Abstract
The birth and adult development of 'Dolly' the sheep, the first mammal produced by the transfer of a terminally differentiated cell nucleus into an egg, provided unequivocal evidence of nuclear equivalence among somatic cells. This ground-breaking experiment challenged a long-standing dogma of irreversible cellular differentiation that prevailed for over a century and enabled the development of methodologies for reversal of differentiation of somatic cells, also known as nuclear reprogramming. Thanks to this new paradigm, novel alternatives for regenerative medicine in humans, improved animal breeding in domestic animals and approaches to species conservation through reproductive methodologies have emerged. Combined with the incorporation of new tools for genetic modification, these novel techniques promise to (i) transform and accelerate our understanding of genetic diseases and the development of targeted therapies through creation of tailored animal models, (ii) provide safe animal cells, tissues and organs for xenotransplantation, (iii) contribute to the preservation of endangered species, and (iv) improve global food security whilst reducing the environmental impact of animal production. This review discusses recent advances that build on the conceptual legacy of nuclear transfer and – when combined with gene editing – will have transformative potential for medicine, biodiversity and sustainable agriculture. We conclude that the potential of these technologies depends on further fundamental and translational research directed at improving the efficiency and safety of these methods.
Highlights
AimInhibition of natural killer cells Inhibition of macrophages Prevention of inflammation Reduction of the risk of transmission of porcine endogenous retroviruses (PERV)
The germ-plasm theory by August Weismann proposed that cells of a developing organism lose developmental plasticity during differentiation (Weismann et al 1889)
Genetic modification of animals has primarily relied on the genetic modification of mouse embryonic stem cells (ESC) and the generation of chimeric founders that are bred to homozygosity (Doetschman et al 1987, Thomas & Capecchi 1987)
Summary
Inhibition of natural killer cells Inhibition of macrophages Prevention of inflammation Reduction of the risk of transmission of porcine endogenous retroviruses (PERV). The recent progress demonstrates the critical need for NT technologies for the generation of these donor animals for xenotransplantation that can be enhanced by the incorporation of efficient gene-editing and -targeting technologies Another avenue that is being explored for autologous transplantation considers the creation of human organs in organogenesis-disabled pigs through interspecies chimerism. A vision for utilizing in vitro systems for growing gametes as a means to reduce generation intervals, known as 'velogenetics', was proposed in the early ’90s when genotype databases and assisted reproduction were beginning to be used (Georges & Massey 1991) These ideas have resurfaced as a result of developments in genetic selection, stem cell technologies and the possibilities of in vitro gamete production in domestic animals (Rexroad et al 2019). A limited gene pool could represent an obstacle for expanding endangered species, the establishment of induced pluripotent stem cells from frozen tissues/blood could offer an alternative route for the generation of gametes that could be used for in vitro breeding
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