(Investigative Ophthalmology and Visual Science. 2004;45:4251-4255.)
© 2004 by The Association for Research in Vision and Ophthalmology, Inc.
DOI: 10.1167/iovs.03-1108
Neurally Selected Embryonic Stem Cells Induce Tumor Formation after Long-Term Survival following Engraftment into the Subretinal Space
Stefan Arnhold,1
Helmut Klein,1
Irina Semkova,2
Klaus Addicks,1 and
Ulrich Schraermeyer2
1From the Department of Anatomy I, University of Cologne, Cologne, Germany; and the
2Section of Vitroretinal Surgery, University Eye Clinic Tübingen, Tübingen, Germany.
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Abstract
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PURPOSE. To determine whether transplantation of embryonic stem (ES) cells into the subretinal space of rhodopsin-knockout mice has a tumorigenic effect.
METHODS. Mouse ES-cell–derived neural precursor cells carrying the sequence for the green fluorescent protein (GFP) gene were grafted subretinally into the eyes of rhodopsin–/– mice, whereas control animals underwent sham surgery. Eyes were retrieved after 2, 4, and 8 weeks after cell injection or sham surgery for histologic analysis.
RESULTS. Gross morphologic, histologic, and immunohistochemical analysis of eyes at 2 and 4 weeks after engraftment exhibited no morphologic alterations, whereas neoplasia formation was detected in 50% of the eyes evaluated at 8 weeks after engraftment. Because the neoplasias expressed differentiation characteristics of the different germ layers, they were considered to be teratomas. The resultant tumor formation affected almost all layers of the eye, including the retina, the vitreous, and the choroid.
CONCLUSIONS. Although ES cells may provide treatment for degenerative disease in the future, their unlimited self-renewal and high differentiation potential poses the risk of tumor induction after engraftment. Thus, more care must be taken before using ES cell transplantation as a therapeutic option for patients with degenerative disease.
Advances in stem cell research and associated technologies over the past decade have increased hopes for the development of cellular therapies for age-related degenerative diseases. These diseases arise due to progressive cell loss; thus, replacing these cells would be an ideal therapy.
With respect to degenerative diseases of the mammalian visual system, the death of specific cell populations within the retina is associated with blinding diseases of the eye, such as age-related macular degeneration (AMD) and retinitis pigmentosa (for review see Ref. 1 ). Transplantation of stem cells into the retina to replace lost cells or to act as supporting cells to prevent further degenerative cell loss is also discussed increasingly as a practical approach for treating blindness. Unfortunately, the application of cellular therapies is limited because of a scarcity of donors for suitable cell populations, such as neural stem or progenitor cells, that can be transplanted either into the subretinal space or into the vitreous chamber.2 3 4 5 However, these cell populations can be obtained in huge quantities by differentiating embryonic stem cells into the respective cell types, thus making cell replacement therapies more plausible.
The isolation of human embryonic stem cells from preimplantation blastocysts has made cell replacement therapy an even more realistic option as human ES cells share similarities with their counterparts in the mouse.6 Many attempts have been made to induce in vitro differentiation of ES cells into many cell types, including hematopoietic precursor,7 heart and skeletal muscle,8 endothelial,9 and neural cells.10 11 12 Interesting data from an in vitro study in which ES cells were exposed to defined extracellular factors demonstrated the differentiation potential of ES cells into retinal neural progenitor cells.13
Herein, we describe the transplantation of GFP-labeled, ES-cell–derived neural precursor cells into the subretinal space of the rhodopsin knockout mouse to determine the integrative capacity of these cells and to evaluate their potential to differentiate into retinal cells. Furthermore, any rescue effects or associated complications exerted by the transplanted cells were evaluated.
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Materials and Methods
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ES Cell Cultivation and Neural Precursor Selection
ES cells of the cell line D3 of the mouse strain 129 were purchased from ATCC (Manassas, VA). To keep ES cells in an undifferentiated state, we cultivated them feeder cell independent, with the supplementation of leukemia inhibitory factor (LIF; 100 nM; Invitrogen-Life Technologies, Gaithersburg, MD) in DMEM (Invitrogen-Life Technologies) plus 15% fetal calf serum (FCS) and the established supplements as previously described.11 The cells were allowed to aggregate in hanging drops to form embryoid bodies (EBs). Hanging drops containing the EBs were rinsed off after 2 days and subsequently cultivated in suspension (DMEM, 10% FCS) for another day. Finally, at day 3, EBs were transferred to tissue culture dishes (DMEM with 10% FCS) and allowed to adhere for 12 hours. Selection of neural precursor cells was achieved by cultivation in an astrocyte-conditioned, serum-free medium containing insulin, transferrin, selene chloride, and fibronectin, as previously described.11 Selection was performed for up to 18 days. The efficiency of the selection procedure was continuously investigated immunocytochemically with an antibody against the intermediary filament nestin, which is specifically expressed in neural precursor cells. To study the further differentiation of selected neural precursor cells, we transferred them to a medium (DMEM/Ham’s F12) with a serum content of 10% FCS.
For an alternative way to induce neurogenesis, ES cells were cultured in hanging drops as spheroidal aggregates (EBs) in DMEM supplemented with 20% FCS for 3 days. Afterward, EBs were cultured in suspension in the presence of 0.1 µM retinoic acid for another 4 days. Seven days after aggregation, embryoid bodies were plated on gelatin-coated culture dishes and supplemented with DMEM (5% FCS without LIF) for up to 14 days with two changes of medium per week.
Subretinal Cell Injection
All animals were cared for in accordance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. Male wild-type and rhodopsin-knockout mice derived on a 129 mouse background14 were anesthetized at 6 weeks of age by intramuscular injection of ketamine (150 mg/kg; Pfizer, New York, NY) and xylazine (15 mg/kg, Rompun; Bayer, Leverkusen, Germany). Before transplantation, neurally selected ES cells were transduced with 50 multiplicities of injection (MOI) of the high-capacity adenoviral vector HC-AD, pigment-epithelium–derived factor (PEDF), and an HC-Ad.FK7–expressing enhanced GFP (EGFP), as previously described.15 Before transplantation, the medium was changed, the cells were washed twice with PBS, and a suspension of 6 x 104 viable neural precursor cells per microliter was grafted (1 µL per eye) into the eye with a 32-gauge syringe (Hamilton, Reno, NV).
For control experiments, ES-cell–derived neural precursor cells without prior vector transduction were used. Selected ES cells were also transplanted into a nonprivileged site, such as the subcutaneous layer of the abdominal wall. Undifferentiated ES cells were also grafted.
Tissue Analysis
Mice were killed by CO2 at 2, 4, and 8 weeks after surgery. The eyes were enucleated and fixed in 4% paraformaldehyde in 0.1 M PBS, embedded in paraffin, and sectioned at 6-µm thickness. Every fifth section was stained with hematoxylin and eosin (HE) and analyzed histologically. Adjacent sections were processed for immunohistochemical analysis using the following antibodies: anti-
-sarcomeric-actin (1:1000, mouse monoclonal) and anti-cytokeratin (1:800, mouse monoclonal; both from Sigma-Aldrich, Munich, Germany).
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Results
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After a 7-day selection period using a protocol specifically developed for the selection of neural precursor cells16 17 or using retinoic acid as an alternative inductor for lineage selection of neuronal cells,18 approximately 90% of the cells were immunopositive for the marker nestin (Fig. 1a) . In conjunction with a defined selection procedure for neural precursor cells this marker can actually be regarded as a specific marker for neural precursor cells. More than 75% of the nestin-immunopositive cells were still in a proliferative state, as shown by colabeling with the proliferation marker Ki67 (Fig. 1b) .
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FIGURE 1. Embryonic stem cells after selection in a serum-free, chemically defined medium. (a) A highly enriched population of nestin-positive neural precursor cells in a counterstain (b) with the proliferation marker ki67. Approximately 80% of the selected precursor cells were immunopositive for ki67. (c) Further cultivation of selected precursor cells in a differentiation medium containing B27 resulted in the differentiation of ßIII-tubulin–positive neurons, (d) forming dense neuronal networks, counterstained with the Hoechst nuclear stain. (e) Cultivation of selected precursor cells in a medium with a serum fraction of 10% FCS also resulted in the differentiation of densely packed ßIII-positive neuronal and (f) GFAP-positive astroglial cells. Scale bar, 25 µm.
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After the selection period, the cells were divided into two fractions. One fraction was plated on polyornithine-coated dishes in a differentiation medium including a B27-supplemented medium (NeuroBasal Medium; Invitrogen, Karlsruhe, Germany) for in vitro analysis of further cell differentiation. Cells exposed to these culture conditions started to differentiate into ßIII-tubulin–immunopositive neuronal cells and formed dense networks (Figs. 1b 1c 1d 1e) or into glial fibrillary protein (GFAP)–positive glial cells (Fig. 1f) . After transduction of an adenoviral vector carrying the sequence for the green fluorescent protein, the other cell fraction was used for grafting experiments in wild-type and rhodopsin-knockout mice.
After implantation of the selected neural precursor cells into the subretinal space, eyes isolated 2 or 4 weeks after grafting did not show any distinctive features. However, 50% of the eyes enucleated 2 months after surgery showed different degrees of macroscopic malformation and enlargement (not shown). Diameters of malformed eyes ranged from 4 to 7 mm, whereas that of normal eyes not subjected to cell engraftment was approximately 3 mm, as detected in low-power micrographs (Figs. 2a 2b 2c) . Furthermore, tumor formation was detected in the eyes subjected to engraftment of nontransfected neural precursor cells (Fig. 2d) , or precursor cells as selected using retinoic acid (Fig. 2e) , as well as unselected ES cells not transfected by an adenoviral vector (Fig. 2f) .
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FIGURE 2. Low-power micrographs of different mouse eyes without treatment and 8 weeks after injection of ES-cell–derived neural precursor cells as well as unselected ES cells. (a) Control eye without cell injection. (b, c) Different degrees of tumor formation after grafting of selected ES-cell–derived neural precursor cells. (d) Severe tumor formation after injection of unselected ES cells. (e) Intraocular tumor induced by retinoic-acid–treated ES cells. (f) Tumor formation after injection of selected, non–vector-transduced ES cells. Scale bar, 100 µm.
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In flatmount preparations of eyes that were evaluated 2 weeks after grafting, ES-cell–derived neural precursor cells were easily detected by their GFP expression in the retina and the subretinal space. The GFP fluorescence partially colabeled with immunofluorescence for the neuronal marker ßIII-tubulin and the glial marker GFAP (Fig. 3) . Using a Ki67 antibody, the proliferative index was determined to be 50% of the grafted cell population. However, of the 25 eyes that were evaluated 2 months after ES-cell implantation, large tumors that had partially destroyed the ocular structure were detectable in 7. Within this tumor development group, the size of the tumor varied. The variation in size correlated with the degree of destruction induced by the tumor. The proliferative index was estimated to be 40% after survival times of 2 months.
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FIGURE 3. GFP-expressing cells 2 weeks after cell injection into the subretinal space. (a) GFP-expressing cell with neuronal morphology in a transverse section of the retina. Dotted line: diameter of the retina. Inset: higher magnification of GFP-expressing neuronal-like cell. (b) GFP expression partially colocalized with the immunofluorescence for the neuronal marker ßIII-tubulin. (c) GFP-expressing cells partially immunopositive for the glial marker GFAP. Scale bar: (a) 100 µm; (inset, b, c) 30 µm.
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Although the corneas and vitreous bodies seemed to be normal, with tumor formation restricted to only the retina, in more severe cases, the typical structure of the eye was completely destroyed by tumor infiltration. The tumor damaged several structures, including the following: the cornea, the anterior chamber, the trabecular meshwork, the iris, the ciliary body, and the choroid, detectable by its heavily pigmented stroma (Fig. 4a) . The retina, the base of the iris, the ciliary body, and the choroid were expanded by a poorly demarcated, densely cellular neoplastic mass (Fig. 4b) . In some cases, the tumor mass extended into the anterior chamber of the eye. Most tumor cells were arranged in packets, with a fine fibrovascular stroma. Multifocally, tumor cells surrounded accumulations of vacuolated eosinophilic extracellular material (Fig. 4c) . Within the tumor mass there were numerous areas with epithelial-like cells arranged in a glandular fashion (Fig. 4d) as well as areas containing chondrocytes (Fig. 4e) . In some preparations, muscle fibers were also discernible (Fig. 4f) . Immunocytochemical analyses using antibodies against -sarcomeric-actin or cytokeratin confirm the differentiation of muscle and epithelial cells (Fig. 5) . Based on these findings, it can be deduced that the tumors were teratomas, as they had typical characteristics of tissues originating from the different germ layers. Transplantation of selected ES cells into the subcutaneous layer of the abdominal wall also induced tumor formation (data not shown).
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FIGURE 4. HE stain of the mixed tumors that developed 8 weeks after subretinal ES cell injection. (a) Tumor involving the iris and ciliary body. (b) Mixed tumor involving the choroid and the sclera, that show a marked thickening. (c) Bony structures within the mixed tumor. (d) Islands of cartilage within the mixed tumor. (e) Epithelial-like cells partially forming immature glandular sinusoids. (f) Muscle fibers within the tumor. Scale bar, 25 µm.
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FIGURE 5. Immunohistochemical staining for the typing of tissue derivatives after ES-cell–derived neural stem cell injection. (a) Muscle cell differentiation, as detected with an antibody against -sarcomeric-actin. (b) Differentiation of epithelial-like cells as detected using an antibody against cytokeratin. Scale bar, 15 µm.
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Discussion
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Because of the unlimited self-renewal capacity and the wide differentiation spectrum19 of ES cells, the potential use of ES cells as therapeutic agents offers hope for those working on regenerative medicine.6 In fact, the use of these cells could eliminate the problem of limited donor tissue for treatments. Moreover, since the establishment of human ES-cell lines from blastocysts in 1998,6 increased efforts to determine how to differentiate particular cell lineages and to design protocols for purifying and expanding desired cell types have been at the forefront of this developing technology. So far, studies of transplanted mouse ES cells have revealed encouraging results for the possible therapeutic application of these cells.10 However, there are still many technical hurdles to overcome before clinical trials of ES-cell transplantation can be undertaken.
In the present study, one of these hurdles was demonstrated by the side effects of the first described transplantation of selected ES-cell–derived neural precursor cells into the subretinal space. Long-term observations revealed that neural precursor engraftment led to the formation of severe intraocular tumors. The incidence of tumor growth was observed only in eyes enucleated after 2 months after engraftment, whereas eyes analyzed 2 weeks after engraftment revealed no hint of pathologic processes. However, GFP-expressing cells were observed in retinal and subretinal locations. Furthermore, there was partial colocalization of GFP expression with the immunofluorescence for the neuron-specific ßIII-tubulin, suggesting that there was an initial differentiation of ES-cell–derived neural precursor cells into retinal neurons. However, the occurrence of tumors in 50% of the eyes in the long-term survival group diminishes hope for an immediate therapeutic application of ES cells in the retina for the treatment of degenerative eye disease.
Our observations are in accordance with data regarding teratoma formation after injection of ES cells into the knee joints of mice.20 Similarly, neoplastic eyes in our investigation suggested the presence of cell derivatives of the different germ layers as indicated by epithelial, chondrogenic, and myogenic cell differentiation. This observation was surprising, because the ES cells underwent a selection procedure that resulted in a highly purified population of neural precursor cells before injection.16 17 However, one has to be aware that even after thorough selection procedures were performed according to the current literature,16 18 there remains a high risk of ectopic differentiation that finally leads to severe tumor formation after engraftment. Unfortunately, there is no reliable selection procedure available to date that results in a 100% pure and secure selection of neural precursor cells from embryonic stem cells.
It is still largely unknown why ES cells, which lack chromosomal abnormalities, are tumorigenic. However, the tumor-inducing effect seems to be more severe in allogenic transplantation, as there are no reports of tumor formation in the numerous transplantation studies investigating the differentiation fate of murine ES cells as a cell source in rat recipients.10 17 21 22 In the meantime, it has been shown that ES cells specifically express a Ras-like gene, which encodes the human orthologue of Eras, a protein that contains amino acid residues that may have the potency to cause oncogenic transformation, even in NIH 3T3 cells.23
In conclusion, our data indicate that although stem cell therapy seems to hold great promise, the possible side effects of using these cells for treatment of degenerative eye disease must not be underestimated. Therefore, even if the problem of transplant rejection is circumvented and the ethical debate retreats, the problem of the risk of tumor formation must be solved before any clinical studies involving these cells are undertaken.
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Acknowledgements
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The authors thank Jolanta Kozlowski and Hanna Janicki for excellent technical assistance and IOVS volunteer editor Stephen Gee (University of North Carolina at Chapel Hill, NC), for editing the manuscript.
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Footnotes
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Submitted for publication October 6, 2003; revised May 10 and August 11, 2004; accepted August 13, 2004.
Disclosure: S. Arnhold, None; H. Klein, None; I. Semkova, None; K. Addicks, None; U. Schraermeyer, None
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. 
1734 solely to indicate this fact.
Corresponding author: Stefan Arnhold, Department of Anatomy I, Joseph-Stelzmann Strasse 9, 50931 Köln, Germany; stefan.arnhold{at}uni-koeln.de.
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Abstract
Materials and Methods
