Name: targeted and selective treatment of pluripotent stem cell-derived teratomas using external beam radiation in a small-animal model
Uploaded: 2019-02-17T13:00:00
Description: Watch this Scientific Journal Video about Targeted and Selective Treatment of Pluripotent Stem Cell-derived Teratomas Using External Beam Radiation in a Small-animal Model at JoVE.com

The authors would like to thank the National Institutes of Health R01 HL134830 (PKN), K08 HL135343 (KS), and 5F32HL134221 (JWR); the Howard Hughes Medical Institute (ASL); and the Stanford Cardiovascular Institute (ASL) for their support.

This animal experiment was approved and performed under the Institutional Review Board and the Administrative Panel on Laboratory Animal Care at Stanford University.
1. Cell Culture of iPSCs
<ol>
	<li>Grow human iPSCs derived by lentiviral reprogramming on 6-well plates coated with basement membrane matrix (e.g., matrigel, referred to as matrix hereon).</li>
	<li>Daily change the media of the iPSCs with enriched culture medium (see Table of Materials) incubating at 37&#160;&...

<ol>
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E., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Vision+Loss+after+Intravitreal+Injection+of+Autologous+&amp;#34;Stem+Cells&amp;#34;+for+AMD.">Vision Loss after Intravitreal Injection of Autologous &amp;#34;Stem Cells&amp;#34; for AMD.</a> The New England Journal of Medicine. 376 (11), 1047-1053 (2017).</li><li>Berkowitz, A. L., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Glioproliferative+Lesion+of+the+Spinal+Cord+as+a+Complication+of+&amp;#34;Stem-Cell+Tourism&amp;#34.">Glioproliferative Lesion of the Spinal Cord as a Complication of &amp;#34;Stem-Cell Tourism&amp;#34.</a> The New England Journal of Medicine. 375, 196-198 (2016).</li><li>Zhang, W. Y., de Almeida, P. E., Wu, J. 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S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Effects+of+cell+number+on+teratoma+formation+by+human+embryonic+stem+cells.">Effects of cell number on teratoma formation by human embryonic stem cells.</a> Cell Cycle. 8 (16), 2608-2612 (2009).</li><li>Tano, K., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+novel+in+vitro+method+for+detecting+undifferentiated+human+pluripotent+stem+cells+as+impurities+in+cell+therapy+products+using+a+highly+efficient+culture+system.">A novel in vitro method for detecting undifferentiated human pluripotent stem cells as impurities in cell therapy products using a highly efficient culture system.</a> PLoS One. 9 (10), e110496 (2014).</li><li>Kuroda, T., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Highly+sensitive+in+vitro+methods+for+detection+of+residual+undifferentiated+cells+in+retinal+pigment+epithelial+cells+derived+from+human+iPS+cells.">Highly sensitive in vitro methods for detection of residual undifferentiated cells in retinal pigment epithelial cells derived from human iPS cells.</a> PLoS One. 7 (5), e37342 (2012).</li><li>Cao, F., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=In+vivo+visualization+of+embryonic+stem+cell+survival,+proliferation,+and+migration+after+cardiac+delivery.">In vivo visualization of embryonic stem cell survival, proliferation, and migration after cardiac delivery.</a> Circulation. 113 (7), 1005-1014 (2006).</li><li>Cao, F., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Molecular+imaging+of+embryonic+stem+cell+misbehavior+and+suicide+gene+ablation.">Molecular imaging of embryonic stem cell misbehavior and suicide gene ablation.</a> Cloning Stem Cells. 9 (1), 107-117 (2007).</li><li>Kotini, A. 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B., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Selection+against+undifferentiated+human+embryonic+stem+cells+by+a+cytotoxic+antibody+recognizing+podocalyxin-like+protein-1.">Selection against undifferentiated human embryonic stem cells by a cytotoxic antibody recognizing podocalyxin-like protein-1.</a> Stem Cells. 26 (6), 1454-1463 (2008).</li><li>Yorke, E., Gelblum, D., Ford, E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Patient+safety+in+external+beam+radiation+therapy.">Patient safety in external beam radiation therapy.</a> American Journal of Roentgenology. 196 (4), 768-772 (2011).</li><li>Zhou, H., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Development+of+a+micro-computed+tomography-based+image-guided+conformal+radiotherapy+system+for+small+animals.">Development of a micro-computed tomography-based image-guided conformal radiotherapy system for small animals.</a> International Journal of Radiation Oncology &#8226; Biology &#8226; Physics. 78 (1), 297-305 (2010).</li><li>Slatkin, D. N., Spanne, P., Dilmanian, F. A., Gebbers, J. O., Laissue, J. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Subacute+neuropathological+effects+of+microplanar+beams+of+x-rays+from+a+synchrotron+wiggler.">Subacute neuropathological effects of microplanar beams of x-rays from a synchrotron wiggler.</a> Proceedings of the National Academy of Sciences of the United States of America. 92 (19), 8783-8787 (1995).</li><li>Lee, A. S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Brief+Report:+External+Beam+Radiation+Therapy+for+the+Treatment+of+Human+Pluripotent+Stem+Cell-Derived+Teratomas.">Brief Report: External Beam Radiation Therapy for the Treatment of Human Pluripotent Stem Cell-Derived Teratomas.</a> Stem Cells. 35 (8), 1994-2000 (2017).</li><li>Berkowitz, A. 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J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=In+vivo+imaging+of+embryonic+stem+cells+reveals+patterns+of+survival+and+immune+rejection+following+transplantation.">In vivo imaging of embryonic stem cells reveals patterns of survival and immune rejection following transplantation.</a> Stem Cells and Development. 17 (6), 1023-1029 (2008).</li><li>Cao, F., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Noninvasive+de+novo+imaging+of+human+embryonic+stem+cell-derived+teratoma+formation.">Noninvasive de novo imaging of human embryonic stem cell-derived teratoma formation.</a> Cancer Research. 69 (7), 2709-2713 (2009).</li><li>Priddle, H., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Bioluminescence+imaging+of+human+embryonic+stem+cells+transplanted+in+vivo+in+murine+and+chick+models.">Bioluminescence imaging of human embryonic stem cells transplanted in vivo in murine and chick models.</a> Cloning and Stem Cells. 11 (2), 259-267 (2009).</li><li>Dale, R. 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Preclinical data and anecdotal cases from victims of &#34;stem cell tourism&#34; confirm that the risk of developing teratomas is a serious drawback associated with PSC treatments23. Development of careful approaches to prevent and treat the neoplastic risk associated with stem cell therapies is, therefore, an important step in facilitating the clinical translation of regenerative stem cell therapies. In this article, we described a method of therapeutic targeting of PSC-associated teratomas using...

The development of stem cell therapies for tissue regeneration has encountered a number of barriers in the past several decades, hampering efforts for efficient clinical deployment. These hurdles include poor cell retention at sites of delivery, stem cell immunogenicity, and the neoplastic potential to form teratomas1. Tumorigenicity is of particular clinical concern as it can potentially harm stem cell transplant recipients2. Accounts of tumor formation due to unregulated stem cell injections have already been reported in multiple clinical settings3,4,5. The potential for teratoma formation is the most frequently cited clinical concern in pluripotent stem cell (PSC) development and has resulted in delays and cancellations of multiple high-profile embryonic stem cell (ESC) and induced pluripotent stem cell (iPSC) trials6,7,8,9. Thus, there is a pressing need for a translational investigation dedicated toward providing appropriate treatment, should these iatrogenic tumors arise.
To date, most strategies to control stem cell misbehavior have focused on reducing the number of PSCs with tumorigenic potential2,10. Unfortunately, only a small number of residual cells (e.g., 1 x 104 to 1 x 105 cells11) is required for teratoma formation, which is far below the detection limit quoted by currently available assays12,13. Other limitations of using these preseparation methods include low efficiency and high expense, reliance on single-cell suspensions that may not be appropriate for newer tissue-engineering approaches, and the potential impairment of cell survival and engraftment.
Few studies have addressed treatment options following teratoma formation. Perhaps the most well-studied strategy is the incorporation of &#34;suicide&#34; genes into stem cells14,15. This method involves genetically manipulating the stem cells to incorporate an inducible apoptosis-activating gene that can be activated by pharmacological stimulation postinjection, thereby providing a rescue approach if injected cells produce teratomas. This approach, however, suffers from significant drawbacks, including off-target effects of genetic modifications of PSCs and the potential for a gradual development of drug resistance16. A similar approach utilizes small molecules to induce selective cell death of PSCs via the inhibition of anti-apoptotic pathways17. Other groups have targeted cell death of PSCs using antibodies against pluripotency surface markers, such as podocalyxin-like protein-1 (PODXL)18. The timing of small-molecule or antibody delivery stands to have a significant impact on the therapeutic potential of PSCs if delivered too early and may lack therapeutic efficacy if delivered too late. In addition, the systemic effects of small molecules and antibodies used in this fashion have not been studied.
An alternative approach to treating these tumors relies on using external beam radiation therapy (EBRT). EBRT is one of the primary modalities currently employed in the treatment of solid tumors19. Innovations in EBRT, including the development of the proton beam and stereotactic radiosurgery, have enabled the enhanced targeting of pathological structures while avoiding damage to normal tissue, making conformal EBRT ideal for addressing teratoma formation in anatomically sensitive structures20. Additionally, this method avoids the genetic manipulation or viral transduction of stem cells, which are both fraught with additional clinical safety and efficacy concerns15. Finally, advances in micro-irradiators have enabled the application of EBRT in rodents21.
In this article, we demonstrate how to create a small-animal model of teratoma formation by injecting human iPSCs in mice. We then show how to apply EBRT to selectively eradicate these tumors in vivo with minimal damage to surrounding tissue. This approach provides a targeted therapy for PSC-derived teratomas while avoiding the off-target effects of the systemic delivery of biological molecules and peptides and the genetic manipulation of the PSCs. For investigational purposes, we offer an optional step to transduce stem cells with reporter genes to track tumor response to radiation therapy via bioluminescence imaging (BLI).

<table>
	<tbody>
		<tr>
			<td>Induced Pluripotent Stem Cell Control Line</td>
			<td>Stanford University</td>
			<td>Nguyen Lab</td>
			<td>Cell culture of iPSC</td>
		</tr>
		<tr>
			<td>Corning matrigel basement membrane matrix 354234</td>
			<td>Fisher Scientific</td>
			<td>CB-40234</td>
			<td>Cell culture of iPSC</td>
		</tr>
		<tr>
			<td>Essential 8 culture medium</td>
			<td>ATCC-The global bioresource center</td>
			<td>30-2203</td>
			<td>Cell culture of iPSC</td>
		</tr>
		<tr>
			<td>Tryple E</td>
			<td>Gibco</td>
			<td>12605-036</td>
			<td>Cell culture of iPSC</td>
		</tr>
		<tr>
			<td>Y27632 inhibitor 2 HCL (ROCK Inhibitor)</td>
			<td>Fisher Scientific</td>
			<td>S104950MG</td>
			<td>Cell culture of iPSC</td>
		</tr>
		<tr>
			<td>Lentivirus</td>
			<td>Cyagen</td>
			<td>P170721-1001cjn</td>
			<td>Transduction of iPSC with double fusion reporter gene</td>
		</tr>
		<tr>
			<td>Polyrbrene Infection/Transfection Reagent</td>
			<td>Millipore Sigma</td>
			<td>TR-1003-G</td>
			<td>Transduction of iPSC with double fusion reporter gene</td>
		</tr>
		<tr>
			<td>Fluc-eGFP reporter gene driven by ubiquitin promoter</td>
			<td>Stanford University</td>
			<td>Sam Gambhir lab</td>
			<td>Transduction of iPSC with double fusion reporter gene</td>
		</tr>
		<tr>
			<td>D-luciferin</td>
			<td>Perkin Elmer</td>
			<td>122799</td>
			<td>Transduction of iPSC with double fusion reporter gene and BLI</td>
		</tr>
		<tr>
			<td>Flow cytometer (BD FACSARIA III)</td>
			<td>BD Biosciences&#160;</td>
			<td>FACSAria</td>
			<td>Transduction of iPSC with double fusion reporter gene</td>
		</tr>
		<tr>
			<td>microplate spectrofluorometer (Glomax Navigator System)</td>
			<td>Promega Bio Systems, Sunnyvale, CA</td>
			<td>GM2000</td>
			<td>Transduction of iPSC with double fusion reporter gene</td>
		</tr>
		<tr>
			<td>Xenogen IVIS 200&#160;</td>
			<td>Perkin Elmer</td>
			<td>124262</td>
			<td>BLI</td>
		</tr>
		<tr>
			<td>Isoflurane</td>
			<td>Sigma-Aldrich</td>
			<td>CDS019936</td>
			<td>irradiation</td>
		</tr>
		<tr>
			<td>X-Rad SmART image-guided irradiator&#160;</td>
			<td>Precision X-ray Inc., North Branford, CT</td>
			<td>X-Rad SmART</td>
			<td>irradiation</td>
		</tr>
		<tr>
			<td>RT_Image software package</td>
			<td>Stanford University (http://rtimage.sourceforge.net/)</td>
			<td>RT_Image v0.2&#946;</td>
			<td>Irradiation</td>
		</tr>
	</tbody>
</table>

targeted and selective treatment of pluripotent stem cell-derived teratomas using external beam radiation in a small-animal model

The growing number of victims of &#34;stem cell tourism,&#34; the unregulated transplantation of stem cells worldwide, has raised concerns about the safety of stem cell transplantation. Although the transplantation of differentiated rather than undifferentiated cells is common practice, teratomas can still arise from the presence of residual undifferentiated stem cells at the time of transplant or from spontaneous mutations in differentiated cells. Because stem cell therapies are often delivered into anatomically sensitive sites, even small tumors can be clinically devastating, resulting in blindness, paralysis, cognitive abnormalities, and cardiovascular dysfunction. Surgical access to these sites may also be limited, leaving patients with few therapeutic options. Controlling stem cell misbehavior is, therefore, critical for the clinical translation of stem cell therapy.
External beam radiation offers an effective means of delivering targeted therapy to decrease the teratoma burden while minimizing injury to surrounding organs. Additionally, this method avoids genetic manipulation or viral transduction of stem cells-which are associated with additional clinical safety and efficacy concerns. Here, we describe a protocol to create pluripotent stem cell-derived teratomas in mice and to apply external beam radiation therapy to selectively ablate these tumors in vivo.

Injected mice typically will demonstrate teratoma growth formation after 4&#8211;8 weeks as confirmed by BLI imaging (Figure 2). Tumors will shrink dramatically when irradiated with a cumulative dose of 18 Gy given one month after cell delivery, resulting in a significant decrease in luciferase signal (Figure 2). Importantly, normal tissues taken 5 mm from the irradiated site do not appear to have any significant damage (<strong ...

Watch this Scientific Journal Video about Targeted and Selective Treatment of Pluripotent Stem Cell-derived Teratomas Using External Beam Radiation in a Small-animal Model at JoVE.com

Targeted and Selective Treatment of Pluripotent Stem Cell-derived Teratomas Using External Beam Radiation in a Small-animal Model

Research on treatment strategies for pluripotent stem cell-derived teratomas is important for the clinical translation of stem cell therapy. Here, we describe a protocol to, first, generate stem cell-derived teratomas in mice and, then, to selectively target and treat these tumors in vivo using a small-animal irradiator.

The growing number of victims of &#34;stem cell tourism,&#34; the unregulated transplantation of stem cells worldwide, has raised concerns about the ...

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