REFERENCES
1. Nehme E, Panda A, Migeotte I, Pasque V. Extra-embryonic mesoderm during development and in in vitro models. Development. 2025;152:DEV204624.
2. Thowfeequ S, Hanna CW, Srinivas S. Origin, fate and function of extraembryonic tissues during mammalian development. Nat Rev Mol Cell Biol. 2024;26:255-75.
3. Luckett WP. Origin and differentiation of the yolk sac and extraembryonic mesoderm in presomite human and rhesus monkey embryos. Am J Anat. 2005;152:59-97.
4. Ross C, Boroviak TE. Origin and function of the yolk sac in primate embryogenesis. Nat Commun. 2020;11:3760.
5. Tyser RCV, Mahammadov E, Nakanoh S, Vallier L, Scialdone A, Srinivas S. Single-cell transcriptomic characterization of a gastrulating human embryo. Nature. 2021;600:285-9.
6. Xiang L, Yin Y, Zheng Y, et al. A developmental landscape of 3D-cultured human pre-gastrulation embryos. Nature. 2019;577:537-42.
7. Bergmann S, Penfold CA, Slatery E, et al. Spatial profiling of early primate gastrulation in utero. Nature. 2022;609:136-43.
8. Srivatsan SR, Regier MC, Barkan E, et al. Embryo-scale, single-cell spatial transcriptomics. Science. 2021;373:111-7.
9. Ren H, Jia X, Yu L. The building blocks of embryo models: embryonic and extraembryonic stem cells. Cell Discov. 2025;11:40.
10. Niu B, Wang D, Hu Y, et al. Deciphering signaling mechanisms and developmental dynamics in extraembryonic mesoderm specification from hESCs. Nat Commun. 2025;16:4688.
11. Okubo T, Takashima Y. Exploring the human extraembryonic mesoderm using naive pluripotent stem cells. Cell Stem Cell. 2022;29:1290-1.
12. Karvas RM, Zemke JE, Ali SS, et al. 3D-cultured blastoids model human embryogenesis from pre-implantation to early gastrulation stages. Cell Stem Cell. 2023;30:1148-65.e7.
13. Shahbazi MN, Zernicka-goetz M. Deconstructing and reconstructing the mouse and human early embryo. Nat Cell Biol. 2018;20:878-87.
14. Siriwardena D, Boroviak TE. Evolutionary divergence of embryo implantation in primates. Phil Trans R Soc B. 2022;377:20210256.
15. Hemberger M, Hanna CW, Dean W. Mechanisms of early placental development in mouse and humans. Nat Rev Genet. 2019;21:27-43.
16. Bedzhov I, Zernicka-Goetz M. Self-organizing properties of mouse pluripotent cells initiate morphogenesis upon implantation. Cell. 2014;156:1032-44.
17. Kim YS, Fan R, Kremer L, et al. Deciphering epiblast lumenogenesis reveals proamniotic cavity control of embryo growth and patterning. Sci Adv. 2021;7:eabe1640.
18. Yamamoto M, Saijoh Y, Perea-Gomez A, et al. Nodal antagonists regulate formation of the anteroposterior axis of the mouse embryo. Nature. 2004;428:387-92.
19. Chen D, Claussen NH, Titus S, et al. Basement membrane perforations guide anterior-posterior axis formation. Nat Commun. 2025;16:6763.
20. Morris SA, Grewal S, Barrios F, et al. Dynamics of anterior-posterior axis formation in the developing mouse embryo. Nat Commun. 2012;3:673.
21. Chuva De Sousa Lopes SM, Roelen BAJ, Lawson KA, Zwijsen A. The development of the amnion in mice and other amniotes. Phil Trans R Soc B. 2022;377:20210258.
22. Pereira PN, Dobreva MP, Graham L, Huylebroeck D, Lawson KA, Zwijsen A. Amnion formation in the mouse embryo: the single amniochorionic fold model. BMC Dev Biol. 2011;11:48.
23. Zhu Q, Ge J, Liu Y, Xu J, Yan S, Zhou F. Decoding anterior-posterior axis emergence among mouse, monkey, and human embryos. Dev Cell. 2023;58:63-79.e4.
24. Lawson KA, Meneses JJ, Pedersen RA. Clonal analysis of epiblast fate during germ layer formation in the mouse embryo. Development. 1991;113:891-911.
25. Tam PPL, Beddington RSP. The formation of mesodermal tissues in the mouse embryo during gastrulation and early organogenesis. Development. 1987;99:109-26.
26. O'rahilly R, Müller F. Developmental stages in human embryos. Carnegie Institution Washington, DC; 1987. Available from: https://publicationsonline.carnegiescience.edu/publications_online/developmental_stages.pdf [Last accessed on 3 Jun 2026].
27. O'rahilly R, Müller F. Developmental stages in human embryos: revised and new measurements. Cells Tissues Organs. 2010;192:73-84.
28. Rossant J, Tam PP. New insights into early human development: lessons for stem cell derivation and differentiation. Cell Stem Cell. 2017;20:18-28.
29. Yang H. Spatiotemporal frameworks of morphogenesis and cell lineage specification in pre- and peri-implantation mammalian embryogenesis: insights and knowledge gaps from mouse embryo. Biology. 2025;14:1596.
30. Nakamura T, Fujiwara K, Saitou M, Tsukiyama T. Non-human primates as a model for human development. Stem Cell Rep. 2021;16:1093-103.
31. Schust DJ, Bonney EA, Sugimoto J, et al. The immunology of syncytialized trophoblast. Int J Mol Sci. 2021;22:1767.
32. Gauster M, Moser G, Wernitznig S, Kupper N, Huppertz B. Early human trophoblast development: from morphology to function. Cell Mol Life Sci. 2022;79:345.
33. Kojima J, Ono M, Kuji N, Nishi H. Human chorionic villous differentiation and placental development. Int J Mol Sci. 2022;23:8003.
34. Baergen K, Burton GJ, Baergen RN. Pathology of the human placenta. 6th ed. Berlin, Heidelberg: Springer; 2012. pp. 43-46.
35. Florian J. The formation of the connecting stalk and the extension of the amniotic cavity towards the tissue of the connecting stalk in young human embryos. J Anat. 1930;64:454.
36. Ghimire S, Mantziou V, Moris N, Martinez Arias A. Human gastrulation: the embryo and its models. Dev Biol. 2021;474:100-8.
37. Budjan C, Liu S, Ranga A, Gayen S, Pourquié O, Hormoz S. Paraxial mesoderm organoids model development of human somites. eLife. 2022;11:e68925.
38. Prummel KD, Nieuwenhuize S, Mosimann C. The lateral plate mesoderm. Development. 2020;147:dev175059.
39. Canu G, Ruhrberg C. First blood: the endothelial origins of hematopoietic progenitors. Angiogenesis. 2021;24:199-211.
40. Burton GJ, Jauniaux E. Placentation in the human and higher primates. In: Geisert RD, Spencer T, editors. Placentation in mammals: tribute to EC amoroso’s lifetime contributions to viviparity. Springer; 2021. pp. 223-54.
41. Streeter GL. The Miller ovum: the youngest normal human embryo thus far known. Contrib Embryol Carnegie Inst. 1926;18:31-48. Available from: https://eurekamag.com/research/092/807/092807357.php?__cf_chl_tk=7Y3qKbU7kGQR.X.xnOrPLtgLgIjr5ZC9z8v3.elxhgk-1780312989-1.0.1.1-sXy5TQAKx5BCzvwNx..BlZ4RVbba9PvZFXqn8d4vsf8 [Last accessed on 3 Jun 2026].
42. Boucher D, Pedersen R. Induction and differentiation of extra-embryonic mesoderm in the mouse. Reprod Fertil Dev. 1996;8:765-77.
43. Zhang H, Bradley A. Mice deficient for BMP2 are nonviable and have defects in amnion/chorion and cardiac development. Development. 1996;122:2977-86.
44. Goumans M, Zwijsen A, Rooijen MAV, Huylebroeck D, Roelen BAJ, Mummery CL. Transforming growth factor-β signalling in extraembryonic mesoderm is required for yolk sac vasculogenesis in mice. Development. 1999;126:3473-83.
45. Mallet C, Vittet D, Feige JJ, Bailly S. TGFβ1 induces vasculogenesis and inhibits angiogenic sprouting in an embryonic stem cell differentiation model: respective contribution of ALK1 and ALK5. Stem Cells. 2009;24:2420-7.
46. Carvalho RLC, Itoh F, Goumans M, et al. Compensatory signalling induced in the yolk sac vasculature by deletion of TGFβ receptors in mice. J Cell Sci. 2007;120:4269-77.
47. Firulli AB, Mcfadden DG, Lin Q, Srivastava D, Olson EN. Heart and extra-embryonic mesodermal defects in mouse embryos lacking the bHLH transcription factor Hand1. Nat Genet. 1998;18:266-70.
48. Downs KM. The mouse allantois: new insights at the embryonic-extraembryonic interface. Phil Trans R Soc B. 2022;377:20210251.
49. Nahaboo W, Eski SE, Despin-Guitard E, et al. Keratin filaments mediate the expansion of extra-embryonic membranes in the post-gastrulation mouse embryo. EMBO J. 2022;41:EMBJ2021108747.
50. Hadas R, Rubinstein H, Mittnenzweig M, et al. Temporal BMP4 effects on mouse embryonic and extraembryonic development. Nature. 2024;634:652-61.
51. Rossant J, Cross JC. Placental development: Lessons from mouse mutants. Nat Rev Genet. 2001;2:538-48.
52. Aoki M, Mieda M, Ikeda T, Hamada Y, Nakamura H, Okamoto H. R-spondin3 is required for mouse placental development. Dev Biol. 2007;301:218-26.
53. Sekulovski N, Carleton AE, Lin C, Taniguchi K. Primate amnion development. Development. 2025;152:dev204621.
54. Rossant J, Tam PP. Early human embryonic development: Blastocyst formation to gastrulation. Dev Cell. 2022;57:152-65.
55. Goh I, Botting RA, Rose A, et al. Yolk sac cell atlas reveals multiorgan functions during human early development. Science. 2023;381:eadd7564.
57. Alippe Y, Hatterschide J, Coyne CB, Diamond MS. Innate immune responses to pathogens at the maternal-fetal interface. Nat Rev Immunol. 2025;25:869-84.
58. Enders AC, King BF. Formation and differentiation of extraembryonic mesoderm in the rhesus monkey. Am J Anat. 2005;181:327-40.
59. Hyun I, Bredenoord AL, Briscoe J, Klipstein S, Tan T. Human embryo research beyond the primitive streak. Science. 2021;371:998-1000.
60. Peng Y, Huang X, Zhou Q. Ethical and policy considerations for human embryo and stem cell research in China. Cell Stem Cell. 2020;27:511-4.
61. Farkas K, Ferretti E. Derivation of human extraembryonic mesoderm-like cells from primitive endoderm. Int J Mol Sci. 2023;24:11366.
62. Ai Z, Niu B, Yin Y, et al. Dissecting peri-implantation development using cultured human embryos and embryo-like assembloids. Cell Res. 2023;33:661-78.
63. Hill JP. II. Croonian lecture. - the developmental history of the primates. Philos Trans R Soc Lond B Biol Sci . 1932;221:45-178.
64. Abell AN, Jordan NV, Huang W, et al. MAP3K4/CBP-regulated H2B acetylation controls epithelial-mesenchymal transition in trophoblast stem cells. Cell Stem Cell. 2011;8:525-37.
65. Enders AC, Schlafke S. Differentiation of the blastocyst of the rhesus monkey. Am J Anat. 2005;162:1-21.
66. Knoth M, Larsen JF. Ultrastructure of a human implantation site. Acta Obstet Gynecol Scand. 2011;51:385-93.
67. Boss AL, Chamley LW, James JL. Placental formation in early pregnancy: how is the centre of the placenta made? Hum Reprod Update. 2018;24:750-60.
68. Florian J. The early development of man, with special reference to the development of the mesoderm and cloacal membrane. J Anat. 1933;67:263.
69. Yang R, Goedel A, Kang Y, et al. Amnion signals are essential for mesoderm formation in primates. Nat Commun. 2021;12:5126.
70. Gérard P. Etudes sur l'ovogenese et l'ontogenese chez les Lemuriens du genre Galago. Arch Biol. 1932;43:93-151. Available from: https://eurekamag.com/research/022/591/022591763.php [Last accessed on 3 Jun 2026].
71. Nakamura T, Okamoto I, Sasaki K, et al. A developmental coordinate of pluripotency among mice, monkeys and humans. Nature. 2016;537:57-62.
72. Oldak B, Wildschutz E, Bondarenko V, et al. Complete human day 14 post-implantation embryo models from naive ES cells. Nature. 2023;622:562-73.
73. Niu Y, Sun N, Li C, et al. Dissecting primate early post-implantation development using long-term in vitro embryo culture. Science. 2019;366:eaaw5754.
74. Pham TXA, Panda A, Kagawa H, et al. Modeling human extraembryonic mesoderm cells using naive pluripotent stem cells. Cell Stem Cell. 2022;29:1346-65.e10.
75. Wang SL, Shi GH, Duan K, Yin Y, Li T. Extraembryonic mesoderm cells derived from human embryonic stem cells rely on Wnt pathway activation. Cell Prolif. 2024;58:e13761.
76. Li J, Zhu Q, Cao J, et al. Cynomolgus monkey embryo model captures gastrulation and early pregnancy. Cell Stem Cell. 2023;30:362-77.e7.
77. Haigh T, Chen C, Jones C, Aplin J. Studies of mesenchymal cells from 1st trimester human placenta: expression of cytokeratin outside the trophoblast lineage. Placenta. 1999;20:615-25.
78. Hislop J, Song Q, Keshavarz FK, et al. Modelling post-implantation human development to yolk sac blood emergence. Nature. 2023;626:367-76.
79. Xiao Z, Cui L, Yuan Y, et al. 3D reconstruction of a gastrulating human embryo. Cell. 2024;187:2855-74.e19.
80. Cui L, Lin S, Yang X, et al. Spatial transcriptomic characterization of a Carnegie stage 7 human embryo. Nat Cell Biol. 2025;27:360-9.
81. Gong Y, Bai B, Sun N, et al. Ex utero monkey embryogenesis from blastocyst to early organogenesis. Cell. 2023;186:2092-110.e23.
82. Mendjan S, Mascetti VL, Ortmann D, et al. NANOG and CDX2 pattern distinct subtypes of human mesoderm during exit from pluripotency. Cell Stem Cell. 2014;15:310-25.
83. Richter A, Valdimarsdottir L, Hrafnkelsdottir HE, et al. BMP4 promotes EMT and mesodermal commitment in human embryonic stem cells via SLUG and MSX2. Stem Cells. 2014;32:636-48.
84. Bernardo AS, Faial T, Gardner L, et al. BRACHYURY and CDX2 mediate BMP-induced differentiation of human and mouse pluripotent stem cells into embryonic and extraembryonic lineages. Cell Stem Cell. 2011;9:144-55.
85. Markouli C, De Deckersberg EC, Dziedzicka D, et al. Sustained intrinsic WNT and BMP4 activation impairs hESC differentiation to definitive endoderm and drives the cells towards extra-embryonic mesoderm. Sci Rep. 2021;11:8242.
86. Hu W, Sancho-Serra C, Gantner CW, et al. Atlas of amnion development during the first trimester of human pregnancy. Nat Cell Biol. 2025;27:1175-85.
87. James JL, Lissaman A, Nursalim YNS, Chamley LW. Modelling human placental villous development: designing cultures that reflect anatomy. Cell Mol Life Sci. 2022;79:384.
88. Bárcena A, Muench MO, Kapidzic M, Fisher SJ. A new role for the human placenta as a hematopoietic site throughout gestation. Reprod Sci. 2009;16:178-87.
89. Calvanese V, Mikkola HKA. The genesis of human hematopoietic stem cells. Blood. 2023;142:519-32.
90. Boyd JD, Hamilton WJ. The Human Placenta. Heffer; 1970. Available from: https://books.google.com.sg/books/about/The_human_placenta.html?id=dKtqAAAAMAAJ&redir_esc=y [Last accessed on 3 Jun 2026].
91. Männer J. When does the human embryonic heart start beating? A review of contemporary and historical sources of knowledge about the onset of blood circulation in man. J Cardiovasc Dev Dis. 2022;9:187.
93. Dieterlen-Livre F, Corbel C, Salan J. Allantois and placenta as developmental sources of hematopoietic stem cells. Int J Dev Biol. 2010;54:1079-87.
94. Zeigler BM, Sugiyama D, Chen M, Guo Y, Downs KM, Speck NA. The allantois and chorion, when isolated before circulation or chorio-allantoic fusion, have hematopoietic potential. Development. 2006;133:4183-92.
95. Bulger EA, Mcdevitt TC, Bruneau BG. CDX2 dose-dependently influences the gene regulatory network underlying human extraembryonic mesoderm development. Biology Open. 2024;13:bio060323.
96. Gekas C, Dieterlen-Lièvre F, Orkin SH, Mikkola HK. The placenta is a niche for hematopoietic stem cells. Dev Cell. 2005;8:365-75.
97. Mikkola HK, Gekas C, Orkin SH, Dieterlen-Lievre F. Placenta as a site for hematopoietic stem cell development. Exp Hematol. 2005;33:1048-54.
98. Dancis J, Samuels BD, Douglas GW. Immunological competence of placenta. Science. 1962;136:382-3.
99. Alvarez-Silva M, Belo-Diabangouaya P, Salaün J, Dieterlen-Lièvre F. Mouse placenta is a major hematopoietic organ. Development. 2003;130:5437-44.
100. Azevedo Portilho N, Pelajo-Machado M. Mechanism of hematopoiesis and vasculogenesis in mouse placenta. Placenta. 2018;69:140-5.
101. Demir R, Kayisli U, Seval Y, et al. Sequential expression of VEGF and its receptors in human placental villi during very early pregnancy: differences between placental vasculogenesis and angiogenesis. Placenta. 2004;25:560-72.
102. Lash G, Naruse K, Innes B, Robson S, Searle R, Bulmer J. Secretion of angiogenic growth factors by villous cytotrophoblast and extravillous trophoblast in early human pregnancy. Placenta. 2010;31:545-8.
103. Ivanovs A, Rybtsov S, Ng ES, Stanley EG, Elefanty AG, Medvinsky A. Human haematopoietic stem cell development: from the embryo to the dish. Development. 2017;144:2323-37.
104. Gritz E, Hirschi KK. Specification and function of hemogenic endothelium during embryogenesis. Cell Mol Life Sci. 2016;73:1547-67.
105. Robin C, Bollerot K, Mendes S, et al. Human placenta is a potent hematopoietic niche containing hematopoietic stem and progenitor cells throughout development. Cell Stem Cell. 2009;5:385-95.
106. Calvanese V, Capellera-Garcia S, Ma F, et al. Mapping human haematopoietic stem cells from haemogenic endothelium to birth. Nature. 2022;604:534-40.
107. Reyes L, Golos TG. Hofbauer cells: their role in healthy and complicated pregnancy. Front Immunol. 2018;9:2628.
108. Jiang X, Zhai J, Xiao Z, et al. Identifying a dynamic transcriptomic landscape of the cynomolgus macaque placenta during pregnancy at single-cell resolution. Dev Cell. 2023;58:806-21.e7.
109. Thomas JR, Appios A, Zhao X, et al. Phenotypic and functional characterization of first-trimester human placental macrophages, Hofbauer cells. J Exp Med. 2021;218:e20200891.
110. Thomas JR, Appios A, Calderbank EF, et al. Primitive haematopoiesis in the human placenta gives rise to macrophages with epigenetically silenced HLA-DR. Nat Commun. 2023;14:1764.
111. Van Handel B, Prashad SL, Hassanzadeh-kiabi N, et al. The first trimester human placenta is a site for terminal maturation of primitive erythroid cells. Blood. 2010;116:3321-30.
112. Yao Y, Xu X, Jin L. Macrophage polarization in physiological and pathological pregnancy. Front Immunol. 2019;10:792.
113. Reyes L, Wolfe B, Golos T. Hofbauer cells: placental macrophages of fetal origin. In: Kloc M, editors. Macrophages: origin, functions and biointervention. Cham: Springer; 2017. pp. 45-60.
114. Castellucci M, Celona A, Bartels H, Steininger B, Benedetto V, Kaufmann P. Mitosis of the Hofbauer cell: possible implications for a fetal macrophage. Placenta. 1987;8:65-76.






