Skip to main content
NCBI home page
Cytotechnology logoLink to Cytotechnology
. 1997 Jan;23(1-3):87–93. doi: 10.1023/A:1007971703392

Apoptosis and its control in cell culture systems

RP Singh 1, G Finka 1, AN Emery 1, M Al-Rubeai 1,✉
PMCID: PMC3449870  PMID: 22358524

Abstract

Apoptosis is a form of programmed cell death which exhibits highly distinctive morphology. Research activity in this area has increased substantially in recent years, primarily due to the realisation that disregulation of apoptosis is involved in the development of a number of pathological conditions, including cancer and AIDS. However, it is now clear that apoptosis also represents the dominant form of cell death during the culture of industrially important cell lines. This review focuses on the induction of apoptosis during industrial cell cultures as well as the effects of the apoptosis suppresser gene bcl-2 on cell survival in conditions relevant to bioreaction environments. We also present new data which demonstrates that bcl-2 can protect cells from apoptosis induced by oxygen deprivation, a finding which has important implications for large scale and intensive cultivation of cells. We also describe experiments which suggest that bcl-2 can reduce the specific nutrient consumption rate of cells.

Full Text

The Full Text of this article is available as a PDF (83.3 KB).

References

  1. Al-Rubeai M, Mills D, Emery AN. Electron microscopy of hybridoma cells with special regard to monoclonal antibody production. Cytotechnol. 1990;4:13–28. doi: 10.1007/BF00148807. [DOI] [PubMed] [Google Scholar]
  2. Al-Rubeai M, Emery AN, Chalder S, Jan DC. Specific antibody productivity and the cell cycle comparisons of batch, continuous and perfusion cultures. Cytotechnol. 1992;9:85–97. doi: 10.1007/BF02521735. [DOI] [PubMed] [Google Scholar]
  3. Ameisen JC. Programmed cell death and AIDS: from hypothesis to experiment. Immunol Today. 1992;13:388–391. doi: 10.1016/0167-5699(92)90086-M. [DOI] [PubMed] [Google Scholar]
  4. Cohen JJ. Overview: Mechanisms Of Apoptosis. Immunol Today. 1993;14:126–138. doi: 10.1016/0167-5699(93)90214-6. [DOI] [PubMed] [Google Scholar]
  5. Cotter T, Al-Rubeai M. Cell death (apoptosis) in cell culture systems. Trends Biotechnol. 1995;13:150–155. doi: 10.1016/S0167-7799(00)88926-X. [DOI] [PubMed] [Google Scholar]
  6. Danheiser SL. Apoptosis draws biotech/big pharma interest. Genet Eng News. 1996;16(2):1. [Google Scholar]
  7. Farbman AI. Electron microscopic study of plate fusion in mouse embryos. Devel Biol. 1968;18:93–116. doi: 10.1016/0012-1606(68)90038-9. [DOI] [PubMed] [Google Scholar]
  8. Finkel TH, Tudor-Williams G, Banda NK, Cotton MF, Curiel T, Monks C, Baba TW, Ruprecht RM, Kupfer A. Apoptosis occurs predominantly in bystander cells and not in productively infected cells of HIV-and SIV-infected lymph nodes. Nature Med. 1995;1:129–134. doi: 10.1038/nm0295-129. [DOI] [PubMed] [Google Scholar]
  9. Franek F. Starvation-induced programmed death of hybridoma cells: Prevention by amino acid mixtures. Biotechnol. 1995;45:86–90. doi: 10.1002/bit.260450112. [DOI] [PubMed] [Google Scholar]
  10. Franek F, Dolnikova J. Nucleosomes occuring in protein-free hybridoma cell cultures. Evidence for programmed cell death. Febs Letters. 1991;248:285–287. doi: 10.1016/0014-5793(91)80705-8. [DOI] [PubMed] [Google Scholar]
  11. Glucksmann A. Cell deaths in normal vertebrate ontogeny. Biol Rev. 1951;26:59–83. doi: 10.1111/j.1469-185x.1951.tb00774.x. [DOI] [PubMed] [Google Scholar]
  12. Harrington EA, Fanidi A, Evan GI. Oncogenes and cell death. Curr Opin Genet Develop. 1994;4:120–129. doi: 10.1016/0959-437x(94)90100-7. [DOI] [PubMed] [Google Scholar]
  13. Itoh Y, Ueda H, Suzuki E. Overexpression of bcl-2, apoptosis supressing gene: prolonged viable culture period of hybridoma and enhanced antibody production. Biotechnol Bioeng. 1995;48:118–122. doi: 10.1002/bit.260480205. [DOI] [PubMed] [Google Scholar]
  14. Kerr JFR, Wyllie AH, Currie AR. Apoptosis: A basic biological phenomenon with wide ranging implications in tissue kinetics. Br J Cancer. 1972;26:239–257. doi: 10.1038/bjc.1972.33. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Laurent-Crawford AG, Krust B, Muller S, Riviere Y, Rey-Cuille MA, Bechet LM, Montagnier L, Hovanessian AG. The cytopathic effect of HIV is associated with apoptosis. Virol. 1991;185:829–839. doi: 10.1016/0042-6822(91)90554-o. [DOI] [PubMed] [Google Scholar]
  16. Mercille S, Massie B. Induction of apoptosis in nutrient limited cultures of hybridoma cells. Biotechnol Bioeng. 1994;44:1140–1154. doi: 10.1002/bit.260440916. [DOI] [PubMed] [Google Scholar]
  17. Mercille S, Massie B. Induction of apoptosis in oxygen-deprived cultures of hybridoma cells. Cytotechnol. 1994;15:117–128. doi: 10.1007/BF00762386. [DOI] [PubMed] [Google Scholar]
  18. Meyaard L, Otto SA, Jonker RR, Mijinster MJ, Keet RPM, Miedema F. PCD of T-cells in HIV-1 infection. Science. 1992;257:217–219. doi: 10.1126/science.1352911. [DOI] [PubMed] [Google Scholar]
  19. Milner AE, Johnson GD, Gregory CD. Prevention of programmed cell death in Burkitt Lymphoma cell lines by Bcl-2-dependent and independent mechanisms. Int J Cancer. 1992;52:636–644. doi: 10.1002/ijc.2910520424. [DOI] [PubMed] [Google Scholar]
  20. Moore A, Donahue CJ, Hooley J, Stocks DL, Bauer KD, Mather J. Apoptosis in CHO cell batch cultures: examination by flow cytometry. Cytotechnol. 1995;17:1–11. doi: 10.1007/BF00749215. [DOI] [PubMed] [Google Scholar]
  21. Oberhammer FA, Wilson JW, Dive C, Morris ID, Hickman JA, Wakeling AE, Walker PR, Sikorska M. Apoptotic death in epithelial cells: Cleavage of DNA to 300 and/or 50 kb fragments prior to or in the absence of internucleosomal fragmentation. EMBOJ. 1993;12:3679–3684. doi: 10.1002/j.1460-2075.1993.tb06042.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Ohyama H, Yamada T, Watanable I. Cell volume reduction associated with interphase death in rat thymocytes. Rad Res. 1981;85:333–339. [PubMed] [Google Scholar]
  23. Piacentini M, Fesus L, Farrace MG, Ghibelli L, Piredda L, Melino G. The expression of “tissue” transglutaminase in two human cancer cell lines is related with the programmed cell death (apoptosis) Euro J Cell Biol. 1991;54:246–254. [PubMed] [Google Scholar]
  24. Raff MC, Barres BA, Brune JF, Coles HS, Ishizaki Y, Jacobson MD. PCD and the control of cell survival: lessons from the nervous system. Science. 1993;262:695–700. doi: 10.1126/science.8235590. [DOI] [PubMed] [Google Scholar]
  25. Sanderson CJ. Morphological aspects of lymphocyte mediated cytotoxicity. In: Clark WR, Goldstein P, editors. Mechanisms of Cell Mediate Cytotoxity. New York: Plenum; 1982. pp. 3–21. [DOI] [PubMed] [Google Scholar]
  26. Saunders JW. Death in embryonic systems. Science. 1966;154:604–612. doi: 10.1126/science.154.3749.604. [DOI] [PubMed] [Google Scholar]
  27. Simpson N, Milner AE and Al-Rubeai M (1996) Prevention of hybridoma cell death by bcl-2 during sub-optimal culture conditions. Biotechnol Bioeng. (In Press). [DOI] [PubMed]
  28. Singh RP, Emery AN and Al-Rubeai M (1996) Enhancement of survivability of mammalian cells by over-expression of the apoptosis suppressor gene bcl-2. Biotechnol Bioeng (In Press). [DOI] [PubMed]
  29. Singh RP, Al-Rubeai M, Gregory CD, Emery AN. Cell death in bioreactors: a role for apoptosis. Biotechnol Bioeng. 1994;44:720–726. doi: 10.1002/bit.260440608. [DOI] [PubMed] [Google Scholar]
  30. Solis-Recendez MG, Pirani A, D'Habit B, Stacey GN, Maugras M. Hybridoma cell cultures continuously undergo apoptosis and reveal a novel 100 bp DNA fragment. J Biotechnol. 1995;38:117–127. doi: 10.1016/0168-1656(94)00120-2. [DOI] [PubMed] [Google Scholar]
  31. Thomas N, Bell PA. Glucocorticoid-induced cell size changes and nuclear fragility in rat thymocytes. Molecular Cellular Endocrinology. 1981;22:71–84. doi: 10.1016/0303-7207(81)90103-9. [DOI] [PubMed] [Google Scholar]
  32. Trump BF, Beresesky IK, Osornio-vargas AR. Cell death and the disease process. In: Bowen ID, Lockshin RA, editors. The role of calcium. New York: Chapman Hall; 1981. pp. 209–42. [Google Scholar]
  33. Tsujimoto Y, Cossman J, Jaff E, Cruce CM. Involvement of the bcl-2 gene in human follicular lymphoma. Science. 1985;228:1440–1443. doi: 10.1126/science.3874430. [DOI] [PubMed] [Google Scholar]
  34. Vaux D, Cory S, Adam J. bcl-2 gene promotes haemopoietic cell sirvival and co-operates with c-myc to immortilize pre-B-cells. Nature. 1988;335:440–442. doi: 10.1038/335440a0. [DOI] [PubMed] [Google Scholar]
  35. Wyllie AH. Glucocorticoid-induced thymocyte apoptosis is associated with endogenous nuclease activation. Nature. 1980;284:555–556. doi: 10.1038/284555a0. [DOI] [PubMed] [Google Scholar]
  36. Wyllie AH. Apoptosis. Br J Cancer. 1993;67:205–208. doi: 10.1038/bjc.1993.40. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Cytotechnology are provided here courtesy of Springer Science+Business Media B.V.

RESOURCES