SCIENCE CHINA Life Sciences, Volume 62 , Issue 1 : 12-21(2019) https://doi.org/10.1007/s11427-018-9334-2

Primate stem cells: bridge the translation from basic research to clinic application

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  • ReceivedApr 15, 2018
  • AcceptedMay 10, 2018
  • PublishedAug 9, 2018


A growing body of literature has shown that stem cells are very effective for the treatment of degenerative diseases in rodents but these exciting results have not translated to clinical practice. The difference results from the divergence in genetic, metabolic, and physiological phenotypes between rodents and humans. The high degree of similarity between non-human primates (NHPs) and humans provides the most accurate models for preclinical studies of stem cell therapy. Using a NHP model to understand the following key issues, which cannot be addressed in humans or rodents, will be helpful for extending stem cell applications in the basic science and the clinic. These issues include pluripotency of primate stem cells, the safety and efficiency of stem cell therapy, and transplantation procedures of stem cells suitable for clinical translation. Here we review studies of the above issues in NHPs and current challenges of stem cell applications in both basic science and clinical therapies. We propose that the use of NHP models, in particular combining the serial production and transplantation procedures of stem cells is the most useful for preclinical studies designed to overcome these challenges.

Funded by

the Yunnan National Key R&D Program and the National Natural Science Foundation of China(31760268)


This work was supported by the Yunnan National Key R&D Program and the National Natural Science Foundation of China (31760268).

Interest statement

The author(s) declare that they have no conflict of interest.


[1] Ai Z., Xiang Z., Li Y., Liu G., Wang H., Zheng Y., Qiu X., Zhao S., Zhu X., Li Y., et al. Conversion of monkey fibroblasts to transplantable telencephalic neuroepithelial stem cells. Biomaterials, 2016, 77: 53-65 CrossRef PubMed Google Scholar

[2] Ai Z.Y., Zhao S.M., Li T.Q.. Research on primate naive pluripotent stem cells and its challenges. Sci Sin Vitae, 2015, 45: 1203-1213 CrossRef Google Scholar

[3] Blesa J., Trigo-Damas I., Del Rey N.L.G., Obeso J.A.. The use of nonhuman primate models to understand processes in Parkinson’s disease. J Neural Transm, 2018, 125: 325-335 CrossRef PubMed Google Scholar

[4] Boroviak T., Loos R., Bertone P., Smith A., Nichols J.. The ability of inner-cell-mass cells to self-renew as embryonic stem cells is acquired following epiblast specification. Nat Cell Biol, 2014, 16: 513-525 CrossRef PubMed Google Scholar

[5] Boroviak T., Loos R., Lombard P., Okahara J., Behr R., Sasaki E., Nichols J., Smith A., Bertone P.. Lineage-specific profiling delineates the emergence and progression of naive pluripotency in mammalian embryogenesis. Dev Cell, 2015, 35: 366-382 CrossRef PubMed Google Scholar

[6] Boroviak T., Nichols J.. Primate embryogenesis predicts the hallmarks of human naïve pluripotency. Development, 2017, 144: 175-186 CrossRef PubMed Google Scholar

[7] Bruhns P.. Properties of mouse and human IgG receptors and their contribution to disease models. Blood, 2012, 119: 5640-5649 CrossRef PubMed Google Scholar

[8] Canet-Aviles R., Lomax G.P., Feigal E.G., Priest C.. Proceedings: cell therapies for Parkinson’s disease from discovery to clinic. Stem Cells Transl Med, 2014, 3: 979-991 CrossRef PubMed Google Scholar

[9] Chan Y.S., Göke J., Ng J.H., Lu X., Gonzales K.A.U., Tan C.P., Tng W.Q., Hong Z.Z., Lim Y.S., Ng H.H.. Induction of a human pluripotent state with distinct regulatory circuitry that resembles preimplantation epiblast. Cell Stem Cell, 2013, 13: 663-675 CrossRef PubMed Google Scholar

[10] Chazaud C., Yamanaka Y.. Lineage specification in the mouse preimplantation embryo. Development, 2016, 143: 1063-1074 CrossRef PubMed Google Scholar

[11] Chen 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: 116-124 CrossRef PubMed Google Scholar

[12] Chong J.J.H., Yang X., Don C.W., Minami E., Liu Y.W., Weyers J.J., Mahoney W.M., Van Biber B., Cook S.M., Palpant N.J., et al. Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts. Nature, 2014, 510: 273-277 CrossRef PubMed ADS Google Scholar

[13] Cox L.A., Olivier M., Spradling-Reeves K., Karere G.M., Comuzzie A.G., VandeBerg J.L.. Nonhuman primates and translational research—cardiovascular disease. ILAR J, 2017, 58: 235-250 CrossRef PubMed Google Scholar

[14] Davies S.J.A., Fitch M.T., Memberg S.P., Hall A.K., Raisman G., Silver J.. Regeneration of adult axons in white matter tracts of the central nervous system. Nature, 1997, 390: 680-683 CrossRef PubMed ADS Google Scholar

[15] De Los Angeles A., Ferrari F., Xi R., Fujiwara Y., Benvenisty N., Deng H., Hochedlinger K., Jaenisch R., Lee S., Leitch H.G., et al. Hallmarks of pluripotency. Nature, 2015, 525: 469-478 CrossRef PubMed ADS Google Scholar

[16] Deglincerti A., Croft G.F., Pietila L.N., Zernicka-Goetz M., Siggia E.D., Brivanlou A.H.. Self-organization of the in vitro attached human embryo. Nature, 2016, 533: 251-254 CrossRef PubMed ADS Google Scholar

[17] Durruthy-Durruthy J., Wossidlo M., Pai S., Takahashi Y., Kang G., Omberg L., Chen B., Nakauchi H., Reijo Pera R., Sebastiano V.. Spatiotemporal reconstruction of the human blastocyst by single-cell gene-expression analysis informs induction of naive pluripotency. Dev Cell, 2016, 38: 100-115 CrossRef PubMed Google Scholar

[18] Džaja, D., Hladnik, A., Bičanić, I., Baković, M., and Petanjek, Z. (2014). Neocortical calretinin neurons in primates: increase in proportion and microcircuitry structure. Front Neuroanat 8, 103. Google Scholar

[19] Freed C.R., Zhou W., Breeze R.E.. Dopamine cell transplantation for Parkinson’s disease: the importance of controlled clinical trials. Neurotherapeutics, 2011, 8: 549-561 CrossRef PubMed Google Scholar

[20] Gafni O., Weinberger L., Mansour A.A.F., 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: 282-286 CrossRef PubMed ADS Google Scholar

[21] Gosselin D., Skola D., Coufal N.G., Holtman I.R., Schlachetzki J.C.M., Sajti E., Jaeger B.N., O’Connor C., Fitzpatrick C., Pasillas M.P., et al. An environment-dependent transcriptional network specifies human microglia identity. Science, 2017, 356: eaal3222 CrossRef PubMed Google Scholar

[22] Grow D.A., McCarrey J.R., Navara C.S.. Advantages of nonhuman primates as preclinical models for evaluating stem cell-based therapies for Parkinson’s disease. Stem Cell Res, 2016, 17: 352-366 CrossRef PubMed Google Scholar

[23] Guo G., von Meyenn F., Santos F., Chen Y., Reik W., Bertone P., Smith A., Nichols J.. Naive pluripotent stem cells derived directly from isolated cells of the human inner cell mass. Stem Cell Rep, 2016, 6: 437-446 CrossRef PubMed Google Scholar

[24] Gutova M., Frank J.A., D’Apuzzo M., Khankaldyyan V., Gilchrist M.M., Annala A.J., Metz M.Z., Abramyants Y., Herrmann K.A., Ghoda L.Y., et al. Magnetic resonance imaging tracking of ferumoxytol-labeled human neural stem cells: studies leading to clinical use. Stem Cells Transl Med, 2013, 2: 766-775 CrossRef PubMed Google Scholar

[25] Hallett P.J., Deleidi M., Astradsson A., Smith G.A., Cooper O., Osborn T.M., Sundberg M., Moore M.A., Perez-Torres E., Brownell A.L., et al. Successful function of autologous iPSC-derived dopamine neurons following transplantation in a non-human primate model of Parkinson’s disease. Cell Stem Cell, 2015, 16: 269-274 CrossRef PubMed Google Scholar

[26] Hayashi K., Ohta H., Kurimoto K., Aramaki S., Saitou M.. Reconstitution of the mouse germ cell specification pathway in culture by pluripotent stem cells. Cell, 2011, 146: 519-532 CrossRef PubMed Google Scholar

[27] Huang K., Maruyama T., Fan G.. The naive state of human pluripotent stem cells: a synthesis of stem cell and preimplantation embryo transcriptome analyses. Cell Stem Cell, 2014, 15: 410-415 CrossRef PubMed Google Scholar

[28] Humbert, O., Peterson, C.W., Norgaard, Z.K., Radtke, S., and Kiem, H.-P. (2017). A nonhuman primate transplantation model to evaluate hematopoietic stem cell gene editing strategies for β-hemoglobinopathies. Mol Ther Methods Clin Dev 8, 75–86. Google Scholar

[29] Iadecola C., Anrather J.. The immunology of stroke: from mechanisms to translation. Nat Med, 2011, 17: 796-808 CrossRef PubMed Google Scholar

[30] Keren-Shaul H., Spinrad A., Weiner A., Matcovitch-Natan O., Dvir-Szternfeld R., Ulland T.K., David E., Baruch K., Lara-Astaiso D., Toth B., et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell, 2017, 169: 1276-1290.e17 CrossRef PubMed Google Scholar

[31] Kikuchi T., Morizane A., Doi D., Magotani H., Onoe H., Hayashi T., Mizuma H., Takara S., Takahashi R., Inoue H., et al. Human iPS cell-derived dopaminergic neurons function in a primate Parkinson’s disease model. Nature, 2017, 548: 592-596 CrossRef PubMed ADS Google Scholar

[32] Kriks S., Shim J.W., Piao J., Ganat Y.M., Wakeman D.R., Xie Z., Carrillo-Reid L., Auyeung G., Antonacci C., Buch A., et al. Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson’s disease. Nature, 2011, 480: 547-551 CrossRef PubMed ADS Google Scholar

[33] Kwiecien, T.D., Sy, C., and Ding, Y. (2014). Rodent models of ischemic stroke lack translational relevance… are baboon models the answer? Neurol Res 36, 417–422. Google Scholar

[34] Li M., Li Z., Yao Y., Jin W.N., Wood K., Liu Q., Shi F.D., Hao J.. Astrocyte-derived interleukin-15 exacerbates ischemic brain injury via propagation of cellular immunity. Proc Natl Acad Sci USA, 2017, 114: E396-E405 CrossRef PubMed Google Scholar

[35] Ma T., Wang C., Wang L., Zhou X., Tian M., Zhang Q., Zhang Y., Li J., Liu Z., Cai Y., et al. Subcortical origins of human and monkey neocortical interneurons. Nat Neurosci, 2013, 16: 1588-1597 CrossRef PubMed Google Scholar

[36] Magnúsdóttir, E., Dietmann, S., Murakami, K., Günesdogan, U., Tang, F., Bao, S., Diamanti, E., Lao, K., Gottgens, B., and Azim Surani, M. (2013). A tripartite transcription factor network regulates primordial germ cell specification in mice. Nat Cell Biol 15, 905. Google Scholar

[37] Malloy K.E., Li J., Choudhury G.R., Torres A., Gupta S., Kantorak C., Goble T., Fox P.T., Clarke G.D., Daadi M.M.. Magnetic resonance imaging-guided delivery of neural stem cells into the basal ganglia of nonhuman primates reveals a pulsatile mode of cell dispersion. Stem Cells Transl Med, 2017, 6: 877-885 CrossRef PubMed Google Scholar

[38] Masaki H., Kato-Itoh M., Takahashi Y., Umino A., Sato H., Ito K., Yanagida A., Nishimura T., Yamaguchi T., Hirabayashi M., et al. Inhibition of apoptosis overcomes stage-related compatibility barriers to chimera formation in mouse embryos. Cell Stem Cell, 2016, 19: 587-592 CrossRef PubMed Google Scholar

[39] Mascetti V.L., Pedersen R.A.. Contributions of mammalian chimeras to pluripotent stem cell research. Cell Stem Cell, 2016, 19: 163-175 CrossRef PubMed Google Scholar

[40] Mestas J., Hughes C.C.W.. Of mice and not men: differences between mouse and human immunology. J Immunol, 2004, 172: 2731-2738 CrossRef Google Scholar

[41] Nakamura T., Okamoto I., Sasaki K., Yabuta Y., Iwatani C., Tsuchiya H., Seita Y., Nakamura S., Yamamoto T., Saitou M.. A developmental coordinate of pluripotency among mice, monkeys and humans. Nature, 2016, 537: 57-62 CrossRef PubMed ADS Google Scholar

[42] Nemati, S.N., Jabbari, R., Hajinasrollah, M., Zare Mehrjerdi, N., Azizi, H., Hemmesi, K., Moghiminasr, R., Azhdari, Z., Talebi, A., Mohitmafi, S., et al. (2014). Transplantation of adult monkey neural stem cells into a contusion spinal cord injury model in rhesus macaque monkeys. Cell J (Yakhteh) 16, 117–130. Google Scholar

[43] Nichols J., Smith A.. Naive and primed pluripotent states. Cell Stem Cell, 2009, 4: 487-492 CrossRef PubMed Google Scholar

[44] Niu Y., Li T., Ji W.. Paving the road for biomedicine: genome editing and stem cells in primates. Natl Sci Rev, 2017, 4: 543-549 CrossRef Google Scholar

[45] Niu Y., Shen B., Cui Y., Chen Y., Wang J., Wang L., Kang Y., Zhao X., Si W., Li W., et al. Generation of gene-modified cynomolgus monkey via Cas9/RNA-mediated gene targeting in one-cell embryos. Cell, 2014, 156: 836-843 CrossRef PubMed Google Scholar

[46] Ohinata Y., Ohta H., Shigeta M., Yamanaka K., Wakayama T., Saitou M.. A signaling principle for the specification of the germ cell lineage in mice. Cell, 2009, 137: 571-584 CrossRef PubMed Google Scholar

[47] Osorno R., Tsakiridis A., Wong F., Cambray N., Economou C., Wilkie R., Blin G., Scotting P.J., Chambers I., Wilson V.. The developmental dismantling of pluripotency is reversed by ectopic Oct4 expression. Development, 2012, 139: 2288-2298 CrossRef PubMed Google Scholar

[48] Pastor W.A., Chen D., Liu W., Kim R., Sahakyan A., Lukianchikov A., Plath K., Jacobsen S.E., Clark A.T.. Naive human pluripotent cells feature a methylation landscape devoid of blastocyst or germline memory. Cell Stem Cell, 2016, 18: 323-329 CrossRef PubMed Google Scholar

[49] Prinz M., Priller J.. Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease. Nat Rev Neurosci, 2014, 15: 300-312 CrossRef PubMed Google Scholar

[50] Pritchard C.D., Slotkin J.R., Yu D., Dai H., Lawrence M.S., Bronson R.T., Reynolds F.M., Teng Y.D., Woodard E.J., Langer R.S.. Establishing a model spinal cord injury in the African green monkey for the preclinical evaluation of biodegradable polymer scaffolds seeded with human neural stem cells. J Neurosci Methods, 2010, 188: 258-269 CrossRef PubMed Google Scholar

[51] Qiu, Z., Farnsworth, S.L., Mishra, A., and Hornsby, P.J. (2013). Patient-specific induced pluripotent stem cells in neurological disease modeling: the importance of nonhuman primate models. Stem Cells Cloning 6, 19–29. Google Scholar

[52] Rammos C., Hendgen-Cotta U.B., Deenen R., Pohl J., Stock P., Hinzmann C., Kelm M., Rassaf T.. Age-related vascular gene expression profiling in mice. Mech Ageing Dev, 2014, 135: 15-23 CrossRef PubMed Google Scholar

[53] Ransohoff R.M., Brown M.A.. Innate immunity in the central nervous system. J Clin Invest, 2012, 122: 1164-1171 CrossRef PubMed Google Scholar

[54] Rosenzweig E.S., Brock J.H., Lu P., Kumamaru H., Salegio E.A., Kadoya K., Weber J.L., Liang J.J., Moseanko R., Hawbecker S., et al. Restorative effects of human neural stem cell grafts on the primate spinal cord. Nat Med, 2018, 24: 484-490 CrossRef PubMed Google Scholar

[55] Rossant J.. Implantation barrier overcome. Nature, 2016, 533: 182-183 CrossRef PubMed ADS Google Scholar

[56] Samata B., Doi D., Nishimura K., Kikuchi T., Watanabe A., Sakamoto Y., Kakuta J., Ono Y., Takahashi J.. Purification of functional human ES and iPSC-derived midbrain dopaminergic progenitors using LRTM1. Nat Commun, 2016, 7: 13097 CrossRef PubMed ADS Google Scholar

[57] Sasaki K., Yokobayashi S., Nakamura T., Okamoto I., Yabuta Y., Kurimoto K., Ohta H., Moritoki Y., Iwatani C., Tsuchiya H., et al. Robust in vitro induction of human germ cell fate from pluripotent stem cells. Cell Stem Cell, 2015, 17: 178-194 CrossRef PubMed Google Scholar

[58] Serra M., Brito C., Correia C., Alves P.M.. Process engineering of human pluripotent stem cells for clinical application. Trends Biotech, 2012, 30: 350-359 CrossRef PubMed Google Scholar

[59] Shahbazi M.N., Jedrusik A., Vuoristo S., Recher G., Hupalowska A., Bolton V., Fogarty N.M.E., Campbell A., Devito L.G., Ilic D., et al. Self-organization of the human embryo in the absence of maternal tissues. Nat Cell Biol, 2016, 18: 700-708 CrossRef PubMed Google Scholar

[60] Shirai H., Mandai M., Matsushita K., Kuwahara A., Yonemura S., Nakano T., Assawachananont J., Kimura T., Saito K., Terasaki H., et al. Transplantation of human embryonic stem cell-derived retinal tissue in two primate models of retinal degeneration. Proc Natl Acad Sci USA, 2016, 113: E81-E90 CrossRef PubMed ADS Google Scholar

[61] Smith A.. Formative pluripotency: the executive phase in a developmental continuum. Development, 2017, 144: 365-373 CrossRef PubMed Google Scholar

[62] Szalay G., Martinecz B., Lénárt N., Környei Z., Orsolits B., Judák L., Császár E., Fekete R., West B.L., Katona G., et al. Microglia protect against brain injury and their selective elimination dysregulates neuronal network activity after stroke. Nat Commun, 2016, 7: 11499 CrossRef PubMed ADS Google Scholar

[63] Tachibana M., Sparman M., Ramsey C., Ma H., Lee H.S., Penedo M.C.T., Mitalipov S.. Generation of chimeric rhesus monkeys. Cell, 2012, 148: 285-295 CrossRef PubMed Google Scholar

[64] Takagi Y., Takahashi J., Saiki H., Morizane A., Hayashi T., Kishi Y., Fukuda H., Okamoto Y., Koyanagi M., Ideguchi M., et al. Dopaminergic neurons generated from monkey embryonic stem cells function in a Parkinson primate model. J Clin Invest, 2005, 115: 102-109 CrossRef PubMed Google Scholar

[65] Takashima 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, 162: 452-453 CrossRef PubMed Google Scholar

[66] Teffer, K., and Semendeferi, K. (2012). Human prefrontal cortex: evolution, development, and pathology. Prog Brain Res 195, 191–218. Google Scholar

[67] Theunissen 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: 471-487 CrossRef PubMed Google Scholar

[68] Wang, M., Jiang, L., Monticone, R.E., and Lakatta, E.G. (2014). Proinflammation: the key to arterial aging. Trends Endocrinol Metab 25, 72–79. Google Scholar

[69] Wang S., Zou C., Fu L., Wang B., An J., Song G., Wu J., Tang X., Li M., Zhang J., et al. Autologous iPSC-derived dopamine neuron transplantation in a nonhuman primate Parkinson’s disease model. Cell Discov, 2015, 1: 15012 CrossRef PubMed Google Scholar

[70] Wang X., Li T., Cui T., Yu D., Liu C., Jiang L., Feng G., Wang L., Fu R., Zhang X., et al. Human embryonic stem cells contribute to embryonic and extraembryonic lineages in mouse embryos upon inhibition of apoptosis. Cell Res, 2017, 28: 126-129 CrossRef PubMed Google Scholar

[71] Ware C.B., Nelson A.M., Mecham B., Hesson J., Zhou W., Jonlin E.C., Jimenez-Caliani A.J., Deng X., Cavanaugh C., Cook S., et al. Derivation of naive human embryonic stem cells. Proc Natl Acad Sci USA, 2014, 111: 4484-4489 CrossRef PubMed ADS Google Scholar

[72] Wu J., Izpisua Belmonte J.C.. Stem cells: a renaissance in human biology research. Cell, 2016, 165: 1572-1585 CrossRef PubMed Google Scholar

[73] Wu J., Platero-Luengo A., Sakurai M., Sugawara A., Gil M.A., Yamauchi T., Suzuki K., Bogliotti Y.S., Cuello C., Morales Valencia M., et al. Interspecies chimerism with mammalian pluripotent stem cells. Cell, 2017, 168: 473-486.e15 CrossRef PubMed Google Scholar

[74] Wyss-Coray T.. Ageing, neurodegeneration and brain rejuvenation. Nature, 2016, 539: 180-186 CrossRef PubMed ADS Google Scholar

[75] Yan, L., Yang, M., Guo, H., Yang, L., Wu, J., Li, R., Liu, P., Lian, Y., Zheng, X., Yan, J., et al. (2013). Single-cell RNA-Seq profiling of human preimplantation embryos and embryonic stem cells. Nat Struct Mol Biol 20, 1131–1139. Google Scholar

[76] Yang S.H., Cheng P.H., Banta H., Piotrowska-Nitsche K., Yang J.J., Cheng E.C.H., Snyder B., Larkin K., Liu J., Orkin J., et al. Towards a transgenic model of Huntington’s disease in a non-human primate. Nature, 2008, 453: 921-924 CrossRef PubMed ADS Google Scholar

[77] Zhu X., Li B., Ai Z., Xiang Z., Zhang K., Qiu X., Chen Y., Li Y., Rizak J.D., Niu Y., et al. A Robust single primate neuroepithelial cell clonal expansion system for neural tube development and disease studies. Stem Cell Rep, 2016, 6: 228-242 CrossRef PubMed Google Scholar

  • Figure 1

    The pluripotency of primate pluripotent stem cells. Primate pluripotent stem cells undergo three different states (naive, formative and primed) over development. ICM, inner cell mass; EPI, epiblast; AME, amniotic epithelium.

  • Figure 2

    The summary of NHP applications in developing procedures of stem cell therapy for clinical translation.

  • Table 1   Some key scientific questions of primate pluripotent stem cells. The labels “+” indicate that the question has been solved. The labels “?” indicate that the question has not been solved



    Naive PSCs

    Formative PSCs

    Chimera competency

    Germline transmission

    Tetraploid complementation



























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