammalian organogenesis. Nature 566, 496–502 (2019).
Bergen, V., Lange, M., Peidli, S., Wolf, F. A. & Theis, F. J. Generalizing RNA velocity to transient cell states through dynamical modeling. Nat. Biotechnol. 38, 1408–1414 (2020).
Street, K. et al. Slingshot: cell lineage and pseudotime inference for single-cell transcriptomics. BMC Genomics 19, 477 (2018).
Qiu, X. et al. Mapping transcriptomic vector fields of single cells. Cell 185, 690–711.e645 (2022).
Wolf, F. A., Angerer, P. & Theis, F. J. SCANPY: large-scale single-cell gene expression data analysis. Genome Biol. 19, 15 (2018).
Hastie, T. J. Generalized Additive Models (Routledge, 1990).
Herman, J. S., Sagar & Grün, D. FateID infers cell fate bias in multipotent progenitors from single-cell RNA-seq data. Nat. Methods 15, 379–386 (2018).
Liu, C. et al. Delineating spatiotemporal and hierarchical development of human fetal innate lymphoid cells. Cell Res. 31, 1106–1122 (2021).
Zheng, S. C. et al. Universal prediction of cell-cycle position using transfer learning. Genome Biol. 23, 41 (2022).
Jin, S. et al. Inference and analysis of cell-cell communication using CellChat. Nat. Commun. 12, 1088 (2021).
Xiao, Z. Human early embryonic development. Figshare https://doi.org/10.6084/m9.figshare.27004099.v1 (2026).
