Introduction

Fish comprise 48% of the known vertebrate species (Altman and Dittmer 1972), which represents an enormous resource for the development of vertebrate cell and tissue models for use in biomedical sciences. The physiology and blood plasma constituents of teleost fish are much like those of terrestrial vertebrates; therefore, the methodology for culture of cells is also similar. Nevertheless, fish cell culture differs somewhat from mammalian cell culture in having a wider temperature range for incubation. Also, osmolality must be adjusted upward for fish of marine origin. Because of lower metabolic rates than eurythermic cells, fish cells can be maintained with little care for long periods of time. Thus, permanent fish cell lines, in contrast to the mammalian cells, are easier to maintain and manipulate, and unlike primary cultures, produce highly reproducible results (Wolf and Quimby 1976).

Early cultures of primary cells may represent a more appropriate model of tissues in vivo (Freshney 2005). The production of short-term primary cultures, however, suffers from a lack of reproducibility in the initiation, and homogeneity of cultures that limit their application (Bols et al. 1994). Established cell lines are typically derived from malignant tumors, or through spontaneous transformation, or through oncogenic immortalization and such changes bring about continuously proliferating (immortal) cell lines (Freshney 2005).

The rainbow trout, Salmo gairdneri gonadal cell line, RTG-2 developed by Wolf and Quimby (1962) was the first permanent cell line of fish origin. Since then many more cell lines have been established. The first review of all fish cell and tissue culture was compiled by Wolf and Mann (1980). A comprehensive global list of freshwater and marine fish cell lines was last published in 1994 by Fryer and Lannan and reported some 159 fish cell lines, established from 74 species or hybrids representing 34 families of fish. We have reviewed the research work carried out since this review and report 124 new established cell lines during this period. Among the cell lines listed, more than 60% were established from Asian region, which contributes more than 80% of total fish production. This include 59 cell lines from 19 freshwater, (Table 1), 53 from 22 marine (Table 2) and 11 from 3 brackish water (Table 3) fishes.

Table 1 Details of cell lines developed from different freshwater fishes from 1994 to 2010
Table 2 Details of cell lines developed from different marine fishes from 1994 to 2010
Table 3 Details of cell lines developed from different brackish water fishes from 1994 to 2010

Establishment of cell lines from different tissues

Most fish cell lines originated from normal tissues viz., skin, gill, heart, liver, kidney, spleen, swim bladder, brain, etc. Particularly, embryos or fins are most frequently listed as the source of the tissues used in the primary culture. After ovary, the second most common tissue used for cultivation is fin, due to its high regenerative ability (Fryer and Lannan 1994). Surprisingly, there are not a high number of cell lines originating from gonadal or ovarian tissues since these tissues would also exhibit high levels of mitosis. Cell lines have also been developed from ovary (Kumar et al. 2001), skin and fin (Lakra and Bhonde 1996), vertebrae (Pombinho et al. 2004), scales (Akimoto et al. 2000), etc. However, only one cell line XM (Barnes et al. 2006) was initiated from skin and fin tissue of fish melanoma; and in some cases, these cells remained tumorogenic in vivo following repeated in vitro passage.

Many fish cell lines have been established from fish tissues for the purpose of detection and isolation of fish viruses. The cell lines from different tissues of different species will be valuable for studying species-specific responses to viral infection at the cellular level. Some pathogenic viruses are known to be organ- or tissue-specific, which makes the establishment of additional cell lines from different organs and tissues of a host species essential for proper monitoring of viral diseases.

Embryonic and larval cells are the most easy to cultivate being mitotically activate. In the past, it was difficult to obtain eggs or fry of some fish species because they are pelagic spawners (Wolf and Quimby 1966). However, due to recent advances, many species, which were previously unavailable in embryonic form, are now routinely cultivated for the aquaculture industry. In recent years, a number of embryonic stem-like cells were established by various workers from fish species. To develop embryonic stem (ES) cell lines and gene targeting technique in fish, extensive studies have been done in small model fishes, such as zebra fish (Danio rerio) and medaka (Oryzias latipes), because they offer the possibility of combining embryological, genetic and molecular analysis of vertebrate development. The ES-like cell lines have been established in medaka (Hong et al. 1996, 2000) and zebrafish (Sun et al. 1995). A pluripotent cell line, LJESl, has been established from blastula-stage embryos of Lateolabrax japonicus, and these cells differentiated into different types of cells after retinoic acid treatment (Chen et al. 2003a). A continuous embryonic (SISE) cell line has been established from blastula-stage embryos of sea bass (Lates calcarifer) (Parameswaran et al. 2006b) and a pluripotent embryonic stem cell line SBES from blastula-stage embryos of sea bass (Lates calcarifer) (Parameswaran et al. 2006c) and catfish (Heteropneustes fossilis) (Lakra 2010).

Media and additives

Nowadays, the commercialization of technology like ready to use sterile plastic wares and tissue culture media, enzyme solutions, other reagents could overcome the problems in the media preparations like pH, osmolality, sterility, anchorage of cells, nutrients. In general, most fish cultures use media developed for mammalian cell culture. Eagle’s Minimal Essential Medium (EMEM) supplemented with fetal bovine serum (FBS) comes close to being an all purpose culture medium for the cells of mammals, birds, reptiles, amphibians and of course fish (Wolf and Quimby 1966). Other media routinely used in fish culture are Glasgow MEM, Hank’s MEM (HMEM) and Leibovitz L-15 medium (L-15). An amino acid-rich nutrient medium such as L-15 that does not require CO2 buffering (Leibovitz 1963) has been successfully used with fish cell lines, thus CO2 incubators are not necessary, and cells can be grown conveniently in any undisturbed areas. Due to this advantage, more than 80% of the cell lines established after 1994 used Leibovitz L-15 media. However, some primary cell lines have had specific culture medium designed to optimize growth during development of the primary culture (Wang et al. 1995).

Fetal bovine serum (FBS) seems to be the most popular choice of supplements with the tissue culture media as it is easy to obtain in large volumes and due to the presence of known and unknown growth factors. Wolf and Quimby (1966) quoted instances in which other types of serum have been used but the results appeared to be of mixed benefits. Fish serum was used (<1%) in combination with FBS in developing fish cell lines (Chen et al. 2004; Lakra et al. 2006a). Serum concentration can also have an effect on primary cultures. Throughout the literature, concentration varies from 5% to as high as 20%. Serum concentrations are not usually much higher than this, as there is evidence that high serum concentrations may inhibit cell growth (Freshney 2005).

Most examples of additives to media are in serum-free or reduced media replacing substances that serum would normally provide (Wang et al. 1995). However, that does not entirely discount the possibility of using further additives to media already supplemented with serum. Kumar et al. (2001) used a large list of additives for example, fish muscle extract, sucrose, prawn shell extract, which were explored during developing a primary culture from ovary tissue of African catfish.

Miller et al. (1994) detailed the use of chemical mitogens used to establish suspension cultures from leukocytes. Cell cultures exhibited a strong proliferative response after exposure to the mitogens. Faisal et al. (1995) exposed cultured liver cells to plant-derived mitogens that stimulated DNA synthesis (indicative of cell proliferation). Various growth factors such as mammalian epidermal growth factor (mEGF) (Watanabe et al. 1987), basic fibroblast growth factor (bFGF) (Chen et al. 2004) had been used to stimulate growth of fish cell lines, and bFGF is a potent mitogen for embryonic stem cells derived from Oryzias latipes (Hong et al. 1996) and sea perch (Chen et al. 2003b), lymphoid cells from Penaeus monodon (Hsu et al. 1995), embryonic cells from Paralichthys olivaceus (Chen et al. 2004).

Immortalization of cells

Normal somatic cells have a finite life span and become senescent after a predictable number of cell divisions (Hayflick and Moorehead 1961). Cellular senescence is triggered by two interdependent mechanisms. One induces cell cycle arrest and is controlled by two tumor suppressor pathways, p19ARF/p53 and p16INK4a/Rb (Kiyono et al. 1998). The second is a critical shortening of the telomeres due to the end-replication problem in chromosome replication (Aviv and Harley 2001). It has been documented that a small number of cells arise spontaneously immortalized by a set of genetic alterations. The alterations most frequently observed in immortalized cells are loss of functional Rb (retinoblastoma) or p53 proteins that control two major cell cycle checkpoints (Bodnar et al. 1998). A number of viral oncogenes, including simian virus-40 (SV40) large T-antigen, adenovirus E1A and E1B and polyoma T-antigen, also immortalize cells of a variety of species (Katakura et al. 1998). A catalytic subunit of telomerase ribonucleoprotein (TERT) with reverse transcriptase activity synthesizes and maintains the telomeres, helping cells escape replicative senescence caused by the shortening of telomeres (Bodnar et al. 1998). The preferred method to immortalize cells is through expression of the telomerase reverse transcriptase protein (TERT) (Takakura et al. 1999), particularly those cells most affected by telomere length (e.g., human). Analysis of several telomerase-immortalized cell lines has verified that the cells maintain a stable genotype and retain critical phenotypic markers. A eukaryotic expression plasmid containing the hTERT cDNA is available in ATCC (catalog number ATCC® MBA-141), which will enable researchers to immortalize their own cells.

On the other hand, cell immortalization techniques have attracted enthusiastic attention because they have provided us with cell clones that usually show continual possibility, excellent revitalization after storage and ease of handling in culture. These techniques were mostly used in developing immortal cell lines in humans and other mammalians. But Barker et al. (2000) documented for the first time that the channel catfish long-term leukocyte lines constitutively expressed high levels of telomerase activity. A United States patent (Number. US 6,436,702 B1) was issued for the immortal cell line (spontaneously transformed) derived from grouper Epinephelus coioides to Shau-Chi Chi in 2002. In this patent, the monitoring of the transformation of cells, which was characterized by a change in chromosome number distribution, plating efficiency, FBS requirements and the immortalization, was not induced by any methods.

Cross-contamination and over passage

The ease of handling and simple growth requirements make cross-contamination of cell lines a more likely possibility. Fish cell lines are relatively easy to culture, and most have simple growth requirements that make cross-contamination a potential problem. Cell line contamination is not an uncommon incident in laboratories handling more than one cell lines, and many reports have been made on cross-contamination of mammalian cell lines (Parodi et al. 2002). Although problems of misidentification and cross-contamination of fish cell lines have rarely been reported, these are issues of concern for cell culturists that can make scientific results and their reproducibility unreliable. Human cell lines have been reported contaminated with simian cells or murine cells or even other human cells, most ubiquitously, HeLa cells (Tokiwa et al. 1989). Although cross-contamination of fish cells with other cell types has not been widely reported, Perry et al. (2001) conveyed the identification of a cell line dubbed Clone 1A believed to be derived from rainbow trout as being CHSE-214, a cell line derived from Chinook salmon embryos (Lannan et al. 1984). Accordingly, awareness of good laboratory practices and careful vigilance with fish cell cultures as detailed by Lannan (1994) should be followed to avoid confusion of cell lines. The problem of intraspecies and interspecies cross-contamination among cell lines has been recognized for half a century, and although reviews have been published, evidence of continued use of misidentification and cellular cross-contamination of cell cultures has not declined (Buehring et al. 2004).

In addition, cell lines maintained in culture over a long period of time may experience mutations that alter the original functional characteristics of the cell lines, identified at earlier passage levels (Yu et al. 1997). Furthermore, cell lines do not behave similarly with increased passage number (Hughes et al. 2007). Long-term subculturing places selective pressure on cell line traits leading to, for example, faster growing cells that eventually overrun slower proliferators in the population.

Authentication

When cell lines are obtained from colleagues, they often lack verification or documentation about the condition or passage number of the lines. This practice increases the likelihood that inferior, mal-performing cultures are used, leading to results that may not be accurate or reproducible (Wenger et al. 2004). Methodologies for characterizing fish cell lines have included random amplified polymorphic DNA methods (RAPD) (Matsuo et al. 1999) and microsatellite DNA profiling (Perry et al. 2001), mitochondrial 16S and 18S rRNA and sequence analysis (Ahmed et al. 2009a), which has proven useful for identifying a handful of fish cell lines. A simple proteomic approach has been made to identify several fish cell lines derived from tissues of the same or different species. Protein expression signatures (PES) of the evaluated fish cell lines have been developed using 2-DE and image analysis, and it could thus serve as an additional, valuable and reliable technique for the identification of fish cell lines (Wagg and Lee 2005).

Applications

The availability of fish cell lines, since the 1960s, has begun to make impacts in scientific research, but at a much slower rate than with mammalian cell lines. Early work with fish cell lines was initiated with RTG-2, mainly for virological studies (Wolf and Quimby 1962). Fish cell lines are also finding roles in areas with impacts beyond that of the diseases of fish and are providing important contributions in studies relating to toxicology, carcinogenesis, genetic regulation and expression and DNA replication and repair. In the almost 50 year since then, fish cell lines have grown in number covering a wide variety of species and tissues of origin and an array of applications. Fish immunology (Bols et al. 2001), toxicology (Bahich and Borenfreund 1991), ecotoxicology (Schirmer 2006), endocrinology (Bols and Lee 1991), virology (Wolf 1988), biomedical research (Hightower and Renfro 1988), disease control (Villena 2003), biotechnology and aquaculture (Bols and Lee 1991) and radiation biology (Ryan et al. 2008) are some of the areas in which fish cell lines have made significant contributions.

As exogenous DNA delivery of cultured cell is very useful for both basic research and biotechnological applications, it is necessary to determine the transfection efficiency and gene expression on newly developed cell lines. Various workers observed significant fluorescent signals when the cell lines were transfected with pEGFP vector DNA, indicating their potential utility for transgenic and genetic manipulation studies (Qin et al. 2006; Ye et al. 2006; Parameswaran et al. 2007; Zhou et al. 2007; Ahmed et al. 2008; Ku et al. 2009).

A common method for determining whether a virus is present in a healthy fish population is to attempt to isolate it in an appropriate cell line. A cell line will also allow further study of viruses isolated in disease outbreaks. The different cell lines were tested for the susceptibility to various viruses. Lai et al. (2003) found that besides these four cell lines, previously established grouper brain, kidney and liver cell lines were also used for a viral susceptibility study, which showed that all the cell lines were sensitive to grouper iridovirus, whereas only brain, fin and liver cell lines were susceptible to the yellow grouper nervous necrosis virus (a nodavirus). Five fish viruses were tested on this cell line to determine its susceptibility to these viruses and this was found to be susceptible to MABV NC1 and nodavirus, and the infection was confirmed by RT-PCR and CPE. (Hameed et al. 2006). The SIGE cell line was found to be susceptible to nodavirus, MABV NC-1 and Y6, (Parameswaran et al. 2007). PBLE was susceptible to Chum salmon reovirus (CSV) and supported CSV replication. (Dewitte-Orr et al. 2006). GS cell cultures showed advanced cytopathic effects after infection with a pathogenic grouper iridovirus (Singapore grouper iridovirus, SGIV) or with a grouper nodavirus (Epinephelus tauvina nervous necrosis virus, ETNNV) (Qin et al. 2006). GBC4 cells were susceptible to GSIV and GNNV infection (Wen et al. 2008).

In addition to testing the virus susceptibility on cell lines, several bacterial toxins have also been tested on different cell lines. All three cell lines RGB, RGG and RGH were found sensitive to the extra cellular products of Photobacterium damselae ssp. piscicida (Ku et al. 2009). The bacterial extra cellular products from Aeromonas sp., or Vibrio anguillarum were found to be toxic to this SICH cell line (Ahmed et al. 2009a). The RE and CB cell lines were not susceptible to four marine fish viruses. Extra cellular products from Aeromonas sp. were toxic to the cell lines (Ahmed et al. 2009b).

Repository of cell lines

To date, out of over 3,400 cell lines deposited at the American Type Culture Collection (ATCC), only 43 cell lines could be found that are of aquatic animals, and only 17 fish cell lines are usable and available for dissemination to the researchers globally. The European Collection of Cell Cultures (ECACC) currently holds over 40,000 cell lines representing 45 different species and 50 tissue types. But only 21 fish cell lines have been listed here. The reluctance to use cell lines stems from researcher’s misconception that cell lines are mostly derived from transformed cells and that differentiated characteristics of the tissues of origin are not maintained (Sato 2008). This may be the case for many mammalian cell lines, but most cell lines derived from fish tissues have been from normal tissues with a few exceptions, most notably EPC and RTH-149 cells, which were derived, respectively, from an epithelioma and a hepatoma. Fryer and Lannan (1994) noted that 14 out of 159 fish cell lines reported up to 1994 were initiated from tumorigenic tissues, which is less than 10%. Furthermore, among the fish cell lines listed at ATCC, only three were derived from tumorigenic tissues. This contrasts with mammalian cell lines where over 50% of listed cell lines at the ATCC were derived from cancerous tissues or transformed cells. Altogether ~283 cell lines have been established from finfish around the world but only 43 fish cell lines are being listed in the international cell repository like ATCC, ECACC. If all the established cell lines would have been deposited in that repository, it would be beneficial to the international research community in order to use those cell lines as they are the best alternative to the whole animal research.

Conclusion

Cell cultures, in particular those derived from fish, have been successfully employed as a biological alternative to the use of whole animals. The increasing use and importance of fish cell lines suggest that cell culturists should be encouraged to place these lines with the international cell repositories like ATCC, EACC or other appropriate repository in order to provide a dependable, high-quality source of cells for the benefit of all.

The number of publications containing spurious data as a result of overpassaged, misidentified, or contaminated cell lines is unknown. The basis for any research, development or production program involving cell cultures is the selection of an identity-verified and low-passage cell line. The use of similar and identified passage numbers throughout a project will better ensure reproducible results and comparisons between laboratories. To further ensure the use of authenticated cell lines, full cell line documentation, including the source and passage numbers used during experiments, should be submitted for scientific publications. Cell lines are critical components of experiments and should be considered as standard research reagents and given the same care and quality control measures that surround the use of kits, enzymes and other laboratory products commercially obtained.