Cultured Cell Experimental Models

  • Naoto TaniEmail author
  • Tomoya Ikeda
  • Shigeki Oritani
  • Tomomi Michiue
  • Takaki Ishikawa
Part of the Current Human Cell Research and Applications book series (CHCRA)


A great advantage of cell culture-based studies is the ability to control the physical/chemical environment, including temperature and oxygen partial pressure, as well as the physiological environment, including the presence of molecules such as hormones and metabolites, by manipulating culture medium composition and ambient conditions. Although the pathophysiology of changes of the physiological and physical/chemical environments in culture systems has not been investigated in detail, we believe that a deeper analysis of the ingredients of culture media and the identification of growth factors necessary for cell proliferation (in other words, characterization of the microenvironment for cells, which is mainly based on culture medium) will provide a deeper understanding of cellular functions and cell–cell interactions.


Cultured cell Forensic Hypoxia/ischemia Death process Oxygen electrode Dissolved oxygen iPS cell 



This article is a summary of portions from all the references. On completing the article, the author expresses his profound appreciation to all collaborators for their contribution to the parts of the contents.


  1. 1.
    Filopoulos D, Cormack SJ, Whyte DG. Normobaric hypoxia increases the growth hormone response to maximal resistance exercise in trained men. Eur J Sport Sci. 2017;17:821–9.CrossRefGoogle Scholar
  2. 2.
    Jung S, Boie G, Doerr HG, Trollmann R. Oxygen-sensitive regulation and neuroprotective effects of growth hormone-dependent growth factors during early postnatal development. Am J Physiol Regul Integr Comp Physiol. 2017;312:R539–48.CrossRefGoogle Scholar
  3. 3.
    Ishikawa T, Michiue T, Maeda H. Evaluation of postmortem serum and cerebrospinal fluid growth hormone levels in relation to the cause of death in forensic autopsy. Hum Cell. 2011;24:74–7.CrossRefGoogle Scholar
  4. 4.
    Yoshida D, Koketshu K, Nomura R, Teramoto A. The CXCR4 antagonist AMD3100 suppresses hypoxia-mediated growth hormone production in GH3 rat pituitary adenoma cells. J Neuro-Oncol. 2010;100:51–64.CrossRefGoogle Scholar
  5. 5.
    Andreassen M, Frystyk J, Faber J, Kristensen LØ, Juul A. Growth hormone (GH) activity is associated with increased serum oestradiol and reduced anti-Müllerian hormone in healthy male volunteers treated with GH and a GH antagonist. Andrology. 2013;1:595–601.CrossRefGoogle Scholar
  6. 6.
    Ishikawa T, Inamori-Kawamoto O, Quan L, Michiue T, Chen JH, Wang Q, Zhu BL, Maeda H. Postmortem urinary catecholamine levels with regard to the cause of death. Leg Med (Tokyo). 2014;16:344–9.CrossRefGoogle Scholar
  7. 7.
    Miyazato T, Ishikawa T, Michiue T, Maeda H. Molecular pathology of pulmonary surfactants and cytokines in drowning compared with other asphyxiation and fatal hypothermia. Int J Legal Med. 2012;126:581–7.CrossRefGoogle Scholar
  8. 8.
    Wang Q, Ishikawa T, Michiue T, Zhu BL, Guan DW, Maeda H. Intrapulmonary aquaporin-5 expression as a possible biomarker for discriminating smothering and choking from sudden cardiac death: a pilot study. Forensic Sci Int. 2012;220:154–7.CrossRefGoogle Scholar
  9. 9.
    Ishikawa T, Quan L, Li DR, Zhao D, Michiue T, Hamel M, Maeda H. Postmortem biochemistry and immunohistochemistry of adrenocorticotropic hormone with special regard to fatal hypothermia. Forensic Sci Int. 2008;179:147–51.CrossRefGoogle Scholar
  10. 10.
    Quan L, Zhu BL, Ishida K, Oritani S, Taniguchi M, Fujita MQ, Maeda H. Intranuclear ubiquitin immunoreactivity of the pigmented neurons of the substantia nigra in fatal acute mechanical asphyxiation and drowning. Int J Leg Med. 2001;115:6–11.CrossRefGoogle Scholar
  11. 11.
    Palmiere C, Tettamanti C, Scarpelli MP, Rousseau G, Egger C, Bongiovanni M. Postmortem biochemical investigation results in situations of fatal mechanical compression of the neck region. Leg Med (Tokyo). 2018;30:59–63.CrossRefGoogle Scholar
  12. 12.
    Pereira DN, Procianoy RS. Effect of perinatal asphyxia on thyroid hormones. J Pediatr (Rio J). 2001;77:175–8.CrossRefGoogle Scholar
  13. 13.
    Hayakawa A, Matoba K, Horioka K, Murakami M, Terazawa K. Appropriate blood sampling sites for measuring Tg concentrations for forensic diagnosis. Leg Med (Tokyo). 2015;17:65–9.CrossRefGoogle Scholar
  14. 14.
    Senol E, Demirel B, Akar T, Gülbahar O, Bakar C, Bukan N. The analysis of hormones and enzymes extracted from endocrine glands of the neck region in deaths due to hanging. Am J Forensic Med Pathol. 2008;29:49–54.CrossRefGoogle Scholar
  15. 15.
    Tamaki K, Sato K, Katsumata Y. Enzyme-linked immunosorbent assay for determination of plasma thyroglobulin and its application to post-mortem diagnosis of mechanical asphyxia. Forensic Sci Int. 1987;33:259–65.CrossRefGoogle Scholar
  16. 16.
    Katsumata Y, Sato K, Oya M, Yada S. Detection of thyroglobulin in blood stains as an aid in the diagnosis of mechanical asphyxia. J Forensic Sci. 1984;29:299–302.PubMedGoogle Scholar
  17. 17.
    Ishikawa T, Michiue T, Zhao D, Komatsu A, Azuma Y, Quan L, Hamel M, Maeda H. Evaluation of postmortem serum and cerebrospinal fluid levels of thyroid-stimulating hormone with special regard to fatal hypothermia. Leg Med (Tokyo). 2009;11(Suppl 1):S228–30.CrossRefGoogle Scholar
  18. 18.
    Dressler J, Mueller E. High thyroglobulin (Tg) concentrations in fatal traumatic brain injuries. Am J Forensic Med Pathol. 2006;27:280–2.CrossRefGoogle Scholar
  19. 19.
    Naicker M, Naidoo S. Expression of thyroid-stimulating hormone receptors and thyroglobulin in limbic regions in the adult human brain. Metab Brain Dis. 2018;33(2):481–9. Scholar
  20. 20.
    Ikeda T, Tani N, Michiue T, Oritani S, Morioka F, Potente S, Ishikawa T. Postmortem histopathological examination of change due to systemic ischemia/hypoxia in the thyroid gland. Forensic Sci Criminol. 2017;2:1–5.CrossRefGoogle Scholar
  21. 21.
    Ishikawa T, Michiue T, Kawamoto O, Seo T, Matsushita S, Maeda H. Histopathology of the thyroid gland in mechanical asphyxia. Rechtsmedizin. 2013;23:319.Google Scholar
  22. 22.
    Ishikawa T, Michiue T, Wang Q, Chen JH, Kawamoto O, Maeda H. Postmortem serum thyroid hormones as possible markers of asphyxia death in forensic autopsy. Rechtsmedizin. 2012;22:281.Google Scholar
  23. 23.
    Mansourian AR. Metabolic pathways of tetraidothyronine and triidothyronine production by thyroid gland: a review of articles. Pak J Biol Sci. 2011;14:1–12.CrossRefGoogle Scholar
  24. 24.
    Bastenie PA, Ermans AM. Thyroiditis and thyroid function. Oxford: Elsevier (Pergamon Press); 2018.Google Scholar
  25. 25.
    Basu M, Pal K, Malhotra AS, Prasad R, Sawhney RC. Free and total thyroid hormones in humans at extreme altitude. Int J Biometeorol. 1995;39:17–21.CrossRefGoogle Scholar
  26. 26.
    Ramirez G, Herrera R, Pineda D, Bittle PA, Rabb HA, Bercu BB. The effects of high altitude on hypothalamic-pituitary secretory dynamics in men. Clin Endocrinol. 1995;43:11–8.CrossRefGoogle Scholar
  27. 27.
    Connors JM, Martin LG. Altitude-induced changes in plasma thyroxine, 3,5,3′-triiodothyronine, and thyrotropin in rats. J Appl Physiol Respir Environ Exerc Physiol. 1982;53:313–5.PubMedGoogle Scholar
  28. 28.
    Li J, Donangelo I, Abe K, Scremin O, Ke S, Li F, Milanesi A, Liu YY, Brent GA. Thyroid hormone treatment activates protective pathways in both in vivo and in vitro models of neuronal injury. Mol Cell Endocrinol. 2017;452:120–30.CrossRefGoogle Scholar
  29. 29.
    Rhee YH, Moon JH, Choi SH, Ahn JC. Low-level laser therapy promoted aggressive proliferation and angiogenesis through decreasing of transforming growth factor-β1 and increasing of Akt/hypoxia inducible factor-1α in anaplastic thyroid cancer. Photomed Laser Surg. 2016;34:229–35.CrossRefGoogle Scholar
  30. 30.
    Ishikawa T, Zhu BL, Maeda H. Effects of therapeutic agents on cellular respiration as an indication of metabolic activity. Hum Exp Toxicol. 2006;25:135–40.CrossRefGoogle Scholar
  31. 31.
    Ishikawa T, Zhu BL, Maeda H. Effect of sodium azide on the metabolic activity of cultured fetal cells. Toxicol Ind Health. 2006;22:337–41.CrossRefGoogle Scholar
  32. 32.
    Amano Y, Okumura C, Yoshida M, Katayama H, Unten S, Arai J, Tagawa T, Hoshina S, Hashimoto H, Ishikawa H. Measuring respiration of cultured cell with oxygen electrode as a metabolic indicator for drug screening. Hum Cell. 1999;12:3–10.PubMedGoogle Scholar
  33. 33.
    Tezuka K, Inada M, Hashimoto H, Ogawa T, Ezure M, Sato E, Okumura C, Arai J-I, Kawamura H, Ishikawa H, Kamoi K. Rapid antibiotics screening method for Actinobacillus actinomycetemcomitans using oxygen electrode system. J Jpn Soc Periodontol. 1999;41:201–9.CrossRefGoogle Scholar
  34. 34.
    Arai J, Yamada K, Yasuda M, Yoshida M, Unten S, Akamatsu M, Ishikawa H. Anticancer susceptibility test method using general-purpose dissolved oxygen meter. Hum Cell. 1998;11:175–8. Japanese.PubMedGoogle Scholar
  35. 35.
    Ishiwata I, Ishiwata C, Soma M, Arai J, Ishikawa H. Establishment of human endometrial adenocarcinoma cell line containing estradiol-17 beta and progesterone receptors. Gynecol Oncol. 1984;17:281–90.CrossRefGoogle Scholar
  36. 36.
    Kasuda S. Elucidation of pathological condition of sepsis by using iPS cells for creation of novel therapy. 2018. (Mar. possible to inspect).
  37. 37.
    Toya SP, Li F, Bonini MG, Gomez I, Mao M, Bachmaier KW, Malik AB. Interaction of a specific population of human embryonic stem cell-derived progenitor cells with CD11b+ cells ameliorates sepsis-induced lung inflammatory injury. Am J Pathol. 2011;178:313–24.CrossRefGoogle Scholar
  38. 38.
    Pérez-Gutthann S, García-Rodríguez LA, Duque-Oliart A, Varas-Lorenzo C. Low-dose diclofenac, naproxen, and ibuprofen cohort study. Pharmacotherapy. 1999;19:854–9.CrossRefGoogle Scholar
  39. 39.
    Verdier F, Chazal I, Descotes J. Anaphylaxis models in the Guinea-pig. Toxicology. 1994;93:55–61.CrossRefGoogle Scholar
  40. 40.
    Cohn JR, Cohn JB, Fellin F, Cantor R. Systemic anaphylaxis from low dose methotrexate. Ann Allergy. 1993;70:384–5.PubMedGoogle Scholar
  41. 41.
    Laroche D, Gomis P, Gallimidi E, Malinovsky JM, Mertes PM. Diagnostic value of histamine and tryptase concentrations in severe anaphylaxis with shock or cardiac arrest during anesthesia. Anesthesiology. 2014;121:272–9.CrossRefGoogle Scholar
  42. 42.
    Palmiere C, Comment L, Mangin P. Allergic reactions following contrast material administration: nomenclature, classification, and mechanisms. Int J Legal Med. 2014;128:95–103.CrossRefGoogle Scholar
  43. 43.
    Mayer DE, Krauskopf A, Hemmer W, Moritz K, Jarisch R, Reiter C. Usefulness of post mortem determination of serum tryptase, histamine and diamine oxidase in the diagnosis of fatal anaphylaxis. Forensic Sci Int. 2011;212:96–101.CrossRefGoogle Scholar
  44. 44.
    Da Broi U, Moreschi C. Post-mortem diagnosis of anaphylaxis: A difficult task in forensic medicine. Forensic Sci Int. 2011;204:1–5.CrossRefGoogle Scholar
  45. 45.
    Yilmaz R, Yuksekbas O, Erkol Z, Bulut ER, Arslan MN. Postmortem findings after anaphylactic reactions to drugs in Turkey. Am J Forensic Med Pathol. 2009;30:346–9.CrossRefGoogle Scholar
  46. 46.
    Svendsen O, Højelse F, Bagdon RE. Tests for local toxicity of intramuscular drug preparations: comparison of in vivo and in vitro methods. Acta Pharmacol Toxicol (Copenh). 1985;56:183–90.CrossRefGoogle Scholar
  47. 47.
    Aikawa N, Kunisato A, Nagao K, Kusaka H, Takaba K, Ohgami K. Detection of thalidomide embryotoxicity by in vitro embryotoxicity testing based on human iPS cells. J Pharmacol Sci. 2014;124:201–7.CrossRefGoogle Scholar
  48. 48.
    Sasaki E, Yokoi T. Role of cytochrome P450-mediated metabolism and involvement of reactive metabolite formations on antiepileptic drug-induced liver injuries. J Toxicol Sci. 2018;43:75–87.CrossRefGoogle Scholar
  49. 49.
    Wang R, Qi X, Yoshida EM, Méndez-Sánchez N, Teschke R, Sun M, Liu X, Su C, Deng J, Deng H, Hou F, Guo X. Clinical characteristics and outcomes of traditional Chinese medicine-induced liver injury: a systematic review. Expert Rev Gastroenterol Hepatol. 2018;12:425–34.CrossRefGoogle Scholar
  50. 50.
    Devarbhavi H, Patil M, Reddy VV, Singh R, Joseph T, Ganga D. Drug-induced acute liver failure in children and adults: results of a single-centre study of 128 patients. Liver Int. 2018;38(7):1322–9. Scholar
  51. 51.
    Tan EH, Low EXS, Dan YY, Tai BC. Systematic review and meta-analysis of algorithms used to identify drug-induced liver injury (DILI) in health record databases. Liver Int. 2018;38(4):742–53. Scholar
  52. 52.
    Sebode M, Schulz L, Lohse AW. “Autoimmune(-Like)” drug and herb induced liver injury: new insights into molecular pathogenesis. Int J Mol Sci. 2017;18:e1954.CrossRefGoogle Scholar
  53. 53.
    Heidari R, Niknahad H, Jamshidzadeh A, Abdoli N. Factors affecting drug-induced liver injury: antithyroid drugs as instances. Clin Mol Hepatol. 2014;20:237–48.CrossRefGoogle Scholar
  54. 54.
    Mitchell SJ, Hilmer SN. Drug-induced liver injury in older adults. Ther Adv Drug Saf. 2010;1:65–77.CrossRefGoogle Scholar
  55. 55.
    Verma N, Kumar P, Mitra S, Taneja S, Dhooria S, Das A, Duseja A, Dhiman RK, Chawla Y. Drug idiosyncrasy due to pirfenidone presenting as acute liver failure: case report and mini-review of the literature. Hepatol Commun. 2017;2:142–7.CrossRefGoogle Scholar
  56. 56.
    Katarey D, Verma S. Drug-induced liver injury. Clin Med (Lond). 2016;16(Suppl 6):s104–9.CrossRefGoogle Scholar
  57. 57.
    Gómez-Lechón MJ, Tolosa L, Donato MT. Metabolic activation and drug-induced liver injury: in vitro approaches for the safety risk assessment of new drugs. J Appl Toxicol. 2016;36:752–68.CrossRefGoogle Scholar
  58. 58.
    Uetrecht J. Immunoallergic drug-induced liver injury in humans. Semin Liver Dis. 2009;29:383–92.CrossRefGoogle Scholar
  59. 59.
    Takayama K, Kawabata K, Nagamoto Y, Kishimoto K, Tashiro K, Sakurai F, Tachibana M, Kanda K, Hayakawa T, Furue MK, Mizuguchi H. 3D spheroid culture of hESC/hiPSC-derived hepatocyte-like cells for drug toxicity testing. Biomaterials. 2013;34:1781–9.CrossRefGoogle Scholar
  60. 60.
    Takayama K, Morisaki Y, Kuno S, Nagamoto Y, Harada K, Furukawa N, Ohtaka M, Nishimura K, Imagawa K, Sakurai F, Tachibana M, Sumazaki R, Noguchi E, Nakanishi M, Hirata K, Kawabata K, Mizuguchi H. Prediction of interindividual differences in hepatic functions and drug sensitivity by using human iPS-derived hepatocytes. Proc Natl Acad Sci U S A. 2014;111:16772–7.CrossRefGoogle Scholar
  61. 61.
    Li S, Guo J, Ying Z, Chen S, Yang L, Chen K, Long Q, Qin D, Pei D, Liu X. Valproic acid-induced hepatotoxicity in Alpers syndrome is associated with mitochondrial permeability transition pore opening-dependent apoptotic sensitivity in an induced pluripotent stem cell model. Hepatology. 2015;61:1730–9.CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Naoto Tani
    • 1
    • 2
    Email author
  • Tomoya Ikeda
    • 1
    • 2
  • Shigeki Oritani
    • 1
  • Tomomi Michiue
    • 1
    • 2
  • Takaki Ishikawa
    • 1
    • 2
  1. 1.Department of Legal MedicineOsaka City University Medical SchoolAbenoJapan
  2. 2.Forensic Autopsy SectionMedico-legal Consultation and Postmortem Investigation Support Center (MLCPI-SC)OsakaJapan

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