Abstract

Embryonic stem (ES) cell based therapy carries great potential in the treatment of neurodegenerative diseases. However, before clinical application is realized, the safety, efficacy and feasibility of this therapeutic approach must be established in animal models. The rhesus macaque is physiologically and phylogenetically similar to the human, and therefore, is a clinically relevant animal model for biomedical research, especially that focused on neurodegenerative conditions. Undifferentiated monkey ES cells can be maintained in a pluripotent state for many passages, as characterized by a collective repertoire of markers representing embryonic cell surface molecules, enzymes and transcriptional factors. They can also be differentiated into lineage-specific phenotypes of all three embryonic germ layers by epigenetic protocols. For cell-based therapy, however, the quality of ES cells and their progeny must be ensured during the process of ES cell propagation and differentiation. While only a limited number of primate ES cell lines have been studied, it is likely that substantial inter-line variability exists. This implies that diverse ES cell lines may differ in developmental stages, lineage commitment, karyotypic normalcy, gene expression, or differentiation potential. These variables, inherited genetically and/or induced epigenetically, carry obvious complications to therapeutic applications. Our laboratory has characterized and isolated rhesus monkey ES cell lines from in vitro produced blastocysts. All tested cell lines carry the potential to form pluripotent embryoid bodies and nestin-positive progenitor cells. These ES cell progeny can be differentiated into phenotypes representing the endodermal, mesodermal and ectodermal lineages. This review article describes the derivation of monkey ES cell lines, characterization of the undifferentiated phenotype, and their differentiation into lineage-specific, particularly neural, phenotypes. The promises and limitations of primate ES cell-based therapy are also discussed.

Highlights

  • Primate and mouse Embryonic stem (ES) cells are similar in their ability to self-renew and differentiate into cells representing all three embryonic germ layers [see [10,11,12,13,14] for review]

  • At least 15 rhesus monkey ES cells lines are available at the Oregon National Primate Research Center

  • The pluripotency of undifferentiated monkey ES cells is defined by a panel of molecular signatures that include embryonic surface antigens, enzymes and transcriptional factors

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Summary

Conclusions

At least 15 rhesus monkey ES cells lines are available at the Oregon National Primate Research Center. Purified nestin+/Musashi1+ progenitor cells can be produced by a neural selection protocol These progenitor cells are multipotent, if not pluripotent, capable of differentiating into insulin-producing endodermal cells, various neuronal phenotypes and glial cells expressing Schwann cell markers and myelinating proteins. The potential exists for the differentiation and enrichment of monkey ES cells into dopaminergic neurons or myelinating glial phenotypes that serve as suitable cell sources for transplantation studies in animal models of Parkinson Disease, multiple sclerosis and spinal cord injury. Such translational studies, in nonhuman primate models, are critical steps to understand the safety, feasibility and efficacy of ES cell-based therapy for the treatment of neural degenerative diseases

Martin GR
10. Robertson EJ
13. Pera MF
46. Fawcett J
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