Amitosis (a- + mitosis), also called 'karyostenosis' or direct cell division or binary fission. It is cell proliferation that does not occur by mitosis, the mechanism usually identified as essential for cell division in eukaryotes. The polyploid macronucleus found in ciliates divides amitotically. While normal mitosis results in a precise division of parental alleles, amitosis results in a random distribution of parental alleles. Ploidy levels of >1000 in some species means both parental alleles can be maintained over many generations, while species with fewer numbers of each chromosome will tend to become homozygous for one or the other parental allele through a process known as phenotypic or allelic assortment.

It does not involve maximal condensation of chromatin into chromosomes, observable by light microscopy as they line up in pairs along the metaphase plate. It does not involve these paired structures being pulled in opposite directions by a mitotic spindle to form daughter cells. Rather, it effects nuclear proliferation without the involvement of chromosomes, unsettling for cell biologists who have come to rely on the mitotic figure as reassurance that chromatin is being equally distributed into daughter cells. The phenomenon of amitosis, even though it is an accepted as occurring in ciliates, continues to meet with skepticism about its role in mammalian cell proliferation, perhaps because it lacks the reassuring iconography of mitosis. Of course the relatively recent discovery of copy number variations (CNV's) in mammalian cells within an organ[1] significantly challenges the age-old assumption that every cell in an organism must inherit an exact copy of the parental genome to be functional. Rather than CNV's resulting from mitosis gone awry, some of this variation may arise from amitosis, and may be both desirable and necessary. Furthermore, it is well to remember that ciliates possess a mechanism for adjusting copy numbers of individual genes during amitosis of the macronucleus.[2]

Amitosis was first described in 1880 by Walther Flemming (more celebrated for describing mitosis) and others[3] (Child, 1907). For a few years thereafter, it was common for biologists to think cells sometimes divided by mitosis but at other times could divide by amitosis. [4] However, since the turn of the twentieth century, amitosis has not received much attention. Using "mitosis in mammalian cells" as a search term in the Medline data-base calls up more than 10,000 studies dealing with mitosis, whereas "amitosis in mammalian cells" retrieves the titles of fewer than 50 papers. Not surprisingly, this absence of data has led many scientists to conclude that amitosis does not exist, or is minimally important—if any means of proliferation can be deemed "minimally important" while the war on cancer is not yet won.

Accordingly, and despite being very much out of fashion, a resurgence of interest in the role of amitosis in mammalian proliferation has been building over the past two to three decades. A review of the resulting literature not only affirms the involvement of amitosis in cell proliferation, it also explores the existence of more than one amitotic mechanism capable of producing "progeny nuclei" without the involvement of "mitotic chromosomes." One form of amitosis involves fissioning, a nucleus splitting in two without the involvement of chromosomes, and has been reported in placental tissue as well as in cells grown from that tissue in rats,[5] in human trophoblasts,[6] and in mouse trophoblasts.[7] Amitosis by fissioning has also been reported in mammalian liver cells[8] and human adrenal cells.[9] Chen and Wan [10] not only reported amitosis in rat liver, but also presented a mechanism for a four-stage amitotic process whereby chromatin threads are reproduced and equally distributed to daughter cells as the nucleus splits in two.

Additional examples of non-mitotic proliferation, and important insights into underlying mechanisms, have resulted from extensive work with polyploid cells. Such cells, long acknowledged to exist, were once believed simply to be anomalous. Accumulating research, including in the liver[11] now suggests that cells containing multiple copies of the genome are importantly involved in a cell's ability to adapt to its environment. A couple of decades of research has shown that polyploid cells are frequently "reduced" to diploid cells by amitosis (Zybina et al.). For instance, naturally occurring polyploid placental cells have been shown capable of producing nuclei with diploid or near-diploid complements of DNA. Furthermore, Zybina and her colleagues[12] have demonstrated that such nuclei, derived from polyploid placental cells, receive one or more copies of a microscopically identifiable region of the chromatin, demonstrating that even without the reassuring iconography of identical chromosomes being distributed into "identical" daughter cells, this particular amitotic process results in representative transmission of chromatin. Studying rat polyploid trophoblasts, this research group has shown that the nuclear envelope of the giant nucleus is involved in this subdivision of a highly polyploid nucleus into low-ploidy nuclei.[13] Polyploid cells are also at the heart of experiments to determine how some cells may survive chemotherapy. Erenpreisa and colleagues have shown that following treatment of cultured cells with mitosis-inhibiting chemicals (similar to what is used in some chemotherapy), a small population of induced polyploid cells survives. Eventually this population can give rise to "normal" diploid cells by formation of polyploid chromatin bouquets that return to an interphase state, and separate into several secondary nuclei.[14] Intriguing phenomena including controlled autophagic degradation of some DNA as well as production of nuclear envelope-limited sheets[15] accompanies the process.[16] Since neither of these depolyploidizations involves mitotic chromosomes, they conform to the broad definition of amitosis.

There are also multiple reports of amitosis occurring when nuclei bud out through the plasma membrane of a polyploid cell. Such a process has been shown to occur in amniotic cells transformed by a virus[17] as well as in mouse embryo fibroblast lines exposed to carcinogens.[18] A similar process called extrusion has been described for mink trophoblasts, a tissue in which fissioning is also observed.[19] Asymmetric cell division has also been described in polyploid giant cancer cells and low eukaryotic cells and reported to occur by the amitotic processes of splitting, budding, or burst-like mechanisms.[20] Similarly, two different kinds of amitosis have been described in monolayers of Ishikawa endometrial cells (Fleming, 2014)

An example of amitosis particularly suited to the formation of multiple differentiated nuclei in a reasonably short period of time has been shown to occur during the differentiation of fluid-enclosing hemispheres called domes from adherent Ishikawa endometrial monolayer cells during an approximately 20-hour period. (Fleming 1995; Fleming, 1999) Aggregates of nuclei from monolayer syncytia become enveloped in mitochondrial membranes, forming structures (mitonucleons) that become elevated as a result of vacuole formation during the initial 6 hours of differentiation (Fleming 1998; Fleming, 2015a). Over the next 4 or 5 hours, chromatin from these aggregated nuclei becomes increasingly pycnotic, eventually undergoing karyolysis and karyorrhexis in the now-elevated predome structures (Fleming, 2015b). In other systems such changes accompany apoptosis but not in the differentiating Ishikawa cells, where the processes appear to accompany changes in DNA essential for the newly created differentiated dome cells. Finally, the chromatin filaments emerging from these processes form a mass from which dozens of dome nuclei are amitotically generated (Fleming, 2015c)over a period of approximately 3 hours with the apparent involvement of nuclear envelope-limited sheets.[21]

That all of this may be an iceberg tip is suggested by research from Walter Thilly's laboratory. Examination of fetal gut (5 to 7 weeks), colonic adenomas, and adenocarcinomas has revealed nuclei that look like hollow bells encased in tubular syncytia. These structures can divide symmetrically by an amitotic nuclear fission process, forming new "bells". Or they can fission asymmetrically resulting in one of seven other nuclear morphotypes, five of which appear to be specific to development since they are rarely observed in adult organisms.[22]

The research that is accumulating about amitosis suggests that such processes are, indeed, involved in the production of the breathtaking 37 trillion or so cells[23] in humans, perhaps particularly during the fetal and embryonic phases of development when the majority of these cells are produced, perhaps within the complexity of implantation, perhaps when large numbers of cells are being differentiated, and perhaps in cancerous cells.

A word of caution: some examples of cell division formerly thought to belong to this "non-mitotic" class, such as the division of some unicellular eukaryotes, may actually occur by the process of "closed mitosis" different from open or semi-closed mitotic processes, all involving mitotic chromosomes and classified by the fate of the nuclear envelope.

ReferencesEdit

  1. ^ O'Huallachain, M.; Karczewski, K. J.; Weissman, S. M.; Urban, A. E.; Snyder, M. P. (2012-10-30). "Extensive genetic variation in somatic human tissues". Proceedings of the National Academy of Sciences. 109 (44): 18018–18023. Bibcode:2012PNAS..10918018O. doi:10.1073/pnas.1213736109. ISSN 0027-8424. PMC 3497787. PMID 23043118.
  2. ^ Prescott, D. M. (June 1994). "The DNA of ciliated protozoa". Microbiological Reviews. 58 (2): 233–267. doi:10.1128/MMBR.58.2.233-267.1994. ISSN 0146-0749. PMC 372963. PMID 8078435.
  3. ^ Macklin, C. C. (June 1916). "Amitosis in Cells Growing in Vitro". The Biological Bulletin. 30 (6): 445–[466]–1. doi:10.2307/1536358. ISSN 0006-3185. JSTOR 1536358.
  4. ^ Holland, Nicholas (2021), "Vicenzo Colucci's 1886 memoir, Intorno alla rigenerazione degli arti e della coda nei tritoni, annotated and translated into English as: Concerning regeneration of the limbs and tail in salamanders", The European Zoological Journal, 88: 837–890
  5. ^ Ferguson, F. G.; Palm, J. (1976-02-15). "Histologic characteristics of cells cultured from rat placental tissue". American Journal of Obstetrics and Gynecology. 124 (4): 415–420. doi:10.1016/0002-9378(76)90103-4. ISSN 0002-9378. PMID 1251862.
  6. ^ Cotte, C.; Easty, G. C.; Neville, A. M.; Monaghan, P. (August 1980). "Preparation of highly purified cytotrophoblast from human placenta with subsequent modulation to form syncytiotrophoblast in monolayer cultures". In Vitro. 16 (8): 639–646. doi:10.1007/bf02619191. ISSN 0073-5655. PMID 7419234. S2CID 20834295.
  7. ^ Kuhn, E. M.; Therman, E.; Susman, B. (May 1991). "Amitosis and endocycles in early cultured mouse trophoblast". Placenta. 12 (3): 251–261. doi:10.1016/0143-4004(91)90006-2. ISSN 0143-4004. PMID 1754574.
  8. ^ David, H.; Uerlings, I. (September 1992). "[Ultrastructure of amitosis and mitosis of the liver]". Zentralblatt für Pathologie. 138 (4): 278–283. ISSN 0863-4106. PMID 1420108.
  9. ^ Magalhães, M. C.; Pignatelli, D.; Magalhães, M. M. (April 1991). "Amitosis in human adrenal cells". Histology and Histopathology. 6 (2): 251–256. ISSN 0213-3911. PMID 1802124.
  10. ^ Chen, Y. Q.; Wan, B. K. (1986). "A study on amitosis of the nucleus of the mammalian cell. I. A study under the light and transmission electron microscope". Acta Anatomica. 127 (1): 69–76. ISSN 0001-5180. PMID 3788448.
  11. ^ Duncan, Andrew W.; Taylor, Matthew H.; Hickey, Raymond D.; Hanlon Newell, Amy E.; Lenzi, Michelle L.; Olson, Susan B.; Finegold, Milton J.; Grompe, Markus (2010-10-07). "The ploidy conveyor of mature hepatocytes as a source of genetic variation". Nature. 467 (7316): 707–710. Bibcode:2010Natur.467..707D. doi:10.1038/nature09414. ISSN 1476-4687. PMC 2967727. PMID 20861837.
  12. ^ Zybina, T. G.; Zybina, E. V.; Kiknadze, I. I.; Zhelezova, A. I. (May 2001). "Polyploidization in the trophoblast and uterine glandular epithelium of the endotheliochorial placenta of silver fox (Vulpes fulvus Desm.), as revealed by the DNA content". Placenta. 22 (5): 490–498. doi:10.1053/plac.2001.0675. ISSN 0143-4004. PMID 11373160.
  13. ^ Zybina, Eugenia V.; Zybina, Tatiana G. (July 2008). "Modifications of nuclear envelope during differentiation and depolyploidization of rat trophoblast cells". Micron (Oxford, England: 1993). 39 (5): 593–606. doi:10.1016/j.micron.2007.05.006. ISSN 0968-4328. PMID 17627829.
  14. ^ Erenpreisa, Jekaterina; Salmina, Kristine; Huna, Anda; Kosmacek, Elizabeth A.; Cragg, Mark S.; Ianzini, Fiorenza; Anisimov, Alim P. (July 2011). "Polyploid tumour cells elicit paradiploid progeny through depolyploidizing divisions and regulated autophagic degradation". Cell Biology International. 35 (7): 687–695. doi:10.1042/CBI20100762. ISSN 1095-8355. PMID 21250945. S2CID 130498.
  15. ^ Olins, A. L.; Buendia, B.; Herrmann, H.; Lichter, P.; Olins, D. E. (1998-11-25). "Retinoic acid induction of nuclear envelope-limited chromatin sheets in HL-60". Experimental Cell Research. 245 (1): 91–104. doi:10.1006/excr.1998.4210. ISSN 0014-4827. PMID 9828104.
  16. ^ Erenpreisa, Jekaterina; Ivanov, Andrey; Cragg, Mark; Selivanova, Galina; Illidge, Timothy (March 2002). "Nuclear envelope-limited chromatin sheets are part of mitotic death". Histochemistry and Cell Biology. 117 (3): 243–255. doi:10.1007/s00418-002-0382-6. ISSN 0948-6143. PMID 11914922. S2CID 7261907.
  17. ^ Walen, Kirsten H. (February 2002). "The origin of transformed cells. studies of spontaneous and induced cell transformation in cell cultures from marsupials, a snail, and human amniocytes". Cancer Genetics and Cytogenetics. 133 (1): 45–54. doi:10.1016/s0165-4608(01)00572-6. ISSN 0165-4608. PMID 11890989.
  18. ^ Sundaram, Meenakshi; Guernsey, Duane L.; Rajaraman, Murali M.; Rajaraman, Rengaswami (February 2004). "Neosis: a novel type of cell division in cancer". Cancer Biology & Therapy. 3 (2): 207–218. doi:10.4161/cbt.3.2.663. ISSN 1538-4047. PMID 14726689.
  19. ^ Isakova, G. K.; Shilova, I. E. (July 2003). "[Frequency ratio of two forms of amitotic division of trophoblast cell nuclei in the mink blastocysts during the period of delayed implantation]". Izvestiia Akademii Nauk. Seriia Biologicheskaia (4): 395–398. ISSN 1026-3470. PMID 12942744.
  20. ^ Zhang, Dan; Wang, Yijia; Zhang, Shiwu (2014). "Asymmetric cell division in polyploid giant cancer cells and low eukaryotic cells". BioMed Research International. 2014: 432652. doi:10.1155/2014/432652. ISSN 2314-6141. PMC 4089188. PMID 25045675.
  21. ^ Olins, A. L.; Buendia, B.; Herrmann, H.; Lichter, P.; Olins, D. E. (1998-11-25). "Retinoic acid induction of nuclear envelope-limited chromatin sheets in HL-60". Experimental Cell Research. 245 (1): 91–104. doi:10.1006/excr.1998.4210. ISSN 0014-4827. PMID 9828104.
  22. ^ Gostjeva, E. V.; Zukerberg, L.; Chung, D.; Thilly, W. G. (2006-01-01). "Bell-shaped nuclei dividing by symmetrical and asymmetrical nuclear fission have qualities of stem cells in human colonic embryogenesis and carcinogenesis". Cancer Genetics and Cytogenetics. 164 (1): 16–24. doi:10.1016/j.cancergencyto.2005.05.005. ISSN 0165-4608. PMID 16364758.
  23. ^ Duncan, Andrew W.; Taylor, Matthew H.; Hickey, Raymond D.; Hanlon Newell, Amy E.; Lenzi, Michelle L.; Olson, Susan B.; Finegold, Milton J.; Grompe, Markus (2010-10-07). "The ploidy conveyor of mature hepatocytes as a source of genetic variation". Nature. 467 (7316): 707–710. Bibcode:2010Natur.467..707D. doi:10.1038/nature09414. ISSN 1476-4687. PMC 2967727. PMID 20861837.

Further readingEdit

Child CM. 1907 Amitosis as a factor in normal and regulatory growth. Anat Anz. 30: 271-97.

Coleman SJ, Gerza L, JonesCJ, Sibley CP, Aplin JD, Heazell AEP. 2013. Syncytial nuclear

Fleming H. 1995 Differentiation in human endometrial cells in monolayer culture: Dependence on a factor in fetal bovine serum J.Cell Biochem. 57:262-270.

Fleming H, Condon R, Peterson G, Guck I, Prescott E, Chatfield K, Duff M. 1998. Role of biotin-containing membranes and nuclear distribution in differentiating human endometrial cells. Journal of Cellular Biochemistry. 71(3): 400-415.

Fleming H. 1999 Structure and function of cultured endometrial epithelial cells. Semin Reprod Endocrinol.17(1):93-106.

Fleming H. 2014 Unusual characteristics of opaque Ishikawa endometrial cells include the envelopment of chromosomes with material containing endogenous biotin in the latter stages of cytokinesis doi:10.7287/peerj.preprints.772v1

Fleming H. 2016a. Mitonucleons formed during Differentiation of Ishikawa Endometrial Epithelial Cells are involved in Vacuole Formation that Elevates Monolayer Cells into Domes. Differentiation of Ishikawa Domes, Part 1, doi:10.7287/peerj.preprints.1728v1

Fleming H. 2016b. Pyknotic chromatin in mitonucleons elevating in syncytia undergo karyorhhexis and karyolysis before coalescing into an irregular chromatin mass: Differentiation of Ishikawa Domes, Part 2, doi:10.7287/peerj.preprints.1729v1

Fleming H. 2016c. Chromatin mass from previously aggregated, pyknotic, and fragmented monolayer nuclei is a source for dome cell nuclei generated by amitosis: Differentiation of Ishikawa Domes, Part 3, doi:10.7287/peerj.preprints.1730v1

Güttinger, S; Laurell, E; Kutay, U (2009), "Orchestrating nuclear envelope disassembly and reassembly during mitosis", Nat Rev Mol Cell Biol 10 (3): 178–191, doi:10.1038/nrm2641, PMID 19234477

Isakova GK, Shilova IE. 2000. Reproduction by "budding" of the trophoblast cells in the mink implanting blastocysts. Dokl Biol Sci. 371:214-6.

Schoenfelder KP, Fox DT 2015 The expanding implications of polyploidy. J Cell Biol. 25;209(4):485-91. doi:10.1083/jcb.201502016.

Thilly WG, Gostjeva EV, Koledova VV, Zukerberg LR, Chung D, Fomina JN, Darroudi F, Stollar BD. 2014. Metakaryotic stem cell nuclei use pangenomic dsRNA/DNA intermediates in genome replication and segregation. Organogenesis. 10(1):44-52. doi:10.4161/org.27684. Epub 2014 Jan 13.

Walen KH. 2004. Spontaneous cell transformation: karyoplasts derived from multinucleated cells produce new cell growth in senescent human epithelial cell cultures. In Vitro Cell Dev Biol Anim. 40(5-6):150-8.

Zybina EV, Zybina TG, Bogdanova MS, Stein GI 2005 Cell Biol Int. 29 (12): 1066-1070