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• W2484685366 abstract "Chimeras are widely acknowledged as the gold standard for assessing stem cell pluripotency, based on their capacity to test donor cell lineage potential in the context of an organized, normally developing tissue. Experimental chimeras provide key insights into mammalian developmental mechanisms and offer a resource for interrogating the fate potential of various pluripotent stem cell states. We highlight the applications and current limitations presented by intra- and inter-species chimeras and consider their future contribution to the stem cell field. Despite the technical and ethical demands of experimental chimeras, including human-interspecies chimeras, they are a provocative resource for achieving regenerative medicine goals. Chimeras are widely acknowledged as the gold standard for assessing stem cell pluripotency, based on their capacity to test donor cell lineage potential in the context of an organized, normally developing tissue. Experimental chimeras provide key insights into mammalian developmental mechanisms and offer a resource for interrogating the fate potential of various pluripotent stem cell states. We highlight the applications and current limitations presented by intra- and inter-species chimeras and consider their future contribution to the stem cell field. Despite the technical and ethical demands of experimental chimeras, including human-interspecies chimeras, they are a provocative resource for achieving regenerative medicine goals. Experimental chimeras are widely recognized as the most stringent assays for validating stem cell pluripotency. Preimplantation chimeras provide donor cells with developmental access to the entire fetus and extraembryonic mesoderm (yolk sac, allantois, and amniotic mesoderm), thereby enabling a broad assessment of donor cell developmental capacity. Tetraploid preimplantation chimeras in particular are considered the most comprehensive test of pluripotency because wholly stem cell-derived mouse offspring are the assessment endpoint. The inner cell mass-like (ICM-like) “naive” mouse embryonic stem cells (mESCs) adhere to the most stringent definitions of pluripotency in that they contribute to all tissues of the developing body in a preimplantation chimera assay including the germline (Bradley et al., 1984Bradley A. Evans M. Kaufman M.H. Robertson E. Formation of germ-line chimaeras from embryo-derived teratocarcinoma cell lines.Nature. 1984; 309: 255-256Crossref PubMed Scopus (1101) Google Scholar, Nagy et al., 1993Nagy A. Rossant J. Nagy R. Abramow-Newerly W. Roder J.C. Derivation of completely cell culture-derived mice from early-passage embryonic stem cells.Proc. Natl. Acad. Sci. USA. 1993; 90: 8424-8428Crossref PubMed Scopus (1974) Google Scholar). Mouse pluripotent stem cells (PSCs) generated by reprogramming of somatic cells either by somatic cell nuclear transfer into nuclear transfer embryonic stem cells (ntESCs) (Munsie et al., 2000Munsie M.J. Michalska A.E. O’Brien C.M. Trounson A.O. Pera M.F. Mountford P.S. Isolation of pluripotent embryonic stem cells from reprogrammed adult mouse somatic cell nuclei.Curr. Biol. 2000; 10: 989-992Abstract Full Text Full Text PDF PubMed Scopus (309) Google Scholar, Kawase et al., 2000Kawase E. Yamazaki Y. Yagi T. Yanagimachi R. Pedersen R.A. Mouse embryonic stem (ES) cell lines established from neuronal cell-derived cloned blastocysts.Genesis. 2000; 28: 156-163Crossref PubMed Scopus (89) Google Scholar) or by direct reprogramming into mouse induced PSCs (miPSCs) (Takahashi and Yamanaka, 2006Takahashi K. Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.Cell. 2006; 126: 663-676Abstract Full Text Full Text PDF PubMed Scopus (18861) Google Scholar) also share the defining feature of mESCs: they have generated mice wholly derived from donor stem cells following tetraploid complementation (Boland et al., 2009Boland M.J. Hazen J.L. Nazor K.L. Rodriguez A.R. Gifford W. Martin G. Kupriyanov S. Baldwin K.K. Adult mice generated from induced pluripotent stem cells.Nature. 2009; 461: 91-94Crossref PubMed Scopus (379) Google Scholar, Lin et al., 2010Lin C.-J. Amano T. Zhang J. Chen Y.E. Tian X.C. Acceptance of embryonic stem cells by a wide developmental range of mouse tetraploid embryos.Biol. Reprod. 2010; 83: 177-184Crossref PubMed Scopus (11) Google Scholar). Recently, chimera assays have been more broadly applied to test the lineage potential of other mammalian pluripotent states. Interestingly, epithelial epiblast-like “primed” PSCs (including mEpiSCs, hESCs, and hiPSCs), unlike their ICM-like counterparts (mESCs, ntESCs, and miPSCs), are barely able to form preimplantation chimeras (James et al., 2006James D. Noggle S.A. Swigut T. Brivanlou A.H. Contribution of human embryonic stem cells to mouse blastocysts.Dev. Biol. 2006; 295: 90-102Crossref PubMed Scopus (131) Google Scholar, Brons et al., 2007Brons I.G.M. Smithers L.E. Trotter M.W.B. Rugg-Gunn P. Sun B. Chuva de Sousa Lopes S.M. Howlett S.K. Clarkson A. Ahrlund-Richter L. Pedersen R.A. Vallier L. Derivation of pluripotent epiblast stem cells from mammalian embryos.Nature. 2007; 448: 191-195Crossref PubMed Scopus (1549) Google Scholar, Tesar et al., 2007Tesar P.J. Chenoweth J.G. Brook F.A. Davies T.J. Evans E.P. Mack D.L. Gardner R.L. McKay R.D. New cell lines from mouse epiblast share defining features with human embryonic stem cells.Nature. 2007; 448: 196-199Crossref PubMed Scopus (1677) Google Scholar, Masaki et al., 2015Masaki H. Kato-Itoh M. Umino A. Sato H. Hamanaka S. Kobayashi T. Yamaguchi T. Nishimura K. Ohtaka M. Nakanishi M. Nakauchi H. Interspecific in vitro assay for the chimera-forming ability of human pluripotent stem cells.Development. 2015; 142: 3222-3230Crossref PubMed Scopus (45) Google Scholar, Chen et al., 2015Chen Y. Niu Y. Li Y. Ai Z. Kang Y. Shi H. Xiang Z. Yang Z. Tan T. Si W. et al.Generation of Cynomolgus Monkey Chimeric Fetuses using Embryonic Stem Cells.Cell Stem Cell. 2015; 17: 116-124Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar). Efforts continue to assess the potential of naive human cells to form preimplantation interspecies chimeras (Gafni et al., 2013Gafni O. Weinberger L. Mansour A.A. Manor Y.S. Chomsky E. Ben-Yosef D. Kalma Y. Viukov S. Maza I. Zviran A. et al.Derivation of novel human ground state naive pluripotent stem cells.Nature. 2013; 504: 282-286Crossref PubMed Scopus (764) Google Scholar, Theunissen et al., 2014Theunissen T.W. Powell B.E. Wang H. Mitalipova M. Faddah D.A. Reddy J. Fan Z.P. Maetzel D. Ganz K. Shi L. et al.Systematic identification of culture conditions for induction and maintenance of naive human pluripotency.Cell Stem Cell. 2014; 15: 471-487Abstract Full Text Full Text PDF PubMed Scopus (543) Google Scholar, Takashima et al., 2014Takashima Y. Guo G. Loos R. Nichols J. Ficz G. Krueger F. Oxley D. Santos F. Clarke J. Mansfield W. et al.Resetting transcription factor control circuitry toward ground-state pluripotency in human.Cell. 2014; 158: 1254-1269Abstract Full Text Full Text PDF PubMed Scopus (607) Google Scholar, Theunissen et al., 2016Theunissen T.W. Friedli M. He Y. Planet E. O’Neil R.C. Markoulaki S. Pontis J. Wang H. Iouranova A. Imbeault M. et al.Molecular Criteria for Defining the Naive Human Pluripotent State.Cell Stem Cell. 2016; (in press. Published online July 13, 2016)https://doi.org/10.1016/j.stem.2016.06.011Abstract Full Text Full Text PDF Scopus (304) Google Scholar). Conversely, epithelial epiblast-like PSCs, which resemble the post-implantation epiblast, instead form post-implantation chimeras (Huang et al., 2012Huang Y. Osorno R. Tsakiridis A. Wilson V. In Vivo differentiation potential of epiblast stem cells revealed by chimeric embryo formation.Cell Rep. 2012; 2: 1571-1578Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar, Kojima et al., 2014Kojima Y. Kaufman-Francis K. Studdert J.B. Steiner K.A. Power M.D. Loebel D.A.F. Jones V. Hor A. de Alencastro G. Logan G.J. et al.The transcriptional and functional properties of mouse epiblast stem cells resemble the anterior primitive streak.Cell Stem Cell. 2014; 14: 107-120Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar, Mascetti and Pedersen, 2016Mascetti V.L. Pedersen R.A. Human-Mouse Chimerism Validates Human Stem Cell Pluripotency.Cell Stem Cell. 2016; 18: 67-72Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar). In this Perspective we focus on the contribution of mammalian chimeras for assessing the competence of PSCs and their respective stem cell states to participate in normal in vivo development. We also consider the lessons gleaned from the embryo's own resident PSCs and how this can inform the in vitro capture of mammalian pluripotent states. A chimera is a composite organism in which the different cell populations are derived from more than one fertilized egg, thereby combining tissues with distinct genetic origins and identities (McLaren, 1976McLaren A. Mammalian Chimaeras. Cambridge University Press, Cambridge1976Google Scholar). The distinct biological mechanisms underpinning chimera formation begin with the persistence of donor cells after transplantation and continue via their participation in the morphogenetic movements of the host embryo, culminating in donor cell differentiation in a manner paralleling the tissue in which they reside. A primary, or embryonic, chimera is one in which the genetically different cell populations co-exist from a very early stage of embryogenesis, even from fertilization (McLaren, 1976McLaren A. Mammalian Chimaeras. Cambridge University Press, Cambridge1976Google Scholar). In light of current and advancing technologies it is pertinent to state that a primary chimera is one in which both host and donor have not undergone organogenesis and thus are capable of contributing to most or all major building blocks of the body. Typically, experimental primary chimeras are formed by combining isolated blastomeres from a minimum of two embryos, by the aggregation of two or more whole early cleaving embryos, or by stem cell transplantation under the zona pellucida or into the blastocyst cavity of a preimplantation embryo. Primary chimera formation, generated by cell transplantation (whether embryo-derived or in vitro-derived stem cells) to the embryo, provides a stringent assessment of stem cell pluripotency. By contrast, a secondary chimera is one in which tissues are combined from two or more adult individuals, or from embryos after the period of organogenesis has begun (McLaren, 1976McLaren A. Mammalian Chimaeras. Cambridge University Press, Cambridge1976Google Scholar). As a consequence of being initiated at a later developmental stage, secondary chimerism is typically limited to one or more tissue-specific lineages. Initially, chimeric potential was assessed by full-term gestation in utero resulting in the birth of offspring: Tarkowski’s pioneering study revealed the capacity for two cleavage-stage embryos to aggregate and form a single chimeric blastocyst (Figure 1A and Figure 2) and for these to develop subsequently to mid- and full-term when transferred to the uteri of foster mothers (Tarkowski, 1961Tarkowski A.K. Mouse chimaeras developed from fused eggs.Nature. 1961; 190: 857-860Crossref PubMed Scopus (347) Google Scholar). These primary chimeras resulted in normal-sized mice termed “quadriparental or allophenic” by Mintz (Mintz, 1965Mintz B. Genetic mosaicism in adult mice of quadriparental lineage.Science. 1965; 148: 1232-1233Crossref PubMed Scopus (95) Google Scholar), and they were composed of a mixture of cells derived from the two parental embryos (McLaren and Bowman, 1969McLaren A. Bowman P. Mouse chimaeras derived from fusion of embryos differing by nine genetic factors.Nature. 1969; 224: 238-240Crossref PubMed Scopus (43) Google Scholar). Chimerism in such embryos extends throughout both embryonic and extraembryonic lineages, including derivatives of the epiblast, trophectoderm, and primitive endoderm.Figure 2Lineage Contributions of Donor and Host Cells in Chimera AssaysShow full captionLineage contribution of donor and host cells in chimera assays depicted in Figure 1. ICM includes the epiblast and primitive endoderm. Epiblast-derived tissues include the entire fetus (Embryo proper), plus extraembryonic mesoderm (ExEm Mesoderm) and amnion.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Lineage contribution of donor and host cells in chimera assays depicted in Figure 1. ICM includes the epiblast and primitive endoderm. Epiblast-derived tissues include the entire fetus (Embryo proper), plus extraembryonic mesoderm (ExEm Mesoderm) and amnion. Later, chimeras were generated with embryonic cells via the technically challenging procedure of direct injection into the cavity of the host blastocyst (Gardner, 1968Gardner R.L. Mouse chimeras obtained by the injection of cells into the blastocyst.Nature. 1968; 220: 596-597Crossref PubMed Scopus (188) Google Scholar) (Figure 1B and Figure 2). After this discovery, mESCs were injected into mouse blastocysts by Evans and co-workers, who reported that mESCs were able to integrate and differentiate into all tissue types in the chimera, including those contributing to the germline (Bradley et al., 1984Bradley A. Evans M. Kaufman M.H. Robertson E. Formation of germ-line chimaeras from embryo-derived teratocarcinoma cell lines.Nature. 1984; 309: 255-256Crossref PubMed Scopus (1101) Google Scholar, Robertson et al., 1986Robertson E. Bradley A. Kuehn M. Evans M. Germ-line transmission of genes introduced into cultured pluripotential cells by retroviral vector.Nature. 1986; 323: 445-448Crossref PubMed Scopus (560) Google Scholar) (Figure 1C and Figure 2). The developmental potential of mESCs was assessed in parallel with 3.5 day ICM after aggregation with normal diploid (2N) embryos (Figure 1C and Figure 2) or with developmentally compromised tetraploid (4N) embryos (Figure 1D and Figure 2), with both donor types capable of colonizing somatic tissues (Nagy et al., 1990Nagy A. Gócza E. Diaz E.M. Prideaux V.R. Iványi E. Markkula M. Rossant J. Embryonic stem cells alone are able to support fetal development in the mouse.Development. 1990; 110: 815-821Crossref PubMed Google Scholar, Nagy et al., 1993Nagy A. Rossant J. Nagy R. Abramow-Newerly W. Roder J.C. Derivation of completely cell culture-derived mice from early-passage embryonic stem cells.Proc. Natl. Acad. Sci. USA. 1993; 90: 8424-8428Crossref PubMed Scopus (1974) Google Scholar). Tarkowski and co-workers first showed that tetraploid embryos demonstrate abortive development (failing between E7.5 and E14) (Tarkowski et al., 1977Tarkowski A.K. Witkowska A. Opas J. Development of cytochalasin in B-induced tetraploid and diploid/tetraploid mosaic mouse embryos.J. Embryol. Exp. Morphol. 1977; 41: 47-64PubMed Google Scholar), but their development can be rescued by complementation with normal diploid embryos to create tetraploid-diploid chimeras. Interestingly, in chimeras made using tetraploid host embryos and diploid embryo, ICM, or mESCs, the resulting epiblast-derived tissues at E13.5 (yolk sac mesoderm, amnion, and fetus) and in newborn mice were derived completely from their diploid component (either embryo, ICM, or cultured mESCs) (Kaufman and Webb, 1990Kaufman M.H. Webb S. Postimplantation development of tetraploid mouse embryos produced by electrofusion.Development. 1990; 110: 1121-1132Crossref PubMed Google Scholar, Nagy et al., 1990Nagy A. Gócza E. Diaz E.M. Prideaux V.R. Iványi E. Markkula M. Rossant J. Embryonic stem cells alone are able to support fetal development in the mouse.Development. 1990; 110: 815-821Crossref PubMed Google Scholar, Nagy et al., 1993Nagy A. Rossant J. Nagy R. Abramow-Newerly W. Roder J.C. Derivation of completely cell culture-derived mice from early-passage embryonic stem cells.Proc. Natl. Acad. Sci. USA. 1993; 90: 8424-8428Crossref PubMed Scopus (1974) Google Scholar). However, the yolk sac endoderm and placenta (trophectoderm) lineages were of complete tetraploid origin. Taken together, these pioneering studies provided evidence that mESCs were able to support complete fetal development, and they established tetraploid complementation as an assessment of stem cell pluripotency. Building on these findings, scientists mutated genes in ESC lines by homologous recombination and transplanted these cells into mouse embryos in order to achieve targeted mutagenesis in the mouse (Doetschman et al., 1988Doetschman T. Maeda N. Smithies O. Targeted mutation of the Hprt gene in mouse embryonic stem cells.Proc. Natl. Acad. Sci. USA. 1988; 85: 8583-8587Crossref PubMed Scopus (183) Google Scholar, Thomas and Capecchi, 1990Thomas K.R. Capecchi M.R. Targeted disruption of the murine int-1 proto-oncogene resulting in severe abnormalities in midbrain and cerebellar development.Nature. 1990; 346: 847-850Crossref PubMed Scopus (731) Google Scholar), birthing a revolution in genetic manipulation of mammalian models. The adoption of gene-targeted ESC lines (Rajewsky et al., 1996Rajewsky K. Gu H. Kühn R. Betz U.A. Müller W. Roes J. Schwenk F. Conditional gene targeting.J. Clin. Invest. 1996; 98: 600-603Crossref PubMed Scopus (241) Google Scholar, Danielian et al., 1998Danielian P.S. Muccino D. Rowitch D.H. Michael S.K. McMahon A.P. Modification of gene activity in mouse embryos in utero by a tamoxifen-inducible form of Cre recombinase.Curr. Biol. 1998; 8: 1323-1326Abstract Full Text Full Text PDF PubMed Google Scholar, Shalem et al., 2015Shalem O. Sanjana N.E. Zhang F. High-throughput functional genomics using CRISPR-Cas9.Nat. Rev. Genet. 2015; 16: 299-311Crossref PubMed Scopus (749) Google Scholar) expanded the utility of chimeras, especially when combined with tetraploid complementation (Seibler et al., 2003Seibler J. Zevnik B. Küter-Luks B. Andreas S. Kern H. Hennek T. Rode A. Heimann C. Faust N. Kauselmann G. et al.Rapid generation of inducible mouse mutants.Nucleic Acids Res. 2003; 31: e12Crossref PubMed Scopus (239) Google Scholar), to discern gene-development interactions (function and dysfunction) in testing lineage potency and disease modeling. The age of designer mice was conceived. Post-implantation mouse embryos have been utilized in experimental biology routinely since the 1970s, when New developed a method in Cambridge for culturing rat and mouse embryos (Sadler and New, 1981Sadler T.W. New D.A. Culture of mouse embryos during neurulation.J. Embryol. Exp. Morphol. 1981; 66: 109-116PubMed Google Scholar). The post-implantation mouse embryo opens a window in developmental time, gastrulation, that would otherwise be inaccessible in other mammals (most notably humans) due to practical and ethical challenges. Accordingly, use of post-implantation mouse embryos as chimeric hosts has enabled the assessment of potency and fate of primitive streak (Kinder et al., 1999Kinder S.J. Tsang T.E. Quinlan G.A. Hadjantonakis A.K. Nagy A. Tam P.P. The orderly allocation of mesodermal cells to the extraembryonic structures and the anteroposterior axis during gastrulation of the mouse embryo.Development. 1999; 126: 4691-4701Crossref PubMed Google Scholar), epiblast (Tam and Zhou, 1996Tam P.P. Zhou S.X. The allocation of epiblast cells to ectodermal and germ-line lineages is influenced by the position of the cells in the gastrulating mouse embryo.Dev. Biol. 1996; 178: 124-132Crossref PubMed Scopus (310) Google Scholar), and early mesoderm (Parameswaran and Tam, 1995Parameswaran M. Tam P.P.L. Regionalisation of cell fate and morphogenetic movement of the mesoderm during mouse gastrulation.Dev. Genet. 1995; 17: 16-28Crossref PubMed Scopus (125) Google Scholar) (Figure 1E and Figure 2). More recently, the ability to generate post-implantation chimeras by the transplantation of epithelial epiblast-like PSCs (commonly referred to as primed) such as mEpiSCs (Huang et al., 2012Huang Y. Osorno R. Tsakiridis A. Wilson V. In Vivo differentiation potential of epiblast stem cells revealed by chimeric embryo formation.Cell Rep. 2012; 2: 1571-1578Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar, Kojima et al., 2014Kojima Y. Kaufman-Francis K. Studdert J.B. Steiner K.A. Power M.D. Loebel D.A.F. Jones V. Hor A. de Alencastro G. Logan G.J. et al.The transcriptional and functional properties of mouse epiblast stem cells resemble the anterior primitive streak.Cell Stem Cell. 2014; 14: 107-120Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar), hESCs, and hiPSCs (Mascetti and Pedersen, 2016Mascetti V.L. Pedersen R.A. Human-Mouse Chimerism Validates Human Stem Cell Pluripotency.Cell Stem Cell. 2016; 18: 67-72Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar) to the post-implantation mouse embryo has removed the barrier to an in vivo functional validation of primed state pluripotency (Figure 1F and Figure 2). Just as the ICM-like pluripotent state of mESCs benefited from pre-implantation embryo chimerism, now the primed state of hPSCs possesses an assay for experimental assessment of its pluripotency. Chimera studies have been used to determine the potency and fate of embryonic cell lineages based on the capacity for the embryo's resident PSCs (the epiblast of ICM and post-implantation embryo) to participate in embryonic development (Figure 2). At the late blastocyst stage (E4.0–4.5), the mouse ICM consists of two morphologically distinct cell populations: a compact mass of epiblast cells enveloped by a layer of primitive endoderm on the blastocoelic surface. In order to understand the origin of the embryonic tissues in the developing fetus, distinct from extraembryonic tissues, chimeras were formed by the injection of either primitive endoderm or epiblast cells (the two populations in the ICM) into genetically distinct mouse blastocysts and were analyzed at late gestation (Gardner and Rossant, 1979Gardner R.L. Rossant J. Investigation of the fate of 4-5 day post-coitum mouse inner cell mass cells by blastocyst injection.J. Embryol. Exp. Morphol. 1979; 52: 141-152PubMed Google Scholar). These two donor populations had mutually exclusive descendants, primitive endoderm contributing to extraembryonic tissues (especially visceral yolk sac endoderm), and the pluripotent epiblast contributing to the entire fetus (including definitive, or gut, endoderm) and to yolk sac mesoderm, but not to yolk sac endoderm (EPI: Figure 1G; PE: Figure 1H; and Figure 2). The results demonstrate that differentiation of the ICM into two populations in the late blastocyst is accompanied by the acquisition of distinct cell types, as evidenced by the fate of the cells following transplantation. Interestingly, at the early blastocyst stage (E3.5), lineage tracing and aggregation chimera experiments also showed that the majority of single early ICM cells were already restricted to be either epiblast or primitive endoderm, despite displaying no morphological or positional distinction (EPI: Figure 1G; PE: Figure 1H) (Chazaud et al., 2006Chazaud C. Yamanaka Y. Pawson T. Rossant J. Early lineage segregation between epiblast and primitive endoderm in mouse blastocysts through the Grb2-MAPK pathway.Dev. Cell. 2006; 10: 615-624Abstract Full Text Full Text PDF PubMed Scopus (649) Google Scholar). The pluripotent epiblast of the mouse embryo undergoes major progressive transitions during development. A principal example of epiblast transition occurs at E5.0 when the round, multi-layered epiblast cells of the preimplantation ICM become a single layer of polarized cells forming a pseudostratified epithelium, which is accompanied by a dramatic reorganization of the epiblast at implantation (Gardner and Cockroft, 1998Gardner R.L. Cockroft D.L. Complete dissipation of coherent clonal growth occurs before gastrulation in mouse epiblast.Development. 1998; 125: 2397-2402PubMed Google Scholar; reviewed in Bedzhov et al., 2014Bedzhov I. Graham S.J.L. Leung C.Y. Zernicka-goetz M. Zernicka-goetz M. Developmental plasticity, cell fate specification and morphogenesis in the early mouse embryo.Philos. Trans. R Soc. Lond. B Biol. Sci. 2014; 369: 1657Crossref Scopus (85) Google Scholar). The chimeric contribution of donor cells from post-implantation stage embryos was also examined by blastocyst injection and reimplantation to maternal recipients. Transplants performed using post-implantation epiblast donor cells from E5.5 and E8 into the preimplantation blastocyst showed embryonic and fetal chimera formation, but with a precipitous decline in chimera frequency as the donor epiblast progressed in developmental stage (E5.5: 10.9%; E8: 1.1%) (Moustafa and Brinster, 1972Moustafa L.A. Brinster R.L. Induced chimaerism by transplanting embryonic cells into mouse blastocysts.J. Exp. Zool. 1972; 181: 193-201Crossref PubMed Scopus (23) Google Scholar). By comparison, when primitive endoderm cells of E5.5 and E6.5 were transplanted, they contributed exclusively to extraembryonic endoderm (mostly parietal) (E5.5: 78.8%; E6.5: 6.2%) (Gardner, 1982Gardner R.L. Investigation of cell lineage and differentiation in the extraembryonic endoderm of the mouse embryo.J. Embryol. Exp. Morphol. 1982; 68: 175-198PubMed Google Scholar). By striking contrast to the diminished preimplantation chimera rate, post-implantation fetal chimeras were readily achieved using embryonic epiblast cells from primitive-streak-stage mouse embryos (Tam, 1989Tam P.P. Regionalisation of the mouse embryonic ectoderm: allocation of prospective ectodermal tissues during gastrulation.Development. 1989; 107: 55-67PubMed Google Scholar, Tam and Zhou, 1996Tam P.P. Zhou S.X. The allocation of epiblast cells to ectodermal and germ-line lineages is influenced by the position of the cells in the gastrulating mouse embryo.Dev. Biol. 1996; 178: 124-132Crossref PubMed Scopus (310) Google Scholar) (Figure 1E and Figure 2). Intriguingly, heterotopic transplants revealed broad epiblast plasticity, whereby their progeny adopted fates typical of their site of transplantation. Transplants to the epiblast region bordering on the extraembryonic ectoderm remarkably contributed to the primordial germ cell (PGC) lineage, even when the epiblast cells originated from the region typically developing into brain. This not only reinforced the evidence for epiblast plasticity from single-cell tracing (Lawson et al., 1991Lawson K.A. Meneses J.J. Pedersen R.A. Clonal analysis of epiblast fate during germ layer formation in the mouse embryo.Development. 1991; 113: 891-911Crossref PubMed Google Scholar), but it also confirmed the origin of PGCs from the embryonic-extraembryonic border region, as observed in cell lineage tracing studies in intact pre- and early- gastrula stage embryos (Lawson and Hage, 1994Lawson K.A. Hage W.J. Clonal analysis of the origin of primordial germ cells in the mouse.Ciba Found. Symp. 1994; 182 (discussion 84–91): 68-84PubMed Google Scholar). Orthotopic primitive streak transplants gave orderly allocation of mesodermal cells to the extraembryonic and embryonic structures, revealing the fate of different streak stages and sites during mouse gastrulation (Kinder et al., 1999Kinder S.J. Tsang T.E. Quinlan G.A. Hadjantonakis A.K. Nagy A. Tam P.P. The orderly allocation of mesodermal cells to the extraembryonic structures and the anteroposterior axis during gastrulation of the mouse embryo.Development. 1999; 126: 4691-4701Crossref PubMed Google Scholar). The fidelity of the fate map obtained using chimeras is confirmed by its similarity to the fate of epiblast cells marked by intracellular injection of intact embryos (Lawson et al., 1991Lawson K.A. Meneses J.J. Pedersen R.A. Clonal analysis of epiblast fate during germ layer formation in the mouse embryo.Development. 1991; 113: 891-911Crossref PubMed Google Scholar). Taken together, these studies prove that post-implantation epiblast and primitive streak tissues can indeed participate in chimera formation, provided that they are transplanted to post-implantation-stage embryos. A central question regarding the identity of the in vivo embryonic counterpart to PSCs arises from comparison between properties exhibited by human ESCs (and hiPSCs) that distinguish them from mouse ESCs, despite their paralleled derivation from the ICM of the blastocyst. Analysis of the epiblast of the ICM and the epiblast of the post-implantation embryo reveals properties shared between the pluripotent compartments in the embryo and their respective stage-matched PSCs in vitro. These properties may hold the key to unlocking stage-specific chimeric competency (Figure 3A). In 2007 two groups reported that PSCs could be isolated from the epiblast layer of post-implantation embryos, designated mEpiSCs (Brons et al., 2007Brons I.G.M. Smithers L.E. Trotter M.W.B. Rugg-Gunn P. Sun B. Chuva de Sousa Lopes S.M. Howlett S.K. Clarkson A. Ahrlund-Richter L. Pedersen R.A. Vallier L. Derivation of pluripotent epiblast stem cells from mammalian embryos.Nature. 2007; 448: 191-195Crossref PubMed Scopus (1549) Google Scholar, Tesar et al., 2007Tesar P.J. Chenoweth J.G. Brook F.A. Davies T.J. Evans E.P. Mack D.L. Gardner R.L. McKay R.D. New cell lines from mouse epiblast share defining features with human embryonic stem cells.Nature. 2007; 448: 196-199Crossref PubMed Scopus (1677) Google Scholar). The discovery of mEpiSCs provided what some might consider to be the missing piece of the jigsaw puzzle in the field of pluripotency, in revealing a much-needed explanation for the differences between ICM-like mESCs and epithelial epiblast-like hPSCs (Krtolica et al., 2007Krtolica A. Genbacev O. Escobedo C. Zdravkovic T. Nordstrom A. Vabu" @default.
• W2484685366 created "2016-08-23" @default.
• W2484685366 creator A5015990351 @default.
• W2484685366 creator A5021147008 @default.
• W2484685366 date "2016-08-01" @default.
• W2484685366 modified "2023-10-13" @default.
• W2484685366 title "Contributions of Mammalian Chimeras to Pluripotent Stem Cell Research" @default.
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