Teratoma: from spontaneous tumors to the pluripotency/malignancy assay

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Floriana Bulic‐Jakus, Ana Katusic Bojanac, Gordana Juric‐Lekic, Maja Vlahovic, Nino Sincic

Published Online: Dec 23 2015

DOI: 10.1002/wdev.219

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A teratoma is a benign tumor containing a mixture of differentiated tissues and organotypic derivatives of the three germ layers, while a teratocarcinoma also contains embryonal carcinoma cells (EC cells). Experimental teratomas and teratocarcinomas have been derived from early mammalian embryos transplanted into the adult animal (ectopic sites). In the rat, the pluripotency of the transplanted epiblast was demonstrated and a quantifiable restriction of developmental potential persisted after subsequent transplantation of chemically defined cultivated postimplantation embryos. The rat is nonpermissive for teratocarcinoma development and rat pluripotent cell lines have been established only recently. Transplantation of mouse embryos, epiblast, or embryonic stem cells (mESCs) gave rise to teratocarcinomas. The pluripotency of reprogrammed human cells has been tested by a ‘gold standard’ trilaminar teratoma assay in immunocompromised mice in vivo. Human pluripotent stem cells proposed for use in regenerative medicine such as human embryonic stem cell (hESC), human nuclear‐transfer/therapeutic cloning embryonic stem cell (NT‐ESC), or human induced pluripotent stem cell (hiPSC) lines, once differentiated in vitro to the desired cell type, should be again tested in a long‐term animal teratoma assay to exclude their malignancy. Such an approach led to a recently implemented human therapy with retinal pigmented epithelium. For greater biosafety, the teratoma assay should be standardized and complemented by assessments of mutations/epimutations, RNA/protein expression, and possible immunogenicity of autologous pluripotent cells. Furthermore, the standardized teratoma assay should be directed more to the assessment of EC/malignant cell features than of differentiated tissues, especially after a unique case of human therapy with neural stem cells was found to lead to malignancy. WIREs Dev Biol 2016, 5:186–209. doi: 10.1002/wdev.219 This article is categorized under: Adult Stem Cells, Tissue Renewal, and Regeneration > Methods and Principles Adult Stem Cells, Tissue Renewal, and Regeneration > Stem Cells and Disease Comparative Development and Evolution > Model Systems

Trilaminar differentiation in mouse teratocarcinomas derived from the embryonic shield transplanted under the kidney capsule. (a) Ectodermal derivative: epidermis (E) with keratinization (K) and derivation of sebaceous glands (asterisk), blood vessels (thick arrow), adipose tissue (A), skeletal muscle (SM) in cross section (SM), and myotube in longitudinal section (thin arrow). Masson trichrome stain, bar = 100 µm. (b) Neural tissue (N), skeletal muscle (SM), mucous gland acinus (M), serous gland acinus (arrowhead), mucoserous gland with a typical serous demilune, and the crescent of Gianuzzi (arrow), HE, bar = 100 µm. (c) Neural tissue (N) with several typical neural tubes (NT), cartilage (C). HE, bar = 100 µm. (d) Undifferentiated neural tissue (N), nests of embryonal carcinoma cells (EC cells) with apoptotic cells (arrows) surrounded by mesenchyme. HE, bar = 100 µm.

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Trilaminar differentiation within a rat experimental teratoma in vivo, derived from the embryonic shield (three germ layers) cultivated in vitro. (a) Ectodermal derivative: keratinized epidermis with well‐visualized typical layers among which stratum granulosum (arrow) and skin appendages such as hair follicles (arrowheads) with hair medulla (thick arrow) and sebaceous glands (asterisk) can be seen. HE, bar = 50 µm. (b) Ectodermal derivative: stratified squamous epithelium (E) with keratin (asterisk); endodermal derivative: pseudostratified ciliated columnar epithelium (thin arrow), pseudostratified ciliated columnar epithelium (thick arrow) with goblet cells (arrowhead); and mesodermal derivative: adipose tissue (A). HE, bar = 50 µm. (c) Mesodermal derivative: cartilage (C) enveloped in perichondrium (thick arrow) with chondrocytes situated in lacunae (thin arrow); thyroid gland (asterisk) with follicles filled with colloid and surrounded by follicular epithelial cells. HE, bar = 50 µm.

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Neural tissue that differentiated within an experimental teratoma in vitro, derived from the rat embryonic shield (three germ layers) cultivated for 14 days. (a) Between the neural cells (asterisk) with long processes (thick arrow) or large light nuclei with nucleoli (thin arrow), a typical neuropil (NP) can be seen, HE, bar = 50 µm. (b) Nestin expression within the neural tissue, immunohistochemistry, diaminobenzidine (DAB), counterstained with hematoxylin. Bar = 50 µm. (c) Neurofilament expression, immunohistochemistry, DAB, counterstained with hematoxylin. Bar = 50 µm. (d) Proliferating cell nuclear antigen (thin arrow) and glial fibrillary acidic protein (thick arrow) expression in neural tissue cells and immature cartilage; immunohistochemistry, double‐staining DAB, fast red, counterstained with hematoxylin. Bar = 50 µm.

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Trilaminar differentiation within a rat experimental teratoma in vitro, derived from the embryonic shield (three germ layers) cultivated for 14 days. (a) Ectodermal derivative: keratinized squamous stratified epithelium differentiated in serum‐supplemented medium (control). Within the epidermis, note the well‐developed stratum corneum (SC), stratum granulosum with keratohyaline granules (SG), stratum spinosum (SS), stratum basale (SB), and the basement membrane below the cells of the basal layer. HE, bar = 50 µm. (b) Mesodermal derivative: skeletal muscle. Note the myotube with centrally positioned nuclei (thin arrow) and the striated muscle, rarely seen in vitro (thick arrows). HE, bar = 50 µm. (c) Mesodermal derivatives: cartilage and blood island. Within the cartilage (C) enveloped in perichondrium (P), note the chondrocytes (thick arrow) and lacunae (thin arrow). Note also a blood island (asterisk). (d) Endodermal derivative: the cylindrical gut epithelium. Note the villi (thick arrow) covered with cylindrical epithelium containing goblet cells (thin arrow). Within the villi note the centrally positioned lamina propria (LP). HE, bar = 50 µm.

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Pluripotency assays. Three pluripotency assays currently exist for mammalian cells such as mouse pluripotent stem cells (mPSCs) or mouse‐induced pluripotent stem cells (miPSCs): tetraploid complementation, chimerism, and the teratoma assay. In tetraploid complementation, pluripotent stem cells are injected into tetraploid embryos. From the cultivated diploid cells (2N), an embryo‐proper and a living animal will develop, while tetraploid cells (4N) will contribute only to the extraembryonic tissues and the placenta. In the chimerism assay, pluripotent cells injected into a diploid blastocyst will be incorporated into the ICM and chimeric offspring will arise. Chimeras which developed germ cells from the injected cells will, after mating, give rise to the offspring originating entirely from cultivated pluripotent cells. Such assays are not done with human pluripotent stem cells (hPSCs), human induced pluripotent stem cells (hiPSCs), or human nuclear transfer stem cells (NT‐SCs). The teratoma assay is the only assay for testing the pluripotency of human cells. After transplantation of mouse or human cells to an ectopic site in the animal, pluripotent stem cells give rise to teratoma tumors that contain derivatives of the three germ layers.

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