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Noninvasive Detection of Human-Induced Pluripotent Stem Cell (hiPSC)-Derived Teratoma with an Integrin-Targeting Agent 99mTc-3PRGD2

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Abstract

Purpose

Since their discovery in 2006, induced pluripotent stem cells (iPSCs) have gained increasing interest for tissue regeneration and transplantation therapies. However, teratoma formation after iPSC transplantation is one of the most serious drawbacks that may limit their further clinical application. We investigated here whether human iPSC-derived teratomas could be detected by an integrin-targeting agent 99mTc-PEG4-E[PEG4-c(RGDfK)]2 (99mTc-3PRGD2).

Methods

Human-induced pluripotent stem cells (hiPSCs) were generated and characterized. In vitro integrin αvβ3 expression levels of hiPSC- and hiPSC-derived teratoma cells were determined by flow cytometry. 99mTc-3PRGD2 was prepared, and planar gamma imaging and biodistribution studies were carried out in teratoma-bearing severe combined immunodeficient (SCID) mice. Positron emission tomography (PET) imaging of teratomas with 2-deoxy-2-[18F]fluoro-d-glucose (18F-FDG) was also performed for comparison. Integrin αvβ3 expression in teratoma tissues was determined by immunofluorescence staining.

Results

99mTc-3PRGD2 showed high (2.82 ± 0.21 and 2.69 ± 0.73%ID/g at 0.5 and 1 h pi, respectively) and specific (teratoma uptake decreased from 2.69 ± 0.73 to 0.53 ± 0.26%ID/g after blocking with cold 3PRGD2) uptake in teratoma tissues, and planar gamma imaging demonstrated the feasibility of noninvasively detecting the teratoma formation with 99mTc-3PRGD2. 18F-FDG showed low teratoma uptake and thus failed to detect the teratomas. Ex vivo immunofluorescence staining validated the integrin αvβ3 expression in the vasculature during teratoma formation.

Conclusion

Gamma imaging with 99mTc-3PRGD2 is a promising approach for the noninvasive monitoring of tumorigenicity after hiPSCs transplantation.

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References

  1. Klimanskaya I, Rosenthal N, Lanza R (2008) Derive and conquer: sourcing and differentiating stem cells for therapeutic applications. Nat Rev Drug Discov 7:131–142

    Article  PubMed  CAS  Google Scholar 

  2. Swijnenburg RJ, Schrepfer S, Govaert JA, Cao F, Ransohoff K, Sheikh AY, Haddad M, Connolly AJ, Davis MM, Robbins RC et al (2008) Immunosuppressive therapy mitigates immunological rejection of human embryonic stem cell xenografts. Proc Natl Acad Sci USA 105:12991–12996

    Article  PubMed  CAS  Google Scholar 

  3. Fong CY, Gauthaman K, Bongso A (2010) Teratomas from pluripotent stem cells: a clinical hurdle. J Cell Biochem 111:769–781

    Article  PubMed  CAS  Google Scholar 

  4. Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676

    Article  PubMed  CAS  Google Scholar 

  5. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–872

    Article  PubMed  CAS  Google Scholar 

  6. Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, Jonsdottir GA, Ruotti V, Stewart R et al (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318:1917–1920

    Article  PubMed  CAS  Google Scholar 

  7. Hussein SM, Nagy K, Nagy A (2011) Human induced pluripotent stem cells: the past, present, and future. Clin Pharmacol Ther 89:741–745

    Article  PubMed  CAS  Google Scholar 

  8. Folkman J (1995) Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1:27–31

    Article  PubMed  CAS  Google Scholar 

  9. Yan X (2010) Angiogenesis: a promising strategy for tumor therapy. Acta Biophys Sin 26:180–193

    CAS  Google Scholar 

  10. Cai W, Niu G, Chen X (2008) Imaging of integrins as biomarkers for tumor angiogenesis. Curr Pharm Des 14:2943–2973

    Article  PubMed  CAS  Google Scholar 

  11. Liu Z, Wang F, Chen X (2008) Integrin alpha(v)beta(3)-targeted cancer therapy. Drug Dev Res 69:329–339

    Article  PubMed  CAS  Google Scholar 

  12. He Q, Liu Z, Jia B, Li X, Shi J, Zhang J, Lan F, Yang Z, Liu Y, Shen L et al (2008) In vivo gamma imaging of the secondary tumors of transplanted human fetal striatum neural stem cells-derived primary tumor cells. Neuroreport 19:1009–1014

    Article  PubMed  Google Scholar 

  13. Liu S (2009) Radiolabeled cyclic RGD peptides as integrin alpha(v)beta(3)-targeted radiotracers: maximizing binding affinity via bivalency. Bioconjug Chem 20:2199–2213

    Article  PubMed  CAS  Google Scholar 

  14. Jia B, Liu Z, Zhu Z, Shi J, Jin X, Zhao H, Li F, Liu S, Wang F (2011) Blood clearance kinetics, biodistribution, and radiation dosimetry of a kit-formulated integrin alphavbeta3-selective radiotracer 99mTc-3PRGD2 in non-human primates. Mol Imaging Biol 13:730–736

    Article  PubMed  Google Scholar 

  15. Ma Q, Ji B, Jia B, Gao S, Ji T, Wang X, Han Z, Zhao G (2011) Differential diagnosis of solitary pulmonary nodules using 99mTc-3P4-RGD2 scintigraphy. Eur J Nucl Med Mol Imaging 38:2145–2152

    Article  PubMed  Google Scholar 

  16. Liu Z, Jia B, Shi J, Jin X, Zhao H, Li F, Liu S, Wang F (2010) Tumor uptake of the RGD dimeric probe 99mTc-G3-2P4-RGD2 is correlated with integrin alphavbeta3 expressed on both tumor cells and neovasculature. Bioconjug Chem 21:548–555

    Article  CAS  Google Scholar 

  17. Liu Z, Jia B, Zhao H, Chen X, Wang F (2011) Specific targeting of human integrin alphavbeta3 with 111In-labeled Abegrin in nude mouse models. Mol Imaging Biol 13:112–120

    Article  PubMed  Google Scholar 

  18. Yoshida Y, Yamanaka S (2010) Recent stem cell advances: induced pluripotent stem cells for disease modeling and stem cell-based regeneration. Circulation 122:80–87

    Article  PubMed  Google Scholar 

  19. Cai W, Zhang Y, Kamp T (2011) Imaging of induced pluripotent stem cells: from cellular reprogramming to transplantation. Am J Nucl Med Mol Imaging 1:18–28

    PubMed  CAS  Google Scholar 

  20. Kraitchman DL, Heldman AW, Atalar E, Amado LC, Martin BJ, Pittenger MF, Hare JM, Bulte JW (2003) In vivo magnetic resonance imaging of mesenchymal stem cells in myocardial infarction. Circulation 107:2290–2293

    Article  PubMed  Google Scholar 

  21. Cao F, Lin S, Xie X, Ray P, Patel M, Zhang X, Drukker M, Dylla S, Connolly AJ, Chen X et al (2006) In vivo visualization of embryonic stem cell survival, proliferation, and migration after cardiac delivery. Circulation 113:1005–1014

    Article  PubMed  Google Scholar 

  22. Rohren EM, Turkington TG, Coleman RE (2004) Clinical applications of PET in oncology. Radiology 231:305–332

    Article  PubMed  Google Scholar 

  23. Sugawara Y, Zasadny KR, Grossman HB, Francis IR, Clarke MF, Wahl RL (1999) Germ cell tumor: differentiation of viable tumor, mature teratoma, and necrotic tissue with FDG PET and kinetic modeling. Radiology 211:249–256

    PubMed  CAS  Google Scholar 

  24. Kollmannsberger C, Oechsle K, Dohmen BM, Pfannenberg A, Bares R, Claussen CD, Kanz L, Bokemeyer C (2002) Prospective comparison of [18F]fluorodeoxyglucose positron emission tomography with conventional assessment by computed tomography scans and serum tumor markers for the evaluation of residual masses in patients with nonseminomatous germ cell carcinoma. Cancer 94:2353–2362

    Article  PubMed  Google Scholar 

  25. Johns Putra L, Lawrentschuk N, Ballok Z, Hannah A, Poon A, Tauro A, Davis ID, Hicks RJ, Bolton DM, Scott AM (2004) 18F-Fluorodeoxyglucose positron emission tomography in evaluation of germ cell tumor after chemotherapy. Urology 64:1202–1207

    Article  PubMed  CAS  Google Scholar 

  26. Aide N, Briand M, Bohn P, Dutoit S, Lasnon C, Chasle J, Rouvet J, Modzelewski R, Vela A, Deslandes E et al (2011) Alphavbeta3 imaging can accurately distinguish between mature teratoma and necrosis in 18F-FDG-negative residual masses after treatment of non-seminomatous testicular cancer: a preclinical study. Eur J Nucl Med Mol Imaging 38:323–333

    Article  PubMed  Google Scholar 

  27. Cao F, Li Z, Lee A, Liu Z, Chen K, Wang H, Cai W, Chen X, Wu JC (2009) Noninvasive de novo imaging of human embryonic stem cell-derived teratoma formation. Cancer Res 69:2709–2713

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was financially supported, in part, by the National Natural Science Foundation of China (NSFC) projects (30930030, 81000625, 31000653, 30870728, 30900373, and 81028009), the Outstanding Youth Fund (81125011), a Beijing Natural Science Foundation project (5112019), a “973” project (2011CB707703), an Innovation Team Project of the Ministry of Education (No. BMU20110263), and grants from the Ministry of Science and Technology of China (2011YQ030114 and 2012ZX09102301-018).

Conflicts of Interest

No potential conflicts of interest were disclosed.

Author information

Authors and Affiliations

  1. Stem Cell Research Center and Department of Cell Biology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China

    Yang Li & Xujie Liu

  2. Medical Isotopes Research Center, Peking University, Beijing, 100191, China

    Zhaofei Liu, Chengyan Dong, Peng He, Xujie Liu, Bing Jia & Fan Wang

  3. Department of Radiation Medicine, School of Basic Medical Sciences, Peking University, Beijing, 100191, China

    Zhaofei Liu, Chengyan Dong, Bing Jia & Fan Wang

  4. Department of Nuclear Medicine, Peking Union Medical College Hospital, Beijing, 100857, China

    Zhaohui Zhu & Fang Li

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  1. Yang Li
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  2. Zhaofei Liu
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  4. Peng He
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  8. Fang Li
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Correspondence to Zhaofei Liu or Fan Wang.

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Li, Y., Liu, Z., Dong, C. et al. Noninvasive Detection of Human-Induced Pluripotent Stem Cell (hiPSC)-Derived Teratoma with an Integrin-Targeting Agent 99mTc-3PRGD2. Mol Imaging Biol 15, 58–67 (2013). https://doi.org/10.1007/s11307-012-0571-1

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