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Cell Transplantation 2022A growing need for organs and novel cell-based therapies has provided a niche for approaches like interspecies chimeras. To generate organs from one donor species in... (Review)
Review
A growing need for organs and novel cell-based therapies has provided a niche for approaches like interspecies chimeras. To generate organs from one donor species in another host species requires techniques such as blastocyst complementation and gene editing to successfully create an embryo that has cells from both the donor and the host. However, the task of developing highly efficacious and competent interspecies chimeras is met by many challenges. These interspecies chimeric barriers impede the formation of chimeras, often leading to lower levels of chimeric competency. The barriers that need to be addressed include the evolutionary distance between species, stage-matching, temporal and spatial synchronization of developmental timing, interspecies cell competition and the survival of pluripotent stem cells and embryos, compatibility of ligand-receptor signaling between species, and the ethical concerns of forming such models. By overcoming the interspecies chimera barriers and creating highly competent chimeras, the technology of organ and cellular generation can be honed and refined to develop fully functioning exogenic organs, tissues, and cells for transplantation.
Topics: Blastocyst; Chimera; Gene Editing; Ligands; Pluripotent Stem Cells
PubMed: 36173102
DOI: 10.1177/09636897221110525 -
International Journal of Molecular... Oct 2022Atherosclerosis-a systemic inflammatory disease-is the number one cause of mortality and morbidity worldwide. As such, the prevention of disease progression is of global... (Review)
Review
Atherosclerosis-a systemic inflammatory disease-is the number one cause of mortality and morbidity worldwide. As such, the prevention of disease progression is of global interest in order to reduce annual deaths at a significant scale. Atherosclerosis is characterized by plaque formation in the arteries, resulting in vascular events such as ischemic stroke or myocardial infarction. A better understanding of the underlying pathophysiological processes at the cellular and molecular level is indispensable to identify novel therapeutic targets that may alleviate disease initiation or progression. Sphingolipids-a lipid class named after the chimeric creature sphinx-are considered to play a critical and, metaphorically, equally chimeric regulatory role in atherogenesis. Previous studies identified six common sphingolipids, namely dihydroceramide (DhCer), ceramide (Cer), sphingosine-1-phosphate (S1P), sphingomyelin (SM), lactosylceramide (LacCer), and glucosylceramide (GluCer) in carotid plaques, and demonstrated their potential as inducers of plaque inflammation. In this review, we point out their specific roles in atherosclerosis by focusing on different cell types, carrier molecules, enzymes, and receptors involved in atherogenesis. Whereas we assume mainly atheroprotective effects for GluCer and LacCer, the sphingolipids DhCer, Cer, SM and S1P mediate chimeric functions. Initial studies demonstrate the successful use of interventions in the sphingolipid pathway to prevent atherosclerosis. However, as atherosclerosis is a multifactorial disease with a variety of underlying cellular processes, it is imperative for future research to emphasize the circumstances in which sphingolipids exert protective or progressive functions and to evaluate their therapeutic benefits in a spatiotemporal manner.
Topics: Antigens, CD; Atherosclerosis; Ceramides; Chimera; Glucosylceramides; Humans; Lactosylceramides; Lysophospholipids; Plaque, Atherosclerotic; Sphingolipids; Sphingomyelins; Sphingosine
PubMed: 36233252
DOI: 10.3390/ijms231911948 -
Development (Cambridge, England) Sep 2011The thymus is the primary organ responsible for generating functional T cells in vertebrates. Although T cell differentiation within the thymus has been an area of... (Review)
Review
The thymus is the primary organ responsible for generating functional T cells in vertebrates. Although T cell differentiation within the thymus has been an area of intense investigation, the study of thymus organogenesis has made slower progress. The past decade, however, has seen a renewed interest in thymus organogenesis, with the aim of understanding how the thymus develops to form a microenvironment that supports T cell maturation and regeneration. This has prompted modern revisits to classical experiments and has driven additional genetic approaches in mice. These studies are making significant progress in identifying the molecular and cellular mechanisms that control specification, early organogenesis and morphogenesis of the thymus.
Topics: Animals; Chick Embryo; Chimera; Mice; Models, Biological; Morphogenesis; Organogenesis; Quail; Signal Transduction; Thymus Gland
PubMed: 21862553
DOI: 10.1242/dev.059998 -
Mechanisms of Development Sep 2004Pluripotent embryonic stem cells are undifferentiated cells capable of proliferation and self-renewal and have the capacity to differentiate into all somatic cell types... (Review)
Review
Pluripotent embryonic stem cells are undifferentiated cells capable of proliferation and self-renewal and have the capacity to differentiate into all somatic cell types and the germ line. They provide an in vitro model of early embryonic differentiation and are a useful means for targeted manipulation of the genome. Pluripotent stem cells in the chick have been derived from stage X blastoderms and 5.5 day gonadal primordial germ cells (PGCs). Blastoderm-derived embryonic stem cells (ESCs) have the capacity for in vitro differentiation into embryoid bodies and derivatives of the three primary germ layers. When grafted onto the chorioallantoic membrane, the ESCs formed a variety of differentiated cell types and attempted to organize into complex structures. In addition, when injected into the unincubated stage X blastoderm, the ESCs can be found in numerous somatic tissues and the germ line. The potential give rise to somatic and germ line chimeras is highly dependent upon the culture conditions and decreases with passage. Likewise, PGC-derived embryonic germ cells (EGCs) can give rise to simple embryoid bodies and can undergo some differentiation in vitro. Interestingly, chicken EG cells contribute to somatic lineages when injected into the stage X blastoderm, but only germ line chimeras have resulted from EGCs injected into the vasculature of the stage 16 embryo. To date, no lines of transgenic chickens have been generated using ESCs or EGCs. Nevertheless, progress towards the culture of avian pluripotent stem cells has been significant. In the future, the answers to fundamental questions regarding segregation of the avian germ line and the molecular basis of pluripotency should foster the full use of avian pluripotent stem cells.
Topics: Animals; Cell Differentiation; Chick Embryo; Chimera; Microscopy, Phase-Contrast; Pluripotent Stem Cells
PubMed: 15296979
DOI: 10.1016/j.mod.2004.05.003 -
Stem Cells and Development Dec 2018The search for a better animal model to simulate human disease has been a "holy grail" of biomedical research for decades. Recent identification of different types of... (Review)
Review
The search for a better animal model to simulate human disease has been a "holy grail" of biomedical research for decades. Recent identification of different types of pluripotent stem (PS) cells and advances in chimera research might soon permit the generation of interspecies chimeras from closely related species, such as those between humans and other primates. In this study, we suggest that the creation of human-primate chimeras-specifically, the transfer of human stem cells into (non-ape) primate hosts-could not only surpass the limitations of current monkey models of neurological and psychiatric disease but would also raise important ethical considerations concerning the use of monkeys in invasive research. Questions regarding the scientific value and ethical concerns raised by the prospect of human-monkey chimeras are more urgent in light of recent advances in PS cell research and attempts to generate interspecies chimeras between humans and animals. While some jurisdictions prohibit the introduction of human PS cells into monkey preimplantation embryos, other jurisdictions may permit and even encourage such experiments. Therefore, it is useful to consider blastocyst complementation experiments more closely in light of advances that could make these chimeras possible and to consider the ethical and political issues that are raised.
Topics: Animals; Disease Models, Animal; Embryo Research; Haplorhini; Humans; Mental Disorders; Neurodegenerative Diseases; Stem Cell Transplantation; Transplantation Chimera
PubMed: 30319057
DOI: 10.1089/scd.2018.0162 -
Journal of Applied Genetics Feb 2018Transgenic chickens have, in general, been produced by two different procedures. The first procedure is based on viral transfection systems. The second procedure, the... (Review)
Review
Transgenic chickens have, in general, been produced by two different procedures. The first procedure is based on viral transfection systems. The second procedure, the non-viral method, is based on genetically modified embryonic cells transferred directly into the recipient embryo. In this review, we analyzed the effectiveness of important elements of the non-viral, cell-based strategy of transgenic chicken production. The main elements of this strategy are: isolation and cultivation of donor embryonic cells; transgene construction; cell transfection in vitro; and chimera production: injection of cells into recipient embryos, raising and identification of germline chimeras, mating germline chimeras, transgene inheritance, and transgene expression. In this overview, recent progress and important limitations in the development of transgenic chickens are presented.
Topics: Animals; Animals, Genetically Modified; Chickens; Chimera; Genetic Engineering; Germ Cells; Transfection
PubMed: 29372515
DOI: 10.1007/s13353-018-0429-6 -
Cell Stem Cell Aug 2016Chimeras are widely acknowledged as the gold standard for assessing stem cell pluripotency, based on their capacity to test donor cell lineage potential in the context... (Review)
Review
Chimeras are widely acknowledged as the gold standard for assessing stem cell pluripotency, based on their capacity to test donor cell lineage potential in the context of an organized, normally developing tissue. Experimental chimeras provide key insights into mammalian developmental mechanisms and offer a resource for interrogating the fate potential of various pluripotent stem cell states. We highlight the applications and current limitations presented by intra- and inter-species chimeras and consider their future contribution to the stem cell field. Despite the technical and ethical demands of experimental chimeras, including human-interspecies chimeras, they are a provocative resource for achieving regenerative medicine goals.
Topics: Animals; Cell Lineage; Chimera; Embryo, Mammalian; Humans; Pluripotent Stem Cells; Species Specificity; Stem Cell Research
PubMed: 27494674
DOI: 10.1016/j.stem.2016.07.018 -
BMC Medical Ethics Mar 2020The burgeoning field of biomedical research involving the mixture of human and animal materials has attracted significant ethical controversy. Due to the many dimensions...
BACKGROUND
The burgeoning field of biomedical research involving the mixture of human and animal materials has attracted significant ethical controversy. Due to the many dimensions of potential ethical conflict involved in this type of research, and the wide variety of research projects under discussion, it is difficult to obtain an overview of the ethical debate. This paper attempts to remedy this by providing a systematic review of ethical reasons in academic publications on human-animal chimera research.
METHODS
We conducted a systematic review of the ethical literature concerning human-animal chimeras based on the research question: "What ethical reasons have been given for or against conducting human-animal chimera research, and how have these reasons been treated in the ongoing debate?" Our search extends until the end of the year 2017, including MEDLINE, Embase, PhilPapers and EthxWeb databases, restricted to peer-reviewed journal publications in English. Papers containing ethical reasons were analyzed, and the reasons were coded according to whether they were endorsed, mentioned or rejected.
RESULTS
Four hundred thirty-one articles were retrieved by our search, and 88 were ultimately included and analyzed. Within these articles, we found 464 passages containing reasons for and against conducting human-animal chimera research. We classified these reasons into five categories and, within these, identified 12 broad and 31 narrow reason types. 15% of the retrieved passages contained reasons in favor of conducting chimera research (Category P), while 85% of the passages contained reasons against it. The reasons against conducting chimera research fell into four further categories: reasons concerning the creation of a chimera (Category A), its treatment (Category B), reasons referring to metaphysical or social issues resulting from its existence (Category C) and to potential downstream effects of chimera research (Category D). A significant proportion of identified passages (46%) fell under Category C.
CONCLUSIONS
We hope that our results, in revealing the conceptual and argumentative structure of the debate and highlighting some its most notable tendencies and prominent positions, will facilitate continued discussion and provide a basis for the development of relevant policy and legislation.
Topics: Animal Experimentation; Animals; Biomedical Research; Chimera; Dissent and Disputes; Humans; Morals
PubMed: 32293411
DOI: 10.1186/s12910-020-00465-7 -
Mechanisms of Development Sep 2004Research to develop a useful method for genetic modification of the chick has been on-going since the first demonstrations in the mouse in the 1980s that genetic... (Review)
Review
Research to develop a useful method for genetic modification of the chick has been on-going since the first demonstrations in the mouse in the 1980s that genetic modification is an invaluable tool for the study of gene function. Manipulation of the chick zygote is possible but inefficient. Considerable progress has been made in developing potentially pluripotent embryo stem cells and their contribution to somatic chimeric birds well-established. Germ line transmission of gametes derived from genetically modified embryo cells has not been described. Transfer of primordial germ cells from a donor embryo to a recipient and production of functional gametes from the donor-derived cells is possible. Genetic modification of primordial germ cells before transfer and their recovery through the germ line has not been achieved. The first transgenic birds described were generated using retroviral vectors. The use of lentiviral vectors may make this approach a feasible method for transgenic production, although there are limitations to the applications of these vectors. It is likely that a method will be developed in the next few years that will enable the use of transgenesis as a tool in the study of development in the chick and for many other applications in basic research and biotechnology.
Topics: Animals; Animals, Genetically Modified; Chick Embryo; Chickens; Chimera; Gene Transfer Techniques; Genes, Reporter; Genetic Vectors; Stem Cells; Viruses; Zygote
PubMed: 15296981
DOI: 10.1016/j.mod.2004.05.012 -
Cellular Signalling Nov 2022The use of small molecule drugs to inhibit active protein targets has revolutionised the treatment options for many diseases in the past 30 years. The greatly improved... (Review)
Review
The use of small molecule drugs to inhibit active protein targets has revolutionised the treatment options for many diseases in the past 30 years. The greatly improved pharmacokinetic properties of modern drugs combined with enhanced cell permeability and oral bioavailability has made these molecules ideal for reaching protein targets of interest in cells and inhibiting disease-driven signalling pathways. However, these small molecule drugs have several limitations which have opened the doors for the development of a new class of compounds, known as proteolysis targeting chimeras (PROTACs). These next generation drugs actively and specifically degrade designated protein targets and hold the potential to greatly expand the druggable genome, including previously drug-resistant targets.
Topics: Chimera; Intercellular Signaling Peptides and Proteins; Proteins; Proteolysis; Ubiquitin-Protein Ligases
PubMed: 35995302
DOI: 10.1016/j.cellsig.2022.110446