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==Parallels with embryonic development== {{Main|embryogenesis}} Much of the research central to embryonic stem cell differentiation and morphogenesis is derived from studies in developmental biology and mammalian embryogenesis.<ref name="ReferenceB"/> For example, immediately after the [[blastocyst]] stage of development (from which ESCs are derived), the embryo undergoes differentiation, whereby cell specification of the [[inner cell mass]] results in the formation of the hypoblast and [[epiblast]].<ref>{{Cite journal | last1 = Bielinska | first1 = M. | last2 = Narita | first2 = N. | last3 = Wilson | first3 = D. B. | title = Distinct roles for visceral endoderm during embryonic mouse development | journal = The International Journal of Developmental Biology | volume = 43 | issue = 3 | pages = 183–205 | year = 1999 | pmid = 10410899 }}</ref> Later on in postimplantation development, the [[anterior|anterior-posterior axis]] is formed and the embryo develops a transient structure known as the primitive streak.<ref>{{Cite journal | last1 = Burdsal | first1 = C. A. | last2 = Damsky | first2 = C. H. | last3 = Pedersen | first3 = R. A. | title = The role of E-cadherin and integrins in mesoderm differentiation and migration at the mammalian primitive streak | journal = Development | volume = 118 | issue = 3 | pages = 829–844 | year = 1993 | doi = 10.1242/dev.118.3.829 | pmid = 7521282 }}</ref> Much of the spatial patterning that occurs during the formation and migration of the primitive streak results from the secretion of [[agonists]] and [[Receptor antagonist|antagonist]]s by various cell populations, including the growth factors from the [[wnt signaling pathway|Wnt]] and [[transforming growth factor beta|transforming growth factor β]] (TGFβ) families (Lefty 1, Nodal), as well as repressors of the same molecules (Dkk-1, Sfrp1, Sfrp5).<ref>{{Cite journal | last1 = Finley | first1 = K. R. | last2 = Tennessen | first2 = J. | last3 = Shawlot | first3 = W. | title = The mouse secreted frizzled-related protein 5 gene is expressed in the anterior visceral endoderm and foregut endoderm during early post-implantation development | journal = Gene Expression Patterns | volume = 3 | issue = 5 | pages = 681–684 | year = 2003 | pmid = 12972006 | doi=10.1016/s1567-133x(03)00091-7 }}</ref><ref>{{Cite journal | last1 = Kemp | first1 = C. | last2 = Willems | first2 = E. | last3 = Abdo | first3 = S. | last4 = Lambiv | first4 = L. | last5 = Leyns | first5 = L. | title = Expression of all Wnt genes and their secreted antagonists during mouse blastocyst and postimplantation development | doi = 10.1002/dvdy.20408 | journal = Developmental Dynamics | volume = 233 | issue = 3 | pages = 1064–1075 | year = 2005 | pmid = 15880404 | pmc = | s2cid = 20596850 | doi-access = free }}</ref><ref>{{Cite journal | last1 = Rivera-Pérez | first1 = J. A. | last2 = Magnuson | first2 = T. | doi = 10.1016/j.ydbio.2005.09.012 | title = Primitive streak formation in mice is preceded by localized activation of Brachyury and Wnt3 | journal = Developmental Biology | volume = 288 | issue = 2 | pages = 363–371 | year = 2005 | pmid = 16289026 | pmc = | doi-access = free }}</ref> Due to the similarities between embryogenesis and ESC differentiation, many of the same growth factors are central to directed differentiation approaches. In addition, advancements of EB culture resulted in the development of [[Gastruloid|embryonic organoids (Gastruloids)]] which show remarkable parallels to embryonic development<ref name="ReferenceH"/><ref name=":2">{{Cite bioRxiv|last1=Turner|first1=David|last2=Alonso-Crisostomo|first2=Luz|last3=Girgin|first3=Mehmet|last4=Baillie-Johnson|first4=Peter|last5=Glodowski|first5=Cherise R.|last6=Hayward|first6=Penelope C.|last7=Collignon|first7=Jérôme|last8=Gustavsen|first8=Carsten|last9=Serup|first9=Palle|date=2017-01-31|title=Gastruloids develop the three body axes in the absence of extraembryonic tissues and spatially localised signalling|biorxiv=10.1101/104539}}</ref><ref name=":0">{{Cite bioRxiv|last1=Turner|first1=David Andrew|last2=Glodowski|first2=Cherise R.|last3=Luz|first3=Alonso-Crisostomo|last4=Baillie-Johnson|first4=Peter|last5=Hayward|first5=Penny C.|last6=Collignon|first6=Jérôme|last7=Gustavsen|first7=Carsten|last8=Serup|first8=Palle|last9=Schröter|first9=Christian|date=2016-05-13|title=Interactions between Nodal and Wnt signalling Drive Robust Symmetry Breaking and Axial Organisation in Gastruloids (Embryonic Organoids)|biorxiv=10.1101/051722}}</ref><ref name=":1">{{Cite journal|last1=Baillie-Johnson|first1=Peter|last2=Brink|first2=Susanne Carina van den|last3=Balayo|first3=Tina|last4=Turner|first4=David Andrew|last5=Arias|first5=Alfonso Martinez|date=2015-11-24|title=Generation of Aggregates of Mouse Embryonic Stem Cells that Show Symmetry Breaking, Polarization and Emergent Collective Behaviour ''In Vitro''|url=http://www.jove.com/video/53252/generation-aggregates-mouse-embryonic-stem-cells-that-show-symmetry|journal=Journal of Visualized Experiments|issue=105|pages=e53252|doi=10.3791/53252|issn=1940-087X|pmc=4692741|pmid=26650833}}</ref><ref>{{Cite journal|last1=Brink|first1=Susanne C. van den|last2=Baillie-Johnson|first2=Peter|last3=Balayo|first3=Tina|last4=Hadjantonakis|first4=Anna-Katerina|last5=Nowotschin|first5=Sonja|last6=Turner|first6=David A.|last7=Arias|first7=Alfonso Martinez|date=2014-11-15|title=Symmetry breaking, germ layer specification and axial organisation in aggregates of mouse embryonic stem cells|journal=Development|language=en|volume=141|issue=22|pages=4231–4242|doi=10.1242/dev.113001|issn=0950-1991|pmc=4302915|pmid=25371360}}</ref><ref>{{Cite journal|last1=Turner|first1=David A.|last2=Hayward|first2=Penelope C.|last3=Baillie-Johnson|first3=Peter|last4=Rué|first4=Pau|last5=Broome|first5=Rebecca|last6=Faunes|first6=Fernando|last7=Arias|first7=Alfonso Martinez|date=2014-11-15|title=Wnt/β-catenin and FGF signalling direct the specification and maintenance of a neuromesodermal axial progenitor in ensembles of mouse embryonic stem cells|journal=Development|language=en|volume=141|issue=22|pages=4243–4253|doi=10.1242/dev.112979|issn=0950-1991|pmc=4302903|pmid=25371361}}</ref> such as symmetry-breaking, localised [[brachyury]] expression, the formation of the [[Anatomical terms of location#Axes|embryonic axes]] (anteroposterior, dorsoventral and Left-Right) and gastrulation-like movements.<ref name="ReferenceH"/><ref name=":2" /><ref name=":0" /><ref name=":1" />
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