Abstract
The past decade’s rapid progress in human pluripotent stem cell (hPSC) research has generated hope for meeting the rising demand of organ donation, which remains the only effective cure for end-stage organ failure, a major cause of death worldwide. Despite the potential, generation of transplantable organs from hPSCs using in vitro differentiation is far-fetched. An in vivo interspecies chimeric complementation strategy relying on chimeric-competent hPSCs and zygote genome editing provides an auspicious alternative for providing unlimited organ source for transplantation.
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Aasen T, Raya A, Barrero MJ et al (2008) Efficient and rapid generation of induced pluripotent stem cells from human keratinocytes. Nat Biotechnol 26:1276–1284. doi:10.1038/nbt.1503
Aida T, Chiyo K, Usami T et al (2015) Cloning-free CRISPR/Cas system facilitates functional cassette knock-in in mice. Genome Biol 16:87. doi:10.1186/s13059-015-0653-x
Badylak SF, Weiss DJ, Caplan A, Macchiarini P (2012) Engineered whole organs and complex tissues. Lancet 379:943–952. doi:10.1016/S0140-6736(12)60073-7
Brevini TAL, Pennarossa G, Gandolfi F (2010) No shortcuts to pig embryonic stem cells. Theriogenology 74:544–550. doi:10.1016/j.theriogenology.2010.04.020
Brons IGM, Smithers LE, Trotter MWB et al (2007) Derivation of pluripotent epiblast stem cells from mammalian embryos. Nature 448:191–195. doi:10.1038/nature05950
Buehr M, Meek S, Blair K et al (2008) Capture of authentic embryonic stem cells from rat blastocysts. Cell 135:1287–1298. doi:10.1016/j.cell.2008.12.007
Byrne GW, Stalboerger PG, Davila E et al (2008) Proteomic identification of non-Gal antibody targets after pig-to-primate cardiac xenotransplantation. Xenotransplantation 15:268–276. doi:10.1111/j.1399-3089.2008.00480.x
Chan Y-S, Göke J, Ng J-H et al (2013) Induction of a human pluripotent state with distinct regulatory circuitry that resembles preimplantation epiblast. Cell Stem Cell 13:663–675. doi:10.1016/j.stem.2013.11.015
Chen J, Lansford R, Stewart V et al (1993) RAG-2-deficient blastocyst complementation: an assay of gene function in lymphocyte development. Proc Natl Acad Sci USA 90:4528–4532. doi:10.1073/pnas.90.10.4528
Chen Y, Niu Y, Li Y et al (2015) Generation of cynomolgus monkey chimeric fetuses using embryonic stem cells. Cell Stem Cell 17:116–124. doi:10.1016/j.stem.2015.06.004
Chu VT, Weber T, Wefers B et al (2015) Increasing the efficiency of homology-directed repair for CRISPR-Cas9-induced precise gene editing in mammalian cells. Nat Biotechnol 33:543–548. doi:10.1038/nbt.3198
Cozzi E, White DJG (1995) The generation of transgenic pigs as potential organ donors for humans. Nat Med 1:964–966. doi:10.1038/nm0995-964
Dhawan A, Puppi J, Hughes RD, Mitry RR (2010) Human hepatocyte transplantation: current experience and future challenges. Nat Rev Gastroenterol Hepatol 7:288–298. doi:10.1038/nrgastro.2010.44
Diamond LE, Quinn CM, Martin MJ et al (2001) A human CD46 transgenic pig model system for the study of discordant xenotransplantation. Transplantation 71:132–142. doi:10.1097/00007890-200101150-00021
Doudna JA, Charpentier E (2014) Genome editing. The new frontier of genome engineering with CRISPR-Cas9. Science 346:1258096. doi:10.1126/science.1258096
Evans MJ, Kaufman MH (1981) Establishment in culture of pluripotential cells from mouse embryos. Nature 292:154–156. doi:10.1038/292154a0
Fodor WL, Williams BL, Matis LA et al (1994) Expression of a functional human complement inhibitor in a transgenic pig as a model for the prevention of xenogeneic hyperacute organ rejection. Proc Natl Acad Sci USA 91:11153–11157. doi:10.1073/pnas.91.23.11153
Fu Y, Foden JA, Khayter C et al (2013) High-frequency off-target mutagenesis induced by CRISPR-Cas nucleases in human cells. Nat Biotechnol 31:822–826. doi:10.1038/nbt.2623
Fu Y, Sander JD, Reyon D et al (2014) Improving CRISPR-Cas nuclease specificity using truncated guide RNAs. Nat Biotechnol 32:279–284. doi:10.1038/nbt.2808
Gafni O, Weinberger L, Mansour AA et al (2013) Derivation of novel human ground state naive pluripotent stem cells. Nature 504:282–286. doi:10.1038/nature12745
Gaj T, Gersbach CA, Barbas CF (2013) ZFN, TALEN, and CRISPR/Cas-based methods for genome engineering. Trends Biotechnol 31:397–405. doi:10.1016/j.tibtech.2013.04.004
Gardner RL, Johnson MH (1973) Investigation of early mammalian development using interspecific chimaeras between rat and mouse. Nature. doi:10.1038/10.1038/newbio246086a0
Geurts AM, Cost GJ, Freyvert Y et al (2009) Knockout rats via embryo microinjection of zinc-finger nucleases. Science 325:433. doi:10.1126/science.1172447
Guilinger JP, Thompson DB, Liu DR (2014) Fusion of catalytically inactive Cas9 to FokI nuclease improves the specificity of genome modification. Nat Biotechnol 32:577–582. doi:10.1038/nbt.2909
Hai T, Teng F, Guo R et al (2014) One-step generation of knockout pigs by zygote injection of CRISPR/Cas system. Cell Res 24:372–375. doi:10.1038/cr.2014.11
Hanna J, Cheng AW, Saha K et al (2010) Human embryonic stem cells with biological and epigenetic characteristics similar to those of mouse ESCs. Proc Natl Acad Sci 107:9222–9227. doi:10.1073/pnas.1004584107
Hauschild J, Petersen B, Santiago Y et al (2011) Efficient generation of a biallelic knockout in pigs using zinc-finger nucleases. Proc Natl Acad Sci 108:12013–12017. doi:10.1073/pnas.1106422108
Honda A, Hirose M, Ogura A (2009) Basic FGF and Activin/Nodal but not LIF signaling sustain undifferentiated status of rabbit embryonic stem cells. Exp Cell Res 315:2033–2042. doi:10.1016/j.yexcr.2009.01.024
Hrvatin S, O’Donnell CW, Deng F et al (2014) Differentiated human stem cells resemble fetal, not adult, β cells. Proc Natl Acad Sci 111:3038–3043. doi:10.1073/pnas.1400709111
Hsu PD, Scott DA, Weinstein JA et al (2013) DNA targeting specificity of RNA-guided Cas9 nucleases. Nat Biotechnol 31:827–832. doi:10.1038/nbt.2647
Huang Y, Osorno R, Tsakiridis A, Wilson V (2012) In Vivo differentiation potential of epiblast stem cells revealed by chimeric embryo formation. Cell Reports 2:1571–1578. doi:10.1016/j.celrep.2012.10.022
Ibrahim Z, Busch J, Awwad M et al (2006) Selected physiologic compatibilities and incompatibilities between human and porcine organ systems. Xenotransplantation 13:488–499. doi:10.1111/j.1399-3089.2006.00346.x
Isotani A, Hatayama H, Kaseda K et al (2011) Formation of a thymus from rat ES cells in xenogeneic nude mouse↔rat ES chimeras. Genes Cells 16:397–405. doi:10.1111/j.1365-2443.2011.01495.x
Kim H, Wu J, Ye S et al (2013) Modulation of β-catenin function maintains mouse epiblast stem cell and human embryonic stem cell self-renewal. Nat Commun 4:2403. doi:10.1038/ncomms3403
Kobayashi T, Yamaguchi T, Hamanaka S et al (2010) Generation of rat pancreas in mouse by interspecific blastocyst injection of pluripotent stem cells. Cell 142:787–799. doi:10.1016/j.cell.2010.07.039
Kojima Y, Kaufman-Francis K, Studdert JB et al (2014) The transcriptional and functional properties of mouse epiblast stem cells resemble the anterior primitive streak. Cell Stem Cell 14:107–120. doi:10.1016/j.stem.2013.09.014
Lai L, Kolber-Simonds D, Park K-W et al (2002) Production of alpha-1,3-galactosyltransferase knockout pigs by nuclear transfer cloning. Science 295:1089–1092. doi:10.1126/science.1068228
Lancaster MA, Knoblich JA (2014) Organogenesis in a dish: modeling development and disease using organoid technologies. Science 345:1247125. doi:10.1126/science.1247125
Li P, Tong C, Mehrian-Shai R et al (2008) germline competent embryonic stem cells derived from rat blastocysts. Cell 135:1299–1310. doi:10.1016/j.cell.2008.12.006
Liégeois NJ, Horner JW, DePinho RA (1996) Lens complementation system for the genetic analysis of growth, differentiation, and apoptosis in vivo. Proc Natl Acad Sci USA 93:1303–1307. doi:10.1073/pnas.93.3.1303
Liu H, Zhu F, Yong J et al (2008) Generation of induced pluripotent stem cells from adult rhesus monkey fibroblasts. Cell Stem Cell 3:587–590. doi:10.1016/j.stem.2008.10.014
Liu H, Chen Y, Niu Y et al (2014) TALEN-mediated gene mutagenesis in rhesus and cynomolgus monkeys. Cell Stem Cell 14:323–328. doi:10.1016/j.stem.2014.01.018
Ma Y, Zhang X, Shen B et al (2013) Generating rats with conditional alleles using CRISPR/Cas9. Cell Res 24:122–125. doi:10.1038/cr.2013.157
Mali P, Aach J, Stranges PB et al (2013) CAS9 transcriptional activators for target specificity screening and paired nickases for cooperative genome engineering. Nat Biotechnol 31:833–838. doi:10.1038/nbt.2675
Martello G, Smith A (2014) The nature of embryonic stem cells. Annu Rev Cell Dev Biol 30:647–675. doi:10.1146/annurev-cellbio-100913-013116
Martin GR (1981) Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci USA 78:7634–7638. doi:10.1073/pnas.78.12.7634
Maruotti J, Muñoz M, Degrelle SA et al (2012) Efficient derivation of bovine embryonic stem cells needs more than active core pluripotency factors. Mol Reprod Dev 79:461–477. doi:10.1002/mrd.22051
Maruyama T, Dougan SK, Truttmann MC et al (2015) Increasing the efficiency of precise genome editing with CRISPR-Cas9 by inhibition of nonhomologous end joining. Nat Biotechnol 33:538–542. doi:10.1038/nbt.3190
Masaki H, Kato-Itoh M, Umino A et al (2015) Interspecific in vitro assay for the chimera-forming ability of human pluripotent stem cells. Development 142:3222–3230. doi:10.1242/dev.124016
Najm FJ, Chenoweth JG, Anderson PD et al (2011) Isolation of epiblast stem cells from preimplantation mouse embryos. Cell Stem Cell 8:318–325. doi:10.1016/j.stem.2011.01.016
Nichols J, Smith A (2009) Naive and primed pluripotent states. Cell Stem Cell 4:487–492. doi:10.1016/j.stem.2009.05.015
Nishinakamura R, Matsumoto Y, Nakao K et al (2001) Murine homolog of SALL1 is essential for ureteric bud invasion in kidney development. Development 128:3105–3115. doi:10.1016/S0092-8674(00)81524-X
Niu Y, Shen B, Cui Y et al (2014) Generation of gene-modified cynomolgus monkey via Cas9/RNA-mediated gene targeting in one-cell embryos. Cell 156:836–843. doi:10.1016/j.cell.2014.01.027
Offield MF, Jetton TL, Labosky PA et al (1996) PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum. Development 122:983–995
Ohinata Y, Payer B, O’Carroll D et al (2005) Blimp1 is a critical determinant of the germ cell lineage in mice. Nature 436:207–213. doi:10.1038/nature03813
Oliver D, Yuan S, McSwiggin H, Yan W (2015) Pervasive genotypic mosaicism in founder mice derived from genome editing through pronuclear injection. PLoS ONE 10:e0129457. doi:10.1371/journal.pone.0129457
Osafune K, Caron L, Borowiak M et al (2008) Marked differences in differentiation propensity among human embryonic stem cell lines. Nat Biotechnol 26:313–315. doi:10.1038/nbt1383
Ott HC, Matthiesen TS, Goh S-K et al (2008) Perfusion-decellularized matrix: using nature’s platform to engineer a bioartificial heart. Nat Med 14:213–221. doi:10.1038/nm1684
Pattanayak V, Lin S, Guilinger JP et al (2013) High-throughput profiling of off-target DNA cleavage reveals RNA-programmed Cas9 nuclease specificity. Nat Biotechnol 31:839–843. doi:10.1038/nbt.2673
Petersen TH, Calle EA, Zhao L et al (2010) Tissue-engineered lungs for in vivo implantation. Science 329:538–541. doi:10.1126/science.1189345
Ran FA, Hsu PD, Lin C-Y et al (2013) Double nicking by RNA-guided CRISPR Cas9 for enhanced genome editing specificity. Cell 154:1380–1389. doi:10.1016/j.cell.2013.08.021
Reubinoff BE, Pera MF, Fong CY et al (2000) Embryonic stem cell lines from human blastocysts: somatic differentiation in vitro. Nat Biotechnol 18:399–404. doi:10.1038/74447
Sharma A, Okabe J, Birch P et al (1996) Reduction in the level of Gal(alpha1,3)Gal in transgenic mice and pigs by the expression of an alpha(1,2)fucosyltransferase. Proc Natl Acad Sci USA 93:7190–7195
Shen B, Zhang W, Zhang J et al (2014) Efficient genome modification by CRISPR-Cas9 nickase with minimal off-target effects. Nat Methods 11:399–402. doi:10.1038/nmeth.2857
Sperber H, Mathieu J, Wang Y et al (2015) The metabolome regulates the epigenetic landscape during naive-to-primed human embryonic stem cell transition. Nat Cell Biol 17:1523–1535. doi:10.1038/ncb3264
Stanger BZ, Tanaka AJ, Melton DA (2007) Organ size is limited by the number of embryonic progenitor cells in the pancreas but not the liver. Nature 445:886–891. doi:10.1038/nature05537
Sung YH, Baek I-J, Kim DH et al (2013) Knockout mice created by TALEN-mediated gene targeting. Nat Biotechnol 31:23–24. doi:10.1038/nbt.2477
Sung YH, Kim JM, Kim H-T et al (2014) Highly efficient gene knockout in mice and zebrafish with RNA-guided endonucleases. Genome Res 24:125–131. doi:10.1101/gr.163394.113
Tachibana M, Sparman M, Ramsey C et al (2012) Generation of chimeric rhesus monkeys. Cell 148:285–295. doi:10.1016/j.cell.2011.12.007
Takahashi K, Tanabe K, Ohnuki M et al (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–872. doi:10.1016/j.cell.2007.11.019
Takashima Y, Guo G, Loos R et al (2014) Resetting transcription factor control circuitry toward ground-state pluripotency in human. Cell 158:1254–1269. doi:10.1016/j.cell.2014.08.029
Tesar PJ, Chenoweth JG, Brook FA et al (2007) New cell lines from mouse epiblast share defining features with human embryonic stem cells. Nature 448:196–199. doi:10.1038/nature05972
Theunissen TW, Powell BE, Wang H et al (2014) Systematic identification of culture conditions for induction and maintenance of naive human pluripotency. Cell Stem Cell 15:471–487. doi:10.1016/j.stem.2014.07.002
Thomson JA, Itskovitz-Eldor J, Shapiro SS et al (1998) Embryonic stem cell lines derived from human blastocysts. Science 282:1145–1147. doi:10.1126/science.282.5391.1145
Trounson A, McDonald C (2015) Stem cell therapies in clinical trials: progress and challenges. Cell Stem Cell 17:11–22. doi:10.1016/j.stem.2015.06.007
Tsai SQ, Wyvekens N, Khayter C et al (2014) Dimeric CRISPR RNA-guided FokI nucleases for highly specific genome editing. Nat Biotechnol 32:569–576. doi:10.1038/nbt.2908
Usui J-I, Kobayashi T, Yamaguchi T et al (2012) Generation of kidney from pluripotent stem cells via blastocyst complementation. Am J Pathol 180:2417–2426. doi:10.1016/j.ajpath.2012.03.007
Uygun BE, Soto-Gutiérrez A, Yagi H et al (2010) Organ reengineering through development of a transplantable recellularized liver graft using decellularized liver matrix. Nat Med 16:814–820. doi:10.1038/nm.2170
Wang H, Yang H, Shivalila CS et al (2013) One-step generation of mice carrying mutations in multiple genes by CRISPR/Cas-mediated genome engineering. Cell 153:910–918. doi:10.1016/j.cell.2013.04.025
Wang J, Xie G, Singh M et al (2014) Primate-specific endogenous retrovirus-driven transcription defines naive-like stem cells. Nature 516:405–409. doi:10.1038/nature13804
Wang L, Wu J, Fang W et al (2015) Regenerative medicine: targeted genome editing in vivo. Cell Res 25:271–272. doi:10.1038/cr.2015.11
Ware CB, Nelson AM, Mecham B et al (2014) Derivation of naive human embryonic stem cells. Proc Natl Acad Sci 111:4484–4489. doi:10.1073/pnas.1319738111
Wu J, Belmonte JCI (2015) Metabolic exit from naive pluripotency. Nat Cell Biol 17:1519–1521. doi:10.1038/ncb3269
Wu SM, Hochedlinger K (2011) Harnessing the potential of induced pluripotent stem cells for regenerative medicine. Nat Cell Biol 13:497–505. doi:10.1038/ncb0511-497
Wu J, Izpisua Belmonte JC (2015) Dynamic pluripotent stem cell states and their applications. Cell Stem Cell 17:509–525. doi:10.1016/j.stem.2015.10.009
Wu J, Okamura D, Li M et al (2015) An alternative pluripotent state confers interspecies chimaeric competency. Nature 521:316–321. doi:10.1038/nature14413
Yang Y-G, Sykes M (2007) Xenotransplantation: current status and a perspective on the future. Nat Rev Immunol 07:519–531. doi:10.1038/nri2099
Yang L, Guell M, Niu D et al (2015) Genome-wide inactivation of porcine endogenous retroviruses (PERVs). Science 350:1101–1104. doi:10.1126/science.aad1191
Yen S-T, Zhang M, Deng JM et al (2014) Somatic mosaicism and allele complexity induced by CRISPR/Cas9 RNA injections in mouse zygotes. Dev Biol 393:3–9. doi:10.1016/j.ydbio.2014.06.017
Ying Q-L, Wray J, Nichols J et al (2008) The ground state of embryonic stem cell self-renewal. Nature 453:519–523. doi:10.1038/nature06968
Yu J, Vodyanik MA, Smuga-Otto K et al (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318:1917–1920. doi:10.1126/science.1151526
Zeilmaker GH (1973) Fusion of rat and mouse morulae and formation of chimaeric blastocysts. Nature 242:115–116. doi:10.1038/242115a0
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Wu, J., Belmonte, J.C.I. Interspecies chimeric complementation for the generation of functional human tissues and organs in large animal hosts. Transgenic Res 25, 375–384 (2016). https://doi.org/10.1007/s11248-016-9930-z
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DOI: https://doi.org/10.1007/s11248-016-9930-z