168:
hanging drops is labor-intensive and not easily amenable to scalable cultures. Additionally, the media can not be easily exchanged within the traditional hanging drop format, necessitating the transfer of hanging drops into bulk suspension cultures after 2–3 days of formation, whereby individual EBs tend to agglomerate. Recently, new technologies have been developed to enable media exchange within a modified hanging drop format. In addition, technologies have also been developed to physically separate cells by forced aggregation of ESCs within individual wells or confined on adhesive substrates, which enables increased throughput, controlled formation of EBs. Ultimately, the methods used for EB formation may impact the heterogeneity of EB populations, in terms of aggregation kinetics, EB size and yield, as well as differentiation trajectories.
324:
cell uptake rates. Therefore, the delivery of morphogens to EBs results in increased heterogeneity and decreased efficiency of differentiated cell populations compared to monolayer cultures. One method of addressing transport limitations within EBs has been through polymeric delivery of morphogens from within the EB structure. Additionally, EBs can be cultured as individual microtissues and subsequently assembled into larger structures for tissue engineering applications. Although the complexity resulting from the three-dimensional adhesions and signaling may recapitulate more native tissue structures, it also creates challenges for understanding the relative contributions of mechanical, chemical, and physical signals to the resulting cell phenotypes and morphogenesis.
39:
160:(ROCK) pathway, including the small molecules Y-27632 and 2,4 disubstituted thiazole (Thiazovivin/Tzv). Alternatively, to avoid dissociation into single cells, EBs can be formed from hESCs by manual separation of adherent colonies (or regions of colonies) and subsequently cultured in suspension. Formation of EBs in suspension is amenable to the formation of large quantities of EBs, but provides little control over the size of the resulting aggregates, often leading to large, irregularly shaped EBs. As an alternative, the
200:. In response to the ECM deposition, EBs often form a cystic cavity, whereby the cells in contact with the basement membrane remain viable and those at the interior undergo apoptosis, resulting in a fluid-filled cavity surrounded by cells. Subsequent differentiation proceeds to form derivatives of the three germ lineages. In the absence of supplements, the “default” differentiation of ESCs is largely toward ectoderm, and subsequent
40:
41:
43:
31:
151:, which is highly expressed on undifferentiated ESCs. When cultured as single cells in the absence of anti-differentiation factors, ESCs spontaneously aggregate to form EBs. Such spontaneous formation is often accomplished in bulk suspension cultures whereby the dish is coated with non-adhesive materials, such as
2911:
Turner, David Andrew; Glodowski, Cherise R.; Luz, Alonso-Crisostomo; Baillie-Johnson, Peter; Hayward, Penny C.; Collignon, Jérôme; Gustavsen, Carsten; Serup, Palle; Schröter, Christian (2016-05-13). "Interactions between Nodal and Wnt signalling Drive Robust
Symmetry Breaking and Axial Organisation
323:
limitations occur within EBs, creating gradients of morphogens, metabolites, and nutrients. It has been estimated that oxygen transport is limited in cell aggregates larger than approximately 300 μm in diameter; however, the development of such gradients are also impacted by molecule size and
310:
In contrast to the differentiation of ESCs in monolayer cultures, whereby the addition of soluble morphogens and the extracellular microenvironment can be precisely and homogeneously controlled, the three-dimensional structure of EBs poses challenges to directed differentiation. For example, the
167:
Formation of EBs can also be more precisely controlled by the inoculation of known cell densities within single drops (10-20 μL) suspended from the lid of a Petri dish, known as hanging drops. While this method enables control of EB size by altering the number of cells per drop, the formation of
2886:
Turner, David; Alonso-Crisostomo, Luz; Girgin, Mehmet; Baillie-Johnson, Peter; Glodowski, Cherise R.; Hayward, Penelope C.; Collignon, Jérôme; Gustavsen, Carsten; Serup, Palle (2017-01-31). "Gastruloids develop the three body axes in the absence of extraembryonic tissues and spatially localised
73:
EBs are differentiation of human embryonic stem cells into embryoid bodies comprising the three embryonic germ layers. They mimic the characteristics seen in early-stage embryos. They are often used as a model system to conduct research on various aspects of developmental biology. They can also
117:
In contrast to monolayer cultures, however, the spheroid structures that are formed when ESCs aggregate enables the non-adherent culture of EBs in suspension, making EB cultures inherently scalable, which is useful for bioprocessing approaches, whereby large yields of cells can be produced for
134:
which yields microtissues that are similar to native tissue structures. Such microtissues are promising to directly or indirectly repair damaged or diseased tissue in regenerative medicine applications, as well as for in vitro testing in the pharmaceutical industry and as a model of embryonic
1484:
Ludwig, T. E.; Levenstein, M. E.; Jones, J. M.; Berggren, W. T.; Mitchen, E. R.; Frane, J. L.; Crandall, L. J.; Daigh, C. A.; Conard, K. R.; Piekarczyk, M. S.; Llanas, R. A.; Thomson, J. A. (2006). "Derivation of human embryonic stem cells in defined conditions".
287:(TGFβ) families (Lefty 1, Nodal), as well as repressors of the same molecules (Dkk-1, Sfrp1, Sfrp5). Due to the similarities between embryogenesis and ESC differentiation, many of the same growth factors are central to directed differentiation approaches.
1432:
Williams, R. L.; Hilton, D. J.; Pease, S.; Willson, T. A.; Stewart, C. L.; Gearing, D. P.; Wagner, E. F.; Metcalf, D.; Nicola, N. A.; Gough, N. M. (1988). "Myeloid leukaemia inhibitory factor maintains the developmental potential of embryonic stem cells".
865:
Yu, J.; Vodyanik, M. A.; Smuga-Otto, K.; Antosiewicz-Bourget, J.; Frane, J. L.; Tian, S.; Nie, J.; Jonsdottir, G. A.; Ruotti, V.; Stewart, R.; Slukvin, I. I.; Thomson, J. A. (2007). "Induced
Pluripotent Stem Cell Lines Derived from Human Somatic Cells".
219:
As a result of the three-dimensional EB structure, complex morphogenesis occurs during EB differentiation, including the appearance of both epithelial- and mesenchymal-like cell populations, as well as the appearance of markers associated with the
155:
or hydrophilic polymers, to promote the preferential adhesion between single cells, rather than to the culture substrate. As hESC undergo apoptosis when cultured as single cells, EB formation often necessitates the use of inhibitors of the
42:
1528:
Watanabe, K.; Ueno, M.; Kamiya, D.; Nishiyama, A.; Matsumura, M.; Wataya, T.; Takahashi, J. B.; Nishikawa, S.; Nishikawa, S. I.; Muguruma, K.; Sasai, Y. (2007). "A ROCK inhibitor permits survival of dissociated human embryonic stem cells".
270:
is formed and the embryo develops a transient structure known as the primitive streak. Much of the spatial patterning that occurs during the formation and migration of the primitive streak results from the secretion of
1355:
Yoon, B. S.; Yoo, S. J.; Lee, J. E.; You, S.; Lee, H. T.; Yoon, H. S. (2006). "Enhanced differentiation of human embryonic stem cells into cardiomyocytes by combining hanging drop culture and 5-azacytidine treatment".
2757:
Finley, K. R.; Tennessen, J.; Shawlot, W. (2003). "The mouse secreted frizzled-related protein 5 gene is expressed in the anterior visceral endoderm and foregut endoderm during early post-implantation development".
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Doetschman, T. C.; Eistetter, H.; Katz, M.; Schmidt, W.; Kemler, R. (1985). "The in vitro development of blastocyst-derived embryonic stem cell lines: Formation of visceral yolk sac, blood islands and myocardium".
2590:
Bauwens, C. L.; Song, H.; Thavandiran, N.; Ungrin, M.; Massé, S. P.; Nanthakumar, K.; Seguin, C.; Zandstra, P. W. (2011). "Geometric
Control of Cardiomyogenic Induction in Human Pluripotent Stem Cells".
254:
Much of the research central to embryonic stem cell differentiation and morphogenesis is derived from studies in developmental biology and mammalian embryogenesis. For example, immediately after the
228:. Tissue-like structures are often exhibited within EBs, including the appearance of blood islands reminiscent of early blood vessel structures in the developing embryo, as well as the patterning of
2057:
Esner, M.; Pachernik, J.; Hampl, A.; Dvorak, P. (2002). "Targeted disruption of fibroblast growth factor receptor-1 blocks maturation of visceral endoderm and cavitation in mouse embryoid bodies".
90:
stage of embryos from mouse (mESC), primate, and human (hESC) sources. Additionally, EBs can be formed from embryonic stem cells derived through alternative techniques, including somatic cell
2399:"Analysis of the temporal and concentration-dependent effects of BMP-4, VEGF, and TPO on development of embryonic stem cell–derived mesoderm and blood progenitors in a defined, serum-free media"
2644:
Eiraku, M.; Takata, N.; Ishibashi, H.; Kawada, M.; Sakakura, E.; Okuda, S.; Sekiguchi, K.; Adachi, T.; Sasai, Y. (2011). "Self-organizing optic-cup morphogenesis in three-dimensional culture".
118:
potential clinical applications. Additionally, although EBs largely exhibit heterogeneous patterns of differentiated cell types, ESCs are capable of responding to similar cues that direct
224:(EMT). Additionally, the inductive effects resulting from signaling between cell populations in EBs results in spatially and temporally defined changes, which promote complex
2722:
Burdsal, C. A.; Damsky, C. H.; Pedersen, R. A. (1993). "The role of E-cadherin and integrins in mesoderm differentiation and migration at the mammalian primitive streak".
2993:
Brink, Susanne C. van den; Baillie-Johnson, Peter; Balayo, Tina; Hadjantonakis, Anna-Katerina; Nowotschin, Sonja; Turner, David A.; Arias, Alfonso
Martinez (2014-11-15).
3487:"Monolayer and Spheroid Culture of Human Liver Hepatocellular Carcinoma Cell Line Cells Demonstrate Distinct Global Gene Expression Patterns and Functional Phenotypes"
3211:
Sachlos, E.; Auguste, D. T. (2008). "Embryoid body morphology influences diffusive transport of inductive biochemicals: A strategy for stem cell differentiation".
1940:
Sargent, C. Y.; Berguig, G. Y.; McDevitt, T. C. (2009). "Cardiomyogenic
Differentiation of Embryoid Bodies is Promoted by Rotary Orbital Suspension Culture".
3052:"Wnt/β-catenin and FGF signalling direct the specification and maintenance of a neuromesodermal axial progenitor in ensembles of mouse embryonic stem cells"
184:. EB differentiation begins with the specification of the exterior cells toward the primitive endoderm phenotype. The cells at the exterior then deposit
3246:
Van Winkle, A. P.; Gates, I. D.; Kallos, M. S. (2012). "Mass
Transfer Limitations in Embryoid Bodies during Human Embryonic Stem Cell Differentiation".
1883:"Reproducible, Ultra High-Throughput Formation of Multicellular Organization from Single Cell Suspension-Derived Human Embryonic Stem Cell Aggregates"
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Park, I. H.; Arora, N.; Huo, H.; Maherali, N.; Ahfeldt, T.; Shimamura, A.; Lensch, M. W.; Cowan, C.; Hochedlinger, K.; Daley, G. Q. (2008).
2225:"Absence of basement membranes after targeting the LAMC1 gene results in embryonic lethality due to failure of endoderm differentiation"
48:
2937:
2135:"Fibroblast growth factor signaling and basement membrane assembly are connected during epithelial morphogenesis of the embryoid body"
2938:"Generation of Aggregates of Mouse Embryonic Stem Cells that Show Symmetry Breaking, Polarization and Emergent Collective Behaviour
2338:
1824:"Microwell-mediated control of embryoid body size regulates embryonic stem cell fate via differential expression of WNT5a and WNT11"
221:
1317:
Larue, L.; Antos, C.; Butz, S.; Huber, O.; Delmas, V.; Dominis, M.; Kemler, R. (1996). "A role for cadherins in tissue formation".
240:. More recently, complex structures, including optic cup-like structures were created in vitro resulting from EB differentiation.
164:
forces imparted in mixed culture platforms increase the homogeneity of EB sizes when ESCs are inoculated within bulk suspensions.
2936:
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369:"Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells"
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stage of development (from which ESCs are derived), the embryo undergoes differentiation, whereby cell specification of the
2086:"Monoclonal antibodies to laminin reveal the heterogeneity of basement membranes in the developing and adult mouse tissues"
2440:"Wnt, Activin, and BMP Signaling Regulate Distinct Stages in the Developmental Pathway from Embryonic Stem Cells to Blood"
311:
visceral endoderm population which forms the exterior of EBs, creates an exterior “shell” consisting of tightly connected
157:
2543:"Synthesis and Organization of Hyaluronan and Versican by Embryonic Stem Cells Undergoing Embryoid Body Differentiation"
2018:"Fibroblast growth factor (FGF) signaling through PI 3-kinase and Akt/PKB is required for embryoid body differentiation"
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Wiles, M. V.; Keller, G. (1991). "Multiple hematopoietic lineages develop from embryonic stem (ES) cells in culture".
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177:
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protocols, EB formation is often used as a method for initiating spontaneous differentiation toward the three
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Thomson, J. A.; Kalishman, J.; Golos, T. G.; Durning, M.; Harris, C. P.; Becker, R. A.; Hearn, J. P. (1995).
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as well as defined growth factor additives, have been developed to promote the differentiation toward
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formats, ESCs within embryoid bodies undergo differentiation and cell specification along the three
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extensions (indicative of neuron organization) and spontaneous contractile activity (indicative of
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704:"Isolation of pluripotent embryonic stem cells from reprogrammed adult mouse somatic cell nuclei"
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34:
Phase image of EBs in suspension culture. Individual EBs are composed of approximately 1000 mESCs
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2844:"Primitive streak formation in mice is preceded by localized activation of Brachyury and Wnt3"
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2184:"Signals for death and survival: A two-step mechanism for cavitation in the vertebrate embryo"
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1138:"Engineering the embryoid body microenvironment to direct embryonic stem cell differentiation"
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which show remarkable parallels to embryonic development such as symmetry-breaking, localised
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3340:"Systematic engineering of 3D pluripotent stem cell niches to guide blood development"
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122:. Therefore, the three-dimensional structure, including the establishment of complex
3533:
3389:"Magnetic manipulation and spatial patterning of multi-cellular stem cell aggregates"
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1682:"High-throughput 3D spheroid culture and drug testing using a 384 hanging drop array"
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70:. These include embryonic stem cells (ESC) and induced pluripotent stem cells (iPSC)
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2274:"Regulation of programmed cell death by basement membranes in embryonic development"
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587:"Transplantation of Living Nuclei from Blastula Cells into Enucleated Frogs' Eggs"
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1993:
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302:(anteroposterior, dorsoventral and Left-Right) and gastrulation-like movements.
74:
contribute to research focused on tissue engineering and regenerative medicine.
3112:"The Multiparametric Effects of Hydrodynamic Environments on Stem Cell Culture"
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In addition, advancements of EB culture resulted in the development of
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differentiation) when EBs are plated onto adhesive substrates such as
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2016:
Chen, Y.; Li, X.; Eswarakumar, V. P.; Seger, R.; Lonai, P. (2000).
319:. Due to such physical restrictions, in combination with EB size,
279:
by various cell populations, including the growth factors from the
2953:
1048:"Controlled, Scalable Embryonic Stem Cell Differentiation Culture"
37:
29:
3438:"Three-Dimensional Culture Alters Primary Cardiac Cell Phenotype"
204:. However, alternative media compositions, including the use of
82:
The pluripotent cell types that comprise embryoid bodies include
1136:
Bratt-Leal, A. S. M.; Carpenedo, R. L.; McDevitt, T. C. (2009).
152:
2793:
Kemp, C.; Willems, E.; Abdo, S.; Lambiv, L.; Leyns, L. (2005).
130:
within the EB microenvironment, enables differentiation and
2438:
Nostro, M. C.; Cheng, X.; Keller, G. M.; Gadue, P. (2008).
2325:. Methods in Enzymology. Vol. 365. pp. 327–341.
2084:
Wan, Y. J.; Wu, T. C.; Chung, A. E.; Damjanov, I. (1984).
1631:
Carpenedo, R. L.; Sargent, C. Y.; McDevitt, T. C. (2007).
538:"Embryonic stem cell lines derived from human blastocysts"
66:) are three-dimensional aggregates formed by pluripotent
3110:
Kinney, M. A.; Sargent, C. Y.; McDevitt, T. C. (2011).
1232:"Stem cell paracrine actions and tissue regeneration"
27:
Three-dimensional aggregate of pluripotent stem cells
2397:Purpura, K. A.; Morin, J.; Zandstra, P. W. (2008).
2697:The International Journal of Developmental Biology
2059:The International Journal of Developmental Biology
1021:Journal of Embryology and Experimental Morphology
919:"Disease-Specific Induced Pluripotent Stem Cells"
479:"Isolation of a primate embryonic stem cell line"
266:. Later on in postimplantation development, the
47:An embryoid body whose cells differentiated into
1828:Proceedings of the National Academy of Sciences
1578:Proceedings of the National Academy of Sciences
1187:Journal of Biomedical Materials Research Part A
94:or the reprogramming of somatic cells to yield
262:results in the formation of the hypoblast and
196:, similar to the composition and structure of
3157:
3155:
2487:
2485:
2483:
1817:
1815:
1350:
1348:
1277:
1275:
1131:
1129:
1087:
1085:
1083:
1013:
1011:
8:
647:; Schnieke, A. E.; McWhir, J.; Kind, A. J.;
3105:
3103:
2547:Journal of Histochemistry and Cytochemistry
2842:Rivera-Pérez, J. A.; Magnuson, T. (2005).
3510:
3485:Chang, T. T.; Hughes-Fulford, M. (2009).
3461:
3412:
3363:
3314:
3187:
3135:
3083:
3026:
2969:
2917:
2892:
2859:
2810:
2612:
2566:
2517:
2463:
2414:
2297:
2248:
2199:
2158:
2109:
2033:
1992:
1916:
1906:
1857:
1847:
1713:
1648:
1607:
1597:
1408:
1255:
1230:Baraniak, P. R.; McDevitt, T. C. (2010).
1206:
1161:
1109:
1063:
991:
942:
833:
776:
727:
620:
610:
561:
512:
502:
402:
392:
1284:Journal of Bioscience and Bioengineering
147:of the Ca2+ dependent adhesion molecule
2912:in Gastruloids (Embryonic Organoids)".
2323:Differentiation of Embryonic Stem Cells
2182:Coucouvanis, E.; Martin, G. R. (1995).
359:
306:Challenges to directing differentiation
2931:
2929:
2906:
2904:
2881:
2879:
7:
244:Parallels with embryonic development
110:, and mesoderm – which comprise all
49:enhanced green fluorescence protein
3356:10.1016/j.biomaterials.2011.10.051
3307:10.1016/j.biomaterials.2010.08.113
3225:10.1016/j.biomaterials.2008.08.012
3180:10.1016/j.biomaterials.2009.01.007
3116:Tissue Engineering Part B: Reviews
1798:10.1016/j.biomaterials.2006.07.012
51:-expressing spontaneously beating
25:
2946:Journal of Visualized Experiments
1092:Murry, C. E.; Keller, G. (2008).
298:expression, the formation of the
292:embryonic organoids (Gastruloids)
222:epithelial-mesenchymal transition
1370:10.1111/j.1432-0436.2006.00063.x
585:Briggs, R.; King, T. J. (1952).
315:-like cells, as well as a dense
2272:Murray, P.; Edgar, D. (2000).
96:induced pluripotent stem cells
1:
2772:10.1016/s1567-133x(03)00091-7
2331:10.1016/s0076-6879(03)65023-8
1410:10.1095/biolreprod.103.017467
729:10.1016/s0960-9822(00)00648-5
563:10.1126/science.282.5391.1145
2416:10.1016/j.exphem.2008.04.003
2201:10.1016/0092-8674(95)90169-8
1908:10.1371/journal.pone.0001565
285:transforming growth factor β
2861:10.1016/j.ydbio.2005.09.012
2278:The Journal of Cell Biology
2229:The Journal of Cell Biology
2139:The Journal of Cell Biology
2090:The Journal of Cell Biology
1994:10.1634/stemcells.2008-0183
1650:10.1634/stemcells.2006-0523
3556:
2510:10.1016/j.stem.2008.09.013
2456:10.1016/j.stem.2007.10.011
1111:10.1016/j.cell.2008.02.008
1065:10.1634/stemcells.22-3-275
935:10.1016/j.cell.2008.07.041
826:10.1016/j.cell.2007.11.019
769:10.1016/j.cell.2006.07.024
247:
176:Within the context of ESC
172:Differentiation within EBs
3503:10.1089/ten.tea.2007.0434
3491:Tissue Engineering Part A
3454:10.1089/ten.tea.2009.0458
3442:Tissue Engineering Part A
3128:10.1089/ten.TEB.2011.0040
2605:10.1089/ten.TEA.2010.0563
2593:Tissue Engineering Part A
1954:10.1089/ten.tea.2008.0145
1942:Tissue Engineering Part A
2760:Gene Expression Patterns
98:(iPS). Similar to ESCs
86:(ESCs) derived from the
2559:10.1369/jhc.2009.954826
2403:Experimental Hematology
1849:10.1073/pnas.0905550106
1599:10.1073/pnas.1002024107
1397:Biology of Reproduction
1331:10.1242/dev.122.10.3185
888:10.1126/science.1151526
504:10.1073/pnas.92.17.7844
394:10.1073/pnas.78.12.7634
268:anterior-posterior axis
2799:Developmental Dynamics
2290:10.1083/jcb.150.5.1215
2035:10.1038/sj.onc.1203726
1142:Biotechnology Progress
367:Martin, G. R. (1981).
143:EBs are formed by the
56:
35:
2848:Developmental Biology
2736:10.1242/dev.118.3.829
2376:10.1242/dev.111.2.259
2241:10.1083/jcb.144.1.151
2151:10.1083/jcb.153.4.811
1236:Regenerative Medicine
612:10.1073/pnas.38.5.455
158:rho associated kinase
120:embryonic development
100:cultured in monolayer
46:
33:
3248:Cells Tissues Organs
2599:(15–16): 1901–1909.
2102:10.1083/jcb.98.3.971
1531:Nature Biotechnology
1487:Nature Biotechnology
186:extracellular matrix
84:embryonic stem cells
3393:Integrative Biology
2666:10.1038/nature09941
2658:2011Natur.472...51E
1899:2008PLoSO...3.1565U
1840:2009PNAS..10616978H
1834:(40): 16978–16983.
1698:2011Ana...136..473T
1590:2010PNAS..107.8129X
1447:1988Natur.336..684W
1296:10.1263/jbb.103.389
1199:10.1002/jbm.a.31851
880:2007Sci...318.1917Y
874:(5858): 1917–1920.
720:2000CBio...10..989M
665:1997Natur.385..810W
603:1952PNAS...38..455B
554:1998Sci...282.1145T
548:(5391): 1145–1147.
495:1995PNAS...92.7844T
440:1981Natur.292..154E
385:1981PNAS...78.7634M
3405:10.1039/c1ib00064k
3068:10.1242/dev.112979
3011:10.1242/dev.113001
2812:10.1002/dvdy.20408
1706:10.1039/c0an00609b
984:10.1007/BF03401776
972:Molecular Medicine
649:Campbell, K. H. S.
344:Induced stem cells
206:fetal bovine serum
188:(ECM), containing
145:homophilic binding
57:
36:
3399:(12): 1224–1232.
3260:10.1159/000330691
3219:(34): 4471–4480.
3174:(13): 2507–2515.
3062:(22): 4243–4253.
3005:(22): 4231–4242.
2028:(33): 3750–3756.
1792:(36): 6032–6042.
1584:(18): 8129–8134.
1441:(6200): 684–687.
1325:(10): 3185–3194.
1248:10.2217/rme.09.74
659:(6619): 810–813.
489:(17): 7844–7848.
434:(5819): 154–156.
379:(12): 7634–7638.
198:basement membrane
44:
16:(Redirected from
3547:
3525:
3524:
3514:
3482:
3476:
3475:
3465:
3433:
3427:
3426:
3416:
3384:
3378:
3377:
3367:
3350:(5): 1271–1280.
3335:
3329:
3328:
3318:
3286:
3280:
3279:
3243:
3237:
3236:
3208:
3202:
3201:
3191:
3159:
3150:
3149:
3139:
3107:
3098:
3097:
3087:
3047:
3041:
3040:
3030:
2990:
2984:
2983:
2973:
2933:
2924:
2923:
2921:
2908:
2899:
2898:
2896:
2883:
2874:
2873:
2863:
2839:
2833:
2832:
2814:
2805:(3): 1064–1075.
2790:
2784:
2783:
2754:
2748:
2747:
2719:
2713:
2712:
2692:
2686:
2685:
2641:
2635:
2634:
2616:
2587:
2581:
2580:
2570:
2538:
2532:
2531:
2521:
2489:
2478:
2477:
2467:
2435:
2429:
2428:
2418:
2409:(9): 1186–1198.
2394:
2388:
2387:
2359:
2353:
2352:
2318:
2312:
2311:
2301:
2284:(5): 1215–1221.
2269:
2263:
2262:
2252:
2220:
2214:
2213:
2203:
2179:
2173:
2172:
2162:
2130:
2124:
2123:
2113:
2081:
2075:
2074:
2054:
2048:
2047:
2037:
2013:
2007:
2006:
1996:
1987:(9): 2300–2310.
1972:
1966:
1965:
1937:
1931:
1930:
1920:
1910:
1878:
1872:
1871:
1861:
1851:
1819:
1810:
1809:
1781:
1775:
1774:
1763:10.1039/b704739h
1757:(8): 1018–1028.
1742:
1736:
1735:
1717:
1677:
1671:
1670:
1652:
1643:(9): 2224–2234.
1628:
1622:
1621:
1611:
1601:
1569:
1563:
1562:
1525:
1519:
1518:
1481:
1475:
1474:
1455:10.1038/336684a0
1429:
1423:
1422:
1412:
1403:(6): 2007–2014.
1388:
1382:
1381:
1352:
1343:
1342:
1314:
1308:
1307:
1279:
1270:
1269:
1259:
1227:
1221:
1220:
1210:
1193:(4): 1075–1085.
1182:
1176:
1175:
1165:
1154:10.1002/btpr.139
1133:
1124:
1123:
1113:
1089:
1078:
1077:
1067:
1043:
1037:
1036:
1015:
1006:
1005:
995:
963:
957:
956:
946:
914:
908:
907:
862:
856:
855:
837:
805:
799:
798:
780:
748:
742:
741:
731:
699:
693:
692:
673:10.1038/385810a0
641:
635:
634:
624:
614:
582:
576:
575:
565:
533:
527:
526:
516:
506:
474:
468:
467:
448:10.1038/292154a0
423:
417:
416:
406:
396:
364:
92:nuclear transfer
45:
21:
3555:
3554:
3550:
3549:
3548:
3546:
3545:
3544:
3530:
3529:
3528:
3484:
3483:
3479:
3435:
3434:
3430:
3386:
3385:
3381:
3337:
3336:
3332:
3288:
3287:
3283:
3245:
3244:
3240:
3210:
3209:
3205:
3161:
3160:
3153:
3109:
3108:
3101:
3049:
3048:
3044:
2992:
2991:
2987:
2948:(105): e53252.
2935:
2934:
2927:
2910:
2909:
2902:
2885:
2884:
2877:
2841:
2840:
2836:
2792:
2791:
2787:
2756:
2755:
2751:
2721:
2720:
2716:
2694:
2693:
2689:
2652:(7341): 51–56.
2643:
2642:
2638:
2589:
2588:
2584:
2540:
2539:
2535:
2491:
2490:
2481:
2437:
2436:
2432:
2396:
2395:
2391:
2361:
2360:
2356:
2341:
2320:
2319:
2315:
2271:
2270:
2266:
2222:
2221:
2217:
2181:
2180:
2176:
2132:
2131:
2127:
2083:
2082:
2078:
2056:
2055:
2051:
2015:
2014:
2010:
1974:
1973:
1969:
1939:
1938:
1934:
1880:
1879:
1875:
1821:
1820:
1813:
1783:
1782:
1778:
1744:
1743:
1739:
1679:
1678:
1674:
1630:
1629:
1625:
1571:
1570:
1566:
1543:10.1038/nbt1310
1527:
1526:
1522:
1499:10.1038/nbt1177
1483:
1482:
1478:
1431:
1430:
1426:
1390:
1389:
1385:
1358:Differentiation
1354:
1353:
1346:
1316:
1315:
1311:
1281:
1280:
1273:
1229:
1228:
1224:
1184:
1183:
1179:
1135:
1134:
1127:
1091:
1090:
1081:
1045:
1044:
1040:
1017:
1016:
1009:
965:
964:
960:
916:
915:
911:
864:
863:
859:
807:
806:
802:
751:Takahashi, K.;
750:
749:
745:
714:(16): 989–992.
708:Current Biology
701:
700:
696:
643:
642:
638:
584:
583:
579:
535:
534:
530:
476:
475:
471:
425:
424:
420:
366:
365:
361:
357:
330:
308:
260:inner cell mass
252:
246:
202:neural lineages
178:differentiation
174:
141:
80:
60:Embryoid bodies
38:
28:
23:
22:
18:Embryoid bodies
15:
12:
11:
5:
3553:
3551:
3543:
3542:
3532:
3531:
3527:
3526:
3497:(3): 559–567.
3477:
3448:(2): 629–641.
3428:
3379:
3330:
3281:
3238:
3203:
3151:
3122:(4): 249–262.
3099:
3042:
2985:
2925:
2919:10.1101/051722
2900:
2894:10.1101/104539
2875:
2854:(2): 363–371.
2834:
2785:
2766:(5): 681–684.
2749:
2730:(3): 829–844.
2714:
2703:(3): 183–205.
2687:
2636:
2582:
2553:(4): 345–358.
2533:
2504:(5): 508–518.
2498:Cell Stem Cell
2479:
2444:Cell Stem Cell
2430:
2389:
2370:(2): 259–267.
2354:
2339:
2313:
2264:
2235:(1): 151–160.
2215:
2194:(2): 279–287.
2174:
2145:(4): 811–822.
2125:
2096:(3): 971–979.
2076:
2065:(6): 817–825.
2049:
2008:
1967:
1948:(2): 331–342.
1932:
1873:
1811:
1776:
1737:
1692:(3): 473–478.
1672:
1623:
1564:
1537:(6): 681–686.
1520:
1493:(2): 185–187.
1476:
1424:
1383:
1364:(4): 149–159.
1344:
1309:
1290:(5): 389–398.
1271:
1242:(1): 121–143.
1222:
1177:
1125:
1104:(4): 661–680.
1079:
1058:(3): 275–282.
1038:
1007:
958:
929:(5): 877–886.
909:
857:
820:(5): 861–872.
800:
743:
694:
636:
597:(5): 455–463.
577:
528:
469:
418:
358:
356:
353:
352:
351:
346:
341:
336:
334:Brain organoid
329:
326:
307:
304:
300:embryonic axes
248:Main article:
245:
242:
173:
170:
140:
137:
126:and paracrine
124:cell adhesions
79:
76:
53:cardiomyocytes
26:
24:
14:
13:
10:
9:
6:
4:
3:
2:
3552:
3541:
3538:
3537:
3535:
3522:
3518:
3513:
3508:
3504:
3500:
3496:
3492:
3488:
3481:
3478:
3473:
3469:
3464:
3459:
3455:
3451:
3447:
3443:
3439:
3432:
3429:
3424:
3420:
3415:
3410:
3406:
3402:
3398:
3394:
3390:
3383:
3380:
3375:
3371:
3366:
3361:
3357:
3353:
3349:
3345:
3341:
3334:
3331:
3326:
3322:
3317:
3312:
3308:
3304:
3300:
3296:
3292:
3285:
3282:
3277:
3273:
3269:
3265:
3261:
3257:
3253:
3249:
3242:
3239:
3234:
3230:
3226:
3222:
3218:
3214:
3207:
3204:
3199:
3195:
3190:
3185:
3181:
3177:
3173:
3169:
3165:
3158:
3156:
3152:
3147:
3143:
3138:
3133:
3129:
3125:
3121:
3117:
3113:
3106:
3104:
3100:
3095:
3091:
3086:
3081:
3077:
3073:
3069:
3065:
3061:
3057:
3053:
3046:
3043:
3038:
3034:
3029:
3024:
3020:
3016:
3012:
3008:
3004:
3000:
2996:
2989:
2986:
2981:
2977:
2972:
2967:
2963:
2959:
2955:
2954:10.3791/53252
2951:
2947:
2943:
2941:
2932:
2930:
2926:
2920:
2915:
2907:
2905:
2901:
2895:
2890:
2887:signalling".
2882:
2880:
2876:
2871:
2867:
2862:
2857:
2853:
2849:
2845:
2838:
2835:
2830:
2826:
2822:
2818:
2813:
2808:
2804:
2800:
2796:
2789:
2786:
2781:
2777:
2773:
2769:
2765:
2761:
2753:
2750:
2745:
2741:
2737:
2733:
2729:
2725:
2718:
2715:
2710:
2706:
2702:
2698:
2691:
2688:
2683:
2679:
2675:
2671:
2667:
2663:
2659:
2655:
2651:
2647:
2640:
2637:
2632:
2628:
2624:
2620:
2615:
2610:
2606:
2602:
2598:
2594:
2586:
2583:
2578:
2574:
2569:
2564:
2560:
2556:
2552:
2548:
2544:
2537:
2534:
2529:
2525:
2520:
2515:
2511:
2507:
2503:
2499:
2495:
2488:
2486:
2484:
2480:
2475:
2471:
2466:
2461:
2457:
2453:
2449:
2445:
2441:
2434:
2431:
2426:
2422:
2417:
2412:
2408:
2404:
2400:
2393:
2390:
2385:
2381:
2377:
2373:
2369:
2365:
2358:
2355:
2350:
2346:
2342:
2340:9780121822682
2336:
2332:
2328:
2324:
2317:
2314:
2309:
2305:
2300:
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2279:
2275:
2268:
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2251:
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2202:
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2178:
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2166:
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2077:
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2068:
2064:
2060:
2053:
2050:
2045:
2041:
2036:
2031:
2027:
2023:
2019:
2012:
2009:
2004:
2000:
1995:
1990:
1986:
1982:
1978:
1971:
1968:
1963:
1959:
1955:
1951:
1947:
1943:
1936:
1933:
1928:
1924:
1919:
1914:
1909:
1904:
1900:
1896:
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1751:Lab on a Chip
1748:
1741:
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282:
278:
274:
269:
265:
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257:
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250:embryogenesis
243:
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239:
235:
234:cardiomyocyte
231:
227:
226:morphogenesis
223:
217:
215:
211:
207:
203:
199:
195:
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187:
183:
182:germ lineages
179:
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169:
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136:
135:development.
133:
132:morphogenesis
129:
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104:germ lineages
101:
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3343:
3333:
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3295:Biomaterials
3294:
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3212:
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3168:Biomaterials
3167:
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1980:
1970:
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1789:
1786:Biomaterials
1785:
1779:
1754:
1750:
1740:
1689:
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1640:
1636:
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1283:
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1024:
1020:
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975:
971:
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926:
922:
912:
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867:
860:
817:
813:
810:Yamanaka, S.
803:
760:
756:
753:Yamanaka, S.
746:
711:
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697:
656:
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639:
594:
590:
580:
545:
541:
531:
486:
482:
472:
431:
427:
421:
376:
372:
362:
349:Pluripotency
309:
289:
253:
218:
175:
166:
162:hydrodynamic
142:
116:
114:cell types.
106:– endoderm,
81:
72:
63:
59:
58:
3056:Development
2999:Development
2724:Development
2364:Development
1686:The Analyst
1319:Development
778:2433/159777
277:antagonists
190:collagen IV
3540:Stem cells
2614:1807/33799
1981:Stem Cells
1637:Stem Cells
1208:1853/37170
1052:Stem Cells
835:2433/49782
645:Wilmut, I.
355:References
339:Gastruloid
313:epithelial
256:blastocyst
216:lineages.
149:E-cadherin
88:blastocyst
78:Background
68:stem cells
3076:0950-1991
3019:0950-1991
2962:1940-087X
1027:: 27–45.
321:transport
296:brachyury
139:Formation
128:signaling
3534:Category
3521:18724832
3472:20001738
3423:22076329
3374:22079776
3325:20864164
3276:42754482
3268:22249133
3233:18793799
3198:19162317
3146:21491967
3094:25371361
3037:25371360
2980:26650833
2940:In Vitro
2870:16289026
2829:20596850
2821:15880404
2780:12972006
2709:10410899
2674:21475194
2631:22010083
2623:21417693
2577:20026669
2528:18983966
2474:18371422
2425:18550259
2349:14696356
2308:10974008
2169:11352941
2071:12382948
2044:10949929
2022:Oncogene
2003:18583540
1962:19193130
1927:18270562
1887:PLOS ONE
1868:19805103
1806:16884768
1771:17653344
1732:35415772
1724:20967331
1667:25461651
1659:17585171
1618:20406903
1551:17529971
1515:11484871
1507:16388305
1419:12930726
1378:16683985
1304:17609152
1266:20017699
1217:18260134
1172:19198003
1120:18295582
1074:15153605
1002:10859025
953:18691744
904:86129154
896:18029452
844:18035408
787:16904174
738:10985386
631:16589125
328:See also
273:agonists
264:epiblast
214:endoderm
210:mesoderm
108:ectoderm
3512:6468949
3463:2813151
3414:4633527
3365:4280365
3316:2987521
3189:2921510
3137:3142632
3085:4302903
3028:4302915
2971:4692741
2914:bioRxiv
2889:bioRxiv
2744:7521282
2682:4421136
2654:Bibcode
2568:2842597
2519:2683270
2465:2533280
2384:1893864
2299:2175256
2259:9885251
2250:2148127
2210:7585945
2160:2192393
2120:6365932
2111:2113154
1918:2215775
1895:Bibcode
1859:2761314
1836:Bibcode
1715:7454010
1694:Bibcode
1609:2889586
1586:Bibcode
1559:8213725
1471:4346252
1463:3143916
1443:Bibcode
1339:8898231
1257:2833273
1163:2693014
1033:3897439
993:1949933
944:2633781
876:Bibcode
868:Science
852:8531539
795:1565219
716:Bibcode
689:4260518
681:9039911
661:Bibcode
622:1063586
599:Bibcode
572:9804556
550:Bibcode
542:Science
523:7544005
491:Bibcode
464:4256553
456:7242681
436:Bibcode
413:6950406
381:Bibcode
238:gelatin
230:neurite
194:laminin
112:somatic
3519:
3509:
3470:
3460:
3421:
3411:
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3323:
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2646:Nature
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1435:Nature
1417:
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1000:
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653:Nature
629:
619:
570:
521:
511:
462:
454:
428:Nature
411:
404:349323
401:
3272:S2CID
2825:S2CID
2678:S2CID
2627:S2CID
1728:S2CID
1663:S2CID
1555:S2CID
1511:S2CID
1467:S2CID
900:S2CID
848:S2CID
791:S2CID
685:S2CID
514:41242
460:S2CID
3517:PMID
3468:PMID
3419:PMID
3370:PMID
3321:PMID
3264:PMID
3229:PMID
3194:PMID
3142:PMID
3090:PMID
3072:ISSN
3033:PMID
3015:ISSN
2976:PMID
2958:ISSN
2866:PMID
2817:PMID
2776:PMID
2740:PMID
2705:PMID
2670:PMID
2619:PMID
2573:PMID
2524:PMID
2470:PMID
2421:PMID
2380:PMID
2345:PMID
2335:ISBN
2304:PMID
2255:PMID
2206:PMID
2188:Cell
2165:PMID
2116:PMID
2067:PMID
2040:PMID
1999:PMID
1958:PMID
1923:PMID
1864:PMID
1802:PMID
1767:PMID
1720:PMID
1655:PMID
1614:PMID
1547:PMID
1503:PMID
1459:PMID
1415:PMID
1374:PMID
1335:PMID
1300:PMID
1262:PMID
1213:PMID
1168:PMID
1116:PMID
1098:Cell
1070:PMID
1029:PMID
998:PMID
949:PMID
923:Cell
892:PMID
840:PMID
814:Cell
783:PMID
757:Cell
734:PMID
677:PMID
627:PMID
568:PMID
519:PMID
452:PMID
409:PMID
283:and
275:and
212:and
192:and
153:agar
3507:PMC
3499:doi
3458:PMC
3450:doi
3409:PMC
3401:doi
3360:PMC
3352:doi
3311:PMC
3303:doi
3256:doi
3252:196
3221:doi
3184:PMC
3176:doi
3132:PMC
3124:doi
3080:PMC
3064:doi
3060:141
3023:PMC
3007:doi
3003:141
2966:PMC
2950:doi
2856:doi
2852:288
2807:doi
2803:233
2768:doi
2732:doi
2728:118
2662:doi
2650:472
2609:hdl
2601:doi
2563:PMC
2555:doi
2514:PMC
2506:doi
2460:PMC
2452:doi
2411:doi
2372:doi
2368:111
2327:doi
2294:PMC
2286:doi
2282:150
2245:PMC
2237:doi
2233:144
2196:doi
2155:PMC
2147:doi
2143:153
2106:PMC
2098:doi
2030:doi
1989:doi
1950:doi
1913:PMC
1903:doi
1854:PMC
1844:doi
1832:106
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1759:doi
1710:PMC
1702:doi
1690:136
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1604:PMC
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1582:107
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1451:doi
1439:336
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1327:doi
1323:122
1292:doi
1288:103
1252:PMC
1244:doi
1203:hdl
1195:doi
1191:87A
1158:PMC
1150:doi
1106:doi
1102:132
1060:doi
988:PMC
980:doi
939:PMC
931:doi
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872:318
830:hdl
822:doi
818:131
773:hdl
765:doi
761:126
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669:doi
657:385
617:PMC
607:doi
558:doi
546:282
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432:292
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317:ECM
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