DOI QR코드

DOI QR Code

Teratoma Formation in Immunocompetent Mice After Syngeneic and Allogeneic Implantation of Germline Capable Mouse Embryonic Stem Cells

  • Aldahmash, Abdullah (Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University and King Khalid University Hospital) ;
  • Atteya, Muhammad (Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University and King Khalid University Hospital) ;
  • Elsafadi, Mona (Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University and King Khalid University Hospital) ;
  • Al-Nbaheen, May (Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University and King Khalid University Hospital) ;
  • Al-Mubarak, Husain Adel (Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University and King Khalid University Hospital) ;
  • Vishnubalaji, Radhakrishnan (Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University and King Khalid University Hospital) ;
  • Al-Roalle, Ali (Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University and King Khalid University Hospital) ;
  • Al-Harbi, Suzan (Biology Department, College of Science, King Abdulaziz University) ;
  • Manikandan, Muthurangan (Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University and King Khalid University Hospital) ;
  • Matthaei, Klaus Ingo (Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University and King Khalid University Hospital) ;
  • Mahmood, Amer (Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University and King Khalid University Hospital)
  • Published : 2013.10.30

Abstract

Background: Embryonic stem cells (ESCs) have the potential to form teratomas when implanted into immunodeficient mice, but data in immunocompetent mice are limited. We therefore investigated teratoma formation after implantation of three different mouse ESC (mESC) lines into immunocompetent mice. Materials and Methods: BALB/c mice were injected with three highly germline competent mESCs (129Sv, BALB/c and C57BL/6) subcutaneously or under the kidney capsule. After 4 weeks, mice were euthanized and examined histologically for teratoma development. The incidence, size and composition of teratomas were compared using Pearson Chi-square, t-test for dependent variables, one-way analysis of variance and the nonparametric Kruskal-Wallis analysis of variance and median test. Results: Teratomas developed from all three cell lines. The incidence of formation was significantly higher under the kidney capsule compared to subcutaneous site and occurred in both allogeneic and syngeneic mice. Overall, the size of teratoma was largest with the 129Sv cell line and under the kidney capsule. Diverse embryonic stem cell-derived tissues, belonging to the three embryonic germ layers, were encountered, reflecting the pluripotency of embryonic stem cells. Most commonly represented tissues were nervous tissue, keratinizing stratified squamous epithelium (ectoderm), smooth muscle, striated muscle, cartilage, bone (mesoderm), and glandular tissue in the form of gut- and respiratory-like epithelia (endoderm). Conclusions: ESCs can form teratomas in immunocompetent mice and, therefore, removal of undifferentiated ESC is a pre-requisite for a safe use of ESC in cell-based therapies. In addition the genetic relationship of the origin of the cell lines to the ability to transplant plays a major role.

Keywords

Mouse embryonic stem cells;teratoma;immunocompetent;syngeneic;allogeneic

References

  1. Mahmood A, Harkness L, Schroder HD, Abdallah BM, Kassem M (2010). Enhanced differentiation of human embryonic stem cells to mesenchymal progenitors by inhibition of TGF-beta/activin/nodal signaling using SB-431542. J Bone Miner Res, 25, 1216-33. https://doi.org/10.1002/jbmr.34
  2. Matthaei KI (2009). Current developments in genetically manipulated mice. In trends in stem cell biology and technology, H. baharvand, ed. Humana Press, New York, pp 123-36.
  3. Pal R, Mamidi MK, Das AK, Rao M, Bhonde R (2013). Development of a multiplex PCR assay for characterization of embryonic stem cells. Methods Mol Biol, 1006, 147-66. https://doi.org/10.1007/978-1-62703-389-3_11
  4. Meyer S, Nolte J, Opitz L, Salinas-Riester G, Engel W (2010). Pluripotent embryonic stem cells and multipotent adult germline stem cells reveal similar transcriptomes including pluripotency-related genes. Mol Hum Reprod, 16, 846-55. https://doi.org/10.1093/molehr/gaq060
  5. Nussbaum J, Minami E, Laflamme MA, et al (2007). Transplantation of undifferentiated murine embryonic stem cells in the heart: teratoma formation and immune response. FASEB J, 21, 1345-57. https://doi.org/10.1096/fj.06-6769com
  6. Oosterhuis JW, Looijenga LHJ (2005). Testicular germ-cell tumours in a broader perspective. Nat Rev Cancer, 5, 210-22. https://doi.org/10.1038/nrc1568
  7. Press JZ, Kenyon JA, Xue H, et al (2008). Xenografts of primary human gynecological tumors grown under the renal capsule of NOD/SCID mice show genetic stability during serial transplantation and respond to cytotoxic chemotherapy. Gynecol Oncol, 110, 256-64. https://doi.org/10.1016/j.ygyno.2008.03.011
  8. Prokhorova TA, Harkness LM, Frandsen U, et al (2009). Teratoma formation by human embryonic stem cells is site dependent and enhanced by the presence of Matrigel. Stem Cells Dev, 18, 47-54. https://doi.org/10.1089/scd.2007.0266
  9. Cui L, Guan Y, Qu Z, et al (2013). WNT signaling determines tumorigenicity and function of ESC-derived retinal progenitors. J Clin Invest, 123, 1647-61. https://doi.org/10.1172/JCI65048
  10. Dressel R, Schindehutte J, Kuhlmann T, et al (2008). The tumorigenicity of mouse embryonic stem cells and in vitro differentiated neuronal cells is controlled by the recipients' immune response. PLoS ONE, 3, 2622. https://doi.org/10.1371/journal.pone.0002622
  11. Fujikawa T, Oh S-H, Pi L, et al (2005). Teratoma formation leads to failure of treatment for type I diabetes using embryonic stem cell-derived insulin-producing cells. Am J Pathol, 166, 1781-91. https://doi.org/10.1016/S0002-9440(10)62488-1
  12. Lengerke C, Fehm T, Kurth R, et al (2011). Expression of the embryonic stem cell marker SOX2 in early-stage breast carcinoma. BMC Cancer, 11, 42. https://doi.org/10.1186/1471-2407-11-42
  13. Fukuda H, Takahashi J, Watanabe K, et al (2006). Fluorescence-activated cell sorting-based purification of embryonic stem cell-derived neural precursors averts tumor formation after transplantation. Stem Cells, 24, 763-71. https://doi.org/10.1634/stemcells.2005-0137
  14. Ichiryu N, Fairchild PJ (2013). Immune privilege of stem cells. Methods Mol Biol, 1029, 1-16. https://doi.org/10.1007/978-1-62703-478-4_1
  15. Lee M-O, Moon SH, Jeong H-C, et al (2013). Inhibition of pluripotent stem cell-derived teratoma formation by small molecules. Proc Natl Acad Sci USA, 110, 3281-90. https://doi.org/10.1073/pnas.1303669110
  16. Li P, Chen Y, Xiaoming M, et al (2013). Suppression of malignancy by Smad3 in mouse embryonic stem cell formed teratoma. Stem Cell Rev, [Epub ahead of print].
  17. Lopez RM, Murcia DB (2008). First description of malignant retrobulbar and intracranial teratoma in a lesser kestrel (Falco naumanni). Avian Pathol, 37, 413-4. https://doi.org/10.1080/03079450802216660
  18. Lukovic D, Stojkovic M, Moreno-Manzano V, Bhattacharya SS, Erceg S (2013). Perspectives and future directions of human pluripotent stem cell-based therapies. Lessons from Geron's clinical trial for spinal cord injury. Stem Cells Dev, [Epub ahead of print].
  19. Magliocca JF, Held IKA, Odorico JS (2006). Undifferentiated murine embryonic stem cells cannot induce portal tolerance but may possess immune privilege secondary to reduced major histocompatibility complex antigen expression. Stem Cells Dev, 15, 707-17. https://doi.org/10.1089/scd.2006.15.707
  20. Abdullah Z, Saric T, Kashkar H, et al (2007). Serpin-6 expression protects embryonic stem cells from lysis by antigen-specific CTL. J Immunol, 178, 3390-9. https://doi.org/10.4049/jimmunol.178.6.3390
  21. Baharvand H, Matthaei KI (2004). Culture condition difference for establishment of new embryonic stem cell lines from the C57BL/6 and BALB/c mouse strains. In vitro Cell Dev Biol Anim, 40, 76-81. https://doi.org/10.1290/1543-706X(2004)040<0076:CCDFEO>2.0.CO;2
  22. Almstrup K, Sonne SB, Hoei-Hansen CE, et al (2006). From embryonic stem cells to testicular germ cell cancer-- should we be concerned? Int J Androl, 29, 211-8. https://doi.org/10.1111/j.1365-2605.2005.00643.x
  23. Amariglio N, Hirshberg A, Scheithauer BW, et al (2009). Donor-derived brain tumor following neural stem cell transplantation in an ataxia telangiectasia patient. PLoS Med, 6, 1000029.
  24. Arnhold S, Klein H, Semkova I, Addicks K, Schraermeyer U (2004). Neurally selected embryonic stem cells induce tumor formation after long-term survival following engraftment into the subretinal space. Invest Ophthalmol Vis Sci, 45, 4251-5. https://doi.org/10.1167/iovs.03-1108
  25. Baker DEC, Harrison NJ, Maltby E, et al (2007). Adaptation to culture of human embryonic stem cells and oncogenesis in vivo. Nat Biotechnol, 25, 207-15. https://doi.org/10.1038/nbt1285
  26. Bustamante-Marin X, Garness JA, Capel B (2013). Testicular teratomas: an intersection of pluripotency, differentiation and cancer biology. Int J Dev Biol, 57, 201-10. https://doi.org/10.1387/ijdb.130136bc
  27. Campbell HD, Fountain S, McLennan IS, et al (2002). Fliih, a gelsolin-related cytoskeletal regulator essential for early mammalian embryonic development. Mol Cell Biol, 22, 3518-26. https://doi.org/10.1128/MCB.22.10.3518-3526.2002
  28. Cooke MJ, Stojkovic M, Przyborski SA (2006). Growth of teratomas derived from human pluripotent stem cells is influenced by the graft site. Stem Cells Dev, 15, 254-9. https://doi.org/10.1089/scd.2006.15.254
  29. Przyborski SA (2005). Differentiation of human embryonic stem cells after transplantation in immune-deficient mice. Stem Cells, 23, 1242-50. https://doi.org/10.1634/stemcells.2005-0014
  30. Swijnenburg R-J, Tanaka M, Vogel H, et al (2005). Embryonic stem cell immunogenicity increases upon differentiation after transplantation into ischemic myocardium. Circulation, 112, 166-72.
  31. Riess P, Molcanyi M, Bentz K, et al (2007). Embryonic stem cell transplantation after experimental traumatic brain injury dramatically improves neurological outcome, but may cause tumors. J Neurotrauma, 24, 216-25. https://doi.org/10.1089/neu.2006.0141
  32. Sadraei H, Abtahi SR, Nematollahi M, et al (2009). Assessment of potassium current in Royan B(1) stem cell derived cardiomyocytes by patch-clamp technique. Res Pharm Sci, 4, 85-97.
  33. Stojkovic P, Lako M, Stewart R, et al (2005). An autogeneic feeder cell system that efficiently supports growth of undifferentiated human embryonic stem cells. Stem Cells, 23, 306-14. https://doi.org/10.1634/stemcells.2004-0137
  34. Szabo P, Mann JR (1994). Expression and methylation of imprinted genes during in vitro differentiation of mouse parthenogenetic and androgenetic embryonic stem cell lines. Development, 120, 1651-60.
  35. Thomson JA, Itskovitz-Eldor J, Shapiro SS, et al (1998). Embryonic stem cell lines derived from human blastocysts. Science, 282, 1145-7. https://doi.org/10.1126/science.282.5391.1145
  36. Wakitani S, Takaoka K, Hattori T, et al (2003). Embryonic stem cells injected into the mouse knee joint form teratomas and subsequently destroy the joint. Rheumatology (Oxford), 42, 162-5. https://doi.org/10.1093/rheumatology/keg024
  37. Wong DJ, Liu H, Ridky TW, et al (2008). Module map of stem cell genes guides creation of epithelial cancer stem cells. Cell Stem Cell, 2, 333-44. https://doi.org/10.1016/j.stem.2008.02.009
  38. Xie X, Cao F, Sheikh AY, et al (2007). Genetic modification of embryonic stem cells with VEGF enhances cell survival and improves cardiac function. Cloning Stem Cells, 9, 549-63. https://doi.org/10.1089/clo.2007.0032
  39. Yang T, Riehl J, Esteve E, et al (2006). Pharmacologic and functional characterization of malignant hyperthermia in the R163C RyR1 knock-in mouse. Anesthesiology, 105, 1164-75. https://doi.org/10.1097/00000542-200612000-00016
  40. Zhang WY, de Almeida PE, Wu JC (2012). Teratoma formation: A tool for monitoring pluripotency in stem cell research. In 'StemBook', (Cambridge (MA): Harvard Stem Cell Institute).

Cited by

  1. An application of embryonic skin cells to repair diabetic skin wound: A wound reparation trail vol.239, pp.12, 2014, https://doi.org/10.1177/1535370214542067
  2. Tissue-Engineering Approaches to Restore Kidney Function vol.15, pp.10, 2015, https://doi.org/10.1007/s11892-015-0643-0
  3. Qualitative and Quantitative Analysis of MR Imaging Findings in Patients with Middle Cerebral Artery Stroke Implanted with Mesenchymal Stem Cells vol.36, pp.6, 2015, https://doi.org/10.3174/ajnr.A4232