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What Is The Success Rate Of Cloning Animals Through Somatic Cell Nuclear Transfer?

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Cloning animals by somatic cell nuclear transfer – biological factors

Reproductive Biological science and Endocrinology volume 1, Article number:98 (2003) Cite this article

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Abstract

Cloning by nuclear transfer using mammalian somatic cells has enormous potential application. However, somatic cloning has been inefficient in all species in which live clones have been produced. High abortion and fetal bloodshed rates are commonly observed. These developmental defects have been attributed to incomplete reprogramming of the somatic nuclei by the cloning process. Diverse strategies have been used to amend the efficiency of nuclear transfer, however, significant breakthroughs are yet to happen. In this review we will talk over studies conducted, in our laboratories and those of others, to gain a better agreement of nuclear reprogramming. Considering cattle are a species widely used for nuclear transfer studies, and more laboratories take succeeded in cloning cattle than whatsoever other specie, this review will be focused on somatic prison cell cloning of cattle.

Introduction

Somatic cell cloning (cloning or nuclear transfer) is a technique in which the nucleus (DNA) of a somatic cell is transferred into an enucleated metaphase-2 oocyte for the generation of a new individual, genetically identical to the somatic jail cell donor (Figure ane). The success of cloning an unabridged animal, Dolly, from a differentiated adult mammary epithelial jail cell [1] has created a revolution in science. It demonstrated that genes inactivated during tissue differentiation can be completely re-activated past a process chosen nuclear reprogramming: the reversion of a differentiated nucleus back to a totipotent status. Somatic cloning may exist used to generate multiple copies of genetically elite farm animals, to produce transgenic animals for pharmaceutical protein product or xeno-transplantation [2–v], or to preserve endangered species. With optimization, it as well promises enormous biomedical potential for therapeutic cloning and allo-transplantation [half-dozen]. In add-on to its practical applications, cloning has become an essential tool for studying gene office [7], genomic imprinting [8], genomic re-programming [nine–12], regulation of development, genetic diseases, and gene therapy, also equally many other topics.

Figure 1
figure 1

Schematic diagram of the somatic cloning process. Cells are nerveless from donor (a) and cultured in vitro (b). A matured oocyte (c) is and so enucleated (d) and a donor cell is transferred into the enucleated oocyte (e). The somatic cell and the oocyte is then fused (f) and the embryos is allowed to develop to a blastocyst in vitro (g). The blastocyst can then be transferred to a recipient (h) and cloned animals are born after completion of gestation (i).

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I of the most difficult challenges faced, however, is cloning'south depression efficiency and high incidence of developmental abnormalities [thirteen–19]. Currently, the efficiency for nuclear transfer is betwixt 0–10%, i.e., 0–10 live births later on transfer of 100 cloned embryos. Developmental defects, including abnormalities in cloned fetuses and placentas, in addition to high rates of pregnancy loss and neonatal death take been encountered by every research team studying somatic cloning. It has been proposed that low cloning efficiency may be largely attributed to the incomplete reprogramming of epigenetic signals [twenty–23].

Factors affecting nuclear reprogramming

Various strategies accept been employed to modify donor cells and the nuclear transfer procedure in attempts to improve the efficiency of nuclear transfer. Most of these efforts are focused on donor cells. These include: a) synchrony of the cell bicycle stage of donor cells [24–26], too as synchrony between donor cells and recipient oocytes [27, 28]; b) using somatic cells from donors of various ages [29–33], tissue origins [26, 34–39], passages [16, 40, 41] and civilisation conditions [42]; c) transfer of stem cells with low levels of epigenetic marks [43–48]; and d) modifying epigenetic marks of donor cells with drugs [49–51]. Although the efficiency of nuclear transfer has been dramatically improved from the initial success charge per unit of one live clone born from 277 embryo transfers [1], none of the aforementioned efforts abolished the common problems associated with nuclear transfer. These observations suggest that further studies on nuclear reprogramming are needed in order to empathise the underlying mechanisms of reprogramming and significantly ameliorate the ability of the differentiated somatic nuclei to be reprogrammed. In the post-obit department, nosotros will discuss several strategies used to improve nuclear transfer efficiencies.

Serum starvation of donor cells

Serum starvation was used in the creation of Dolly and was believed essential to the success of nuclear transfer [1]. Serum starvation induces quiescence of cultured cells, and arrests them at the cell cycle stage of G0. Nigh laboratories that have succeeded with nuclear transfer have utilized a serum starvation treatment. However, there is a argue as to whether inducing quiescence is required for successful nuclear transfer. Cibelli et al. [52] proposed that G0 was unnecessary and that calves could be produced from cycling cells. In his study, actively dividing bovine fibroblasts were used for nuclear transfer and iv calves were born from 28 embryos transferred to eleven recipients. Because 56% of cycling cells in that study were in G1 stage, it is likely that all cloned animals produced in this study were from donor cells at G1 stage. Cells at G2, S or M would not be expected to generate cloned animals in this study considering they are incompatible with the recipient oocytes used. This study demonstrated that cells at G1 stage tin produce alive cloned animals and G0 induction is not essential.

Since the report of Cibelli and colleagues, many laboratories have compared nuclear transfer using donor cells with and without serum starvation. In our study, we used cells from a 17-yr old male Japanese Blackness beef balderdash and found that serum starvation was non required for successful cloning because cloned embryos and animals were produced from cells not subjected to serum starvation (Tabular array i) [16]. Furthermore, serum starvation did non have a beneficial result on the blastocyst evolution of cloned embryos.

Table 1 Evolution of embryos cloned from donor cells from a 17-year onetime bull with and without serum starvation treatment

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In other studies in which serum starvation vs. no starvation were directly compared, evidence was found that both quiescent and proliferating somatic donor cells can be fully reprogrammed afterward nuclear transfer and upshot in viable offspring [25, 26, 29, 53, 54]. Still, it is still debatable which jail cell cycle stage, G0 or G1, result in the best cloning efficiency. Interestingly, Zechkerchenko et al. [53] observed a positive consequence of serum starvation on the efficiency of nuclear transfer using bovine fetal fibroblasts. Although Cho et al. [55] did non detect an improvement in blastocyst rate from any of four different cell types (cumulus, fibroblast, uterine and oviduct epithelial cells). Similar observations were noted by Hills et al. [29] who reported that serum starvation of adult donor cells did non improve development rates of cloned embryos to blastocyst, but when fetal cells were serum-starved, there was a pregnant increase in their blastocyst development. Conversely, Rho et al. [54] found that fetal transgenic lines were non unlike in blastocyst development with or without serum starvation or confluency.

Recently, Kasinathan et al. [25] evaluated methods for generating G0 and G1 prison cell populations and compared their development following cloning. They found that a loftier degree of confluence was more effective than serum starvation for arresting cells in G0, and G1 cells could be obtained using a "milkshake-off" procedure. In this study, no differences in in vitro development were observed between embryos derived from the high-confluence cells (G0) or from the "shaken-off" cells (G1). Yet, when embryos from each handling were transferred into 50 recipients, five calves (10% of embryos transferred) were obtained from embryos derived from the "milk shake-off" cells, whereas no embryos from the confluent cells survived beyond 180 days of gestation. Kasinathan et al. [25] concluded that nuclear transfer donor cell cycle stage is important, particularly effecting belatedly fetal development, and that actively dividing G1 cells support higher development rates than cells in G0. Despite the fact that Kasinathan's study did not produce live clones from G0 cells, a loftier nuclear transfer success charge per unit was obtained by Cho et al. [55] who subjected donor cells to serum starvation and found no improvement in blastocyst development from adult donor cells, but resulted in a 27.3% calving rate.

To further complicate the matter, Wells et al. [26] compared 2 dissimilar types of non-transfected bovine fetal fibroblasts (BFFs) that were synchronized in G0, G1 or different phases within G1. They showed that serum starvation into G0 resulted in a significantly higher pct of viable calves at term than did synchronization in early on G1 or late G1. For transgenic fibroblasts, however, cells selected in G1 showed significantly higher evolution to term of calves and college post-natal survival to weaning, than cells in G0. They suggest that information technology may exist necessary to coordinate donor cell type and prison cell bike phase to maximize overall cloning efficiency.

In summary, it is clear that quiescence is non necessary for the success of nuclear transfer because cells not subjected to serum starvation can too produce alive clones. Fifty-fifty so, it remains unclear which prison cell cycle stage, G0 or G1, imparts a higher nuclear transfer efficiency. This question will go along to be debated until large-scale nuclear transfer studies can exist conducted.

Cloning competence of various somatic cell types

Many somatic prison cell types, including mammary epithelial cells, ovarian cumulus cells, fibroblast cells from skin and internal organs, diverse internal organ cells, Sertoli cells [38, 56], macrophage [56] and blood leukocytes [34, 35] have been successfully utilized for nuclear transfer. A clear consensus, however, has non however been reached as to the superior somatic cell type for nuclear transfer. This is due in part to the fact that dissimilar laboratories employ various procedures; and cell culture, nuclear transfer, and micromanipulation all require critical technical skills. In lodge to brand these comparisons valid, the procedures and techniques used, too equally the skill of lab personnel, must exist identical for each donor animate being and cell type. To compare the competence of unlike jail cell types for reprogramming past cloning, we avoided animate being variation by looking at the cloning competence of three cell types: ovarian cumulus, mammary epithelial and skin fibroblast cells, all from the aforementioned donor animal, a 13-yr-old aristocracy diary cow.

The power of donor cells to be reprogrammed was assessed by the development of cloned embryos in vitro and by the nascency of cloned calves following embryo transfer. As shown in Tables 2 and three, although no differences were detected in the cleavage rates of embryos from three different cell types, cumulus cells produced the highest rate of blastocyst development in this study and resulted in 6 full-term cloned calves. Furthermore, iv out of the 6 calves derived from cumulus cells survived and were however healthy at nearly 4 years of age (Table three). In dissimilarity, the poorest in vitro development, and no total-term survival, was obtained with mammary epithelial cells. Skin fibroblast cells resulted in an intermediate rate of in vitro development and gave rise to 4 full-term cloned calves.

Table 2 Summary of in vitro development of cloned embryos from different cell types

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Tabular array 3 Summary of embryo transfer and calving of cloned embryos from unlike cell types

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Our results showed that the donor cell type can significantly affect embryo development in vitro besides every bit in vivo. Cumulus cells proved to be the well-nigh constructive jail cell type for somatic cloning co-ordinate to both the in vitro development test as well as total-term survival. These results advise that Deoxyribonucleic acid from cumulus cells is more effectively reprogrammed following nuclear transfer. Our results agreed with those obtained in mice [57] where they compared the nuclear transfer efficiency of neuronal, Sertoli and cumulus cells, and obtained the best alive nascency rate from cumulus cell-derived cloned embryos. Furthermore, it was reported that cumulus prison cell-derived cloned mice do not accept widespread dysregulation of imprinting [23]. Kato et al. [xv, 36] compared cells from the liver, testis, skin, ear, along with cumulus and oviductal cells and concluded that cumulus and oviduct epithelial cells are the most suitable for nuclear donors. Evidence supporting the superiority of cumulus cells for nuclear transfer too comes from the study of Forsberg et al. [58] who conducted big numbers of embryo transfer in cattle. It was shown that cumulus cells gave an overall xv.ii% calving rate, while fetal genital ridge cells, and fibroblast cells produced a 9% calving rate. Adult fibroblast cells, in this study, gave the lowest calving rate of only 5%.

In summary, among the somatic cell types tested, the consensus from numerous laboratories is that cumulus cells give the highest cloning efficiency and outcome in the least number of abnormalities in cloned animals.

Effect of donor age

By using a design like to the donor cell blazon comparing, we studied the cloning efficiency of fibroblast cells from donors of different ages. We found that cells from fetuses and newborn animals were more efficient in nuclear transfer. Even so, when cells from developed animals were used, little changes were observed in the cloning efficiency of cells from cattle varying in age from 2 to16-years-old (Table iv).

Table 4 Cloning competence of cells from donor animals of dissimilar ages

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Similarly, Renard et al. [31], Hills et al. [29] and Wakayama and Yanagimachi [56] also reported that development rates of somatic cloned embryo remained similar regardless of donor age. Still, Kato et al. [36] noted that clones derived from adult cells frequently aborted in the later stages of pregnancy, and calves developing to term showed a higher number of abnormalities than did those derived from newborn or fetal cells. Forsberg et al. [58] transferred a big number of cloned embryos in cattle. They also ended that, in general, embryos cloned from fetal cells produced higher pregnancy and calving rates than those from adult cells.

In conclusion, it appears that cells from fetuses, likewise equally aged adults, tin lead to comparable blastocyst development of cloned embryos. Withal, fetal cells may be better than developed cells in producing healthy live births. This might be due to the fact that the somatic cells of adult animals have accumulated more genetic mutations/are more terminally differentiated than fetal cells, and are thus more probable to fail at full term evolution.

Issue of jail cell culture duration (passage numbers)

Our grouping was the start to directly compare passage event of donor cells on the outcome of nuclear transfer [16]. In our study, we found that cells of afterwards passages (up to xv) could too support clone development to full term (Tabular array five).

Tabular array v Cloning efficiency of cells at dissimilar passages

Full size tabular array

Comparable to our findings were those of Arat et al. [40] who established a chief cell line from granulosa cells and transfected them with the green fluorescence protein (GFP) gene. Non-transfected cells were used for cloning between passage ten and 15 as either serum-starved or serum-fed donor cells. There were no differences in evolution to the blastocyst stage for nuclear transfer embryos from transfected or non-transfected or from serum-starved or serum-fed cells. Blastocyst evolution rates of embryos produced from donor cells at passage 15, all the same, were significantly college than those produced with cells at passage ten, xi, and thirteen. Developmental competence of after passages, up to 16 [54] and equally loftier every bit 36, from fibroblast from a cloned fetus [41], accept also been reported.

The demonstration that afterward passages can support clone development is essential for utilizing somatic cloning for gene-knockout studies, in which single cells must be clonally expanded to generate sufficient cells for nuclear transfer [7]. These afore-mentioned studies suggest that cells of higher passages were receptive to nuclear reprogramming. Additional support for this hypothesis comes from a recent study past Enright et al. [59] who showed that cells of later on passages incorporate less epigenetic modifications, i.due east., their histones are more acetylated than in earlier passages. This observation agrees with an earlier notion that in vitro culture of cells can induce expression of genes that were not expressed before civilization [60, 61]. Furthermore, Hills et al. [62] reported that a greater proportion of late passage cells (passage eighteen), vs. earlier passage cells (passage 2), were establish to be in G0/G1 whether or non they were in serum-starved culture conditions.

Effect of modification of pre-existing epigenetic marks in donor cells

Histone acetylation and Dna methylation are heritable modifications of the chromatin that do not involve changes in gene sequences (epigenetic signals). These epigenetic modifications are believed responsible for the derivation of diverse cell types with the same genetic makeup. In natural reproduction, relatively depression levels of DNA methylation be in the gametes, which are further de-methylated during early embryo evolution [63, 64]. With nuclear transplantation, the somatic donor nucleus carries the specific epigenetic modifications of its tissue type, which must be erased during nuclear reprogramming. Therefore, the levels of epigenetic modification existing in donor cells may affect their reprogrammability post-obit nuclear transfer. As discussed earlier, a discrepancy in the donor cell's susceptibility to reprogramming has been observed betwixt different cell types, resulting in differences in vitro and in vivo development of cloned embryos. Therefore, treating donor cells with pharmacological agents to remove some epigenetic marks prior to nuclear transfer may improve the ability of the donor cells to be fully reprogrammed by the recipient karyoplast.

Two reagents have been widely used for the alteration of the levels of epigenetic modification of somatic cells. Trichostatin A (TSA) and 5-aza-deoxy-cytadine (five-aza-dC) have been found to increase histone acetylation and decrease Deoxyribonucleic acid methylation, respectively. These changes accept been associated with increases of gene expression. Recently, we conducted studies in which the pre-existing epigenetic marks in donor cells were reduced by these drugs [49]. Nosotros found that global epigenetic marks in donor cells can be modified by handling with TSA or 5-aza-dC. Unfortunately, treating donor cells with 5-aza-dC reduced blastocyst formation of cloned embryos. Previously, Jones et al. [l] and Zhou et al. [51] treated bovine fetal fibroblast cells and mouse stem cells with much college doses of five-aza-C (one or 5 μm) and also plant that blastocyst development of cloned embryos were reduced. The consensus from these studies [49–51] suggests that lowering the levels of DNA methylation in donor cells does not always meliorate development of cloned embryos. At high concentrations, v-aza-dC may have been cytotoxic to the donor cells. Additionally, prolonged handling at a lower concentration, as was the case in our study, may take acquired severe hypo-methylation, and resulted in disrupted expression of essential genes important for embryo development. Therefore, further experiments are required to test the effects of lower concentrations and shorter durations of 5-aza-dC handling on donor cells.

Treating donor cells with TSA, by contrast, significantly improved development of cloned embryos. Previous reports indicated that handling of mouse stem cells with TSA reduced evolution of cloned embryos [51]. The differences between these findings may be due to the variation in the concentrations of TSA used. Prior to nuclear transfer, we treated donor cells with a broad range of TSA concentrations and identified the lowest concentration capable of inducing histone hyperacetylation (ane.25 μM). The everyman concentration tested (0.08 μM), did non cause hyperacetylation, but resulted in observable changes in prison cell morphology, similar to those described previously [65]. It was this lower concentration of TSA (0.08 μM) that improved development of cloned embryos in our study, while the higher concentration (1.25 μM) inhibited embryo development. The detrimental consequence of a higher dose of TSA on embryo development may exist explained past the fact that treatment of cells with high concentrations of TSA causes chromatin breaks and apoptosis [66].

Conclusion

Somatic jail cell cloning by nuclear transfer is a relatively new applied science with many potential applications. However, at the current stage of development, the reprogramming of epigenetic inheritance by nuclear transfer is withal incomplete. Further efforts and new paradigms are needed to perfect this technology and extend it to its fullest potential.

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Acknowledgement

The authors would like to give thanks Marina Julian for careful reading and editing this manuscript.

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Authors and Affiliations

  1. Center for Regenerative Biological science/Section of Brute Science, Academy of Connecticut, 06269-4243, Storrs, Connecticut, United states of america

    X Cindy Tian, Brian Enright & Xiangzhong Yang

  2. Kagoshima Prefectural Cattle Breeding and Genetic Establish, Kagoshima, Japan

    Chikara Kubota

  3. Evergen Biotechnologies, Inc. Incubator Program at the University of Connecticut, 1392 Storrs Road, 06269, Storrs, CT, U.s.

    Xiangzhong Yang

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Correspondence to Xiangzhong Yang.

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Tian, X.C., Kubota, C., Enright, B. et al. Cloning animals by somatic cell nuclear transfer – biological factors. Reprod Biol Endocrinol ane, 98 (2003). https://doi.org/10.1186/1477-7827-ane-98

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  • DOI : https://doi.org/10.1186/1477-7827-one-98

Keywords

  • nuclear transfer
  • donor jail cell types
  • donor age
  • serum starvation
  • jail cell passage

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