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Nature Reviews. Genetics Jul 2019The derivation of induced pluripotent stem cells (iPSCs) over a decade ago sparked widespread enthusiasm for the development of new models of human disease, enhanced... (Review)
Review
The derivation of induced pluripotent stem cells (iPSCs) over a decade ago sparked widespread enthusiasm for the development of new models of human disease, enhanced platforms for drug discovery and more widespread use of autologous cell-based therapy. Early studies using directed differentiation of iPSCs frequently uncovered cell-level phenotypes in monogenic diseases, but translation to tissue-level and organ-level diseases has required development of more complex, 3D, multicellular systems. Organoids and human-rodent chimaeras more accurately mirror the diverse cellular ecosystems of complex tissues and are being applied to iPSC disease models to recapitulate the pathobiology of a broad spectrum of human maladies, including infectious diseases, genetic disorders and cancer.
Topics: Animals; Cell Differentiation; Cell Lineage; Chimera; Communicable Diseases; Drug Discovery; Genetic Diseases, Inborn; Genetic Therapy; Humans; Induced Pluripotent Stem Cells; Models, Animal; Models, Biological; Neoplasms; Organoids; Tissue Engineering; Tissue Transplantation; Transplantation, Heterologous
PubMed: 30737492
DOI: 10.1038/s41576-019-0100-z -
Cell Stem Cell Mar 2021Dynamic pluripotent stem cell (PSC) states are in vitro adaptations of pluripotency continuum in vivo. Previous studies have generated a number of PSCs with distinct...
Dynamic pluripotent stem cell (PSC) states are in vitro adaptations of pluripotency continuum in vivo. Previous studies have generated a number of PSCs with distinct properties. To date, however, no known PSCs have demonstrated dual competency for chimera formation and direct responsiveness to primordial germ cell (PGC) specification, a unique functional feature of formative pluripotency. Here, by modulating fibroblast growth factor (FGF), transforming growth factor β (TGF-β), and WNT pathways, we derived PSCs from mice, horses, and humans (designated as XPSCs) that are permissive for direct PGC-like cell induction in vitro and are capable of contributing to intra- or inter-species chimeras in vivo. XPSCs represent a pluripotency state between naive and primed pluripotency and harbor molecular, cellular, and phenotypic features characteristic of formative pluripotency. XPSCs open new avenues for studying mammalian pluripotency and dissecting the molecular mechanisms governing PGC specification. Our method may be broadly applicable for the derivation of analogous stem cells from other mammalian species.
Topics: Animals; Cell Differentiation; Chimera; Germ Cells; Horses; Mice; Pluripotent Stem Cells
PubMed: 33271070
DOI: 10.1016/j.stem.2020.11.003 -
Cell Research Sep 2021Degrading pathogenic proteins by degrader technologies such as PROTACs (proteolysis-targeting chimeras) provides promising therapeutic strategies, but selective...
Degrading pathogenic proteins by degrader technologies such as PROTACs (proteolysis-targeting chimeras) provides promising therapeutic strategies, but selective degradation of non-protein pathogenic biomolecules has been challenging. Here, we demonstrate a novel strategy to degrade non-protein biomolecules by autophagy-tethering compounds (ATTECs), using lipid droplets (LDs) as an exemplar target. LDs are ubiquitous cellular structures storing lipids and could be degraded by autophagy. We hypothesized that compounds interacting with both the LDs and the key autophagosome protein LC3 may enhance autophagic degradation of LDs. We designed and synthesized such compounds by connecting LC3-binding molecules to LD-binding probes via a linker. These compounds were capable of clearing LDs almost completely and rescued LD-related phenotypes in cells and in two independent mouse models with hepatic lipidosis. We further confirmed that the mechanism of action of these compounds was mediated through LC3 and autophagic degradation. Our proof-of-concept study demonstrates the capability of degrading LDs by ATTECs. Conceptually, this strategy could be applied to other protein and non-protein targets.
Topics: Animals; Autophagosomes; Autophagy; Chimera; Lipid Droplets; Lipid Metabolism; Mice; Proteins
PubMed: 34239073
DOI: 10.1038/s41422-021-00532-7 -
Science (New York, N.Y.) Apr 2020Embryonic development is a complex process that is unamenable to direct observation. In this study, we implanted a window to the mouse uterus to visualize the developing...
Embryonic development is a complex process that is unamenable to direct observation. In this study, we implanted a window to the mouse uterus to visualize the developing embryo from embryonic day 9.5 to birth. This removable intravital window allowed manipulation and high-resolution imaging. In live mouse embryos, we observed transient neurotransmission and early vascularization of neural crest cell (NCC)-derived perivascular cells in the brain, autophagy in the retina, viral gene delivery, and chemical diffusion through the placenta. We combined the imaging window with in utero electroporation to label and track cell division and movement within embryos and observed that clusters of mouse NCC-derived cells expanded in interspecies chimeras, whereas adjacent human donor NCC-derived cells shrank. This technique can be combined with various tissue manipulation and microscopy methods to study the processes of development at unprecedented spatiotemporal resolution.
Topics: Animals; Brain; Cell Division; Cell Movement; Chimera; Electroporation; Embryo, Mammalian; Embryonic Development; Female; Gene Transfer Techniques; Intravital Microscopy; Mice; Mice, Transgenic; Neovascularization, Physiologic; Neural Crest; Placenta; Pregnancy; Retina; Synaptic Transmission; Uterus
PubMed: 32273467
DOI: 10.1126/science.aba0210 -
Generation of rat pancreas in mouse by interspecific blastocyst injection of pluripotent stem cells.Cell Sep 2010The complexity of organogenesis hinders in vitro generation of organs derived from a patient's pluripotent stem cells (PSCs), an ultimate goal of regenerative medicine....
The complexity of organogenesis hinders in vitro generation of organs derived from a patient's pluripotent stem cells (PSCs), an ultimate goal of regenerative medicine. Mouse wild-type PSCs injected into Pdx1(-/-) (pancreatogenesis-disabled) mouse blastocysts developmentally compensated vacancy of the pancreatic "developmental niche," generating almost entirely PSC-derived pancreas. To examine the potential for xenogenic approaches in blastocyst complementation, we injected mouse or rat PSCs into rat or mouse blastocysts, respectively, generating interspecific chimeras and thus confirming that PSCs can contribute to xenogenic development between mouse and rat. The development of these mouse/rat chimeras was primarily influenced by host blastocyst and/or foster mother, evident by body size and species-specific organogenesis. We further injected rat wild-type PSCs into Pdx1(-/-) mouse blastocysts, generating normally functioning rat pancreas in Pdx1(-/-) mice. These data constitute proof of principle for interspecific blastocyst complementation and for generation in vivo of organs derived from donor PSCs using a xenogenic environment.
Topics: Animals; Blastocyst; Chimera; Diabetes Mellitus; Embryonic Development; Gene Knock-In Techniques; Homeodomain Proteins; Mice; Mice, Inbred Strains; Organogenesis; Pancreas; Pluripotent Stem Cells; Rats; Rats, Wistar; Trans-Activators
PubMed: 20813264
DOI: 10.1016/j.cell.2010.07.039 -
Medecine Sciences : M/S Oct 2021Inter-species chimeras are both fantastic and monstrous creatures from Greek or Egyptian mythology, and a long-established research tool. Recent advances in the field of...
Inter-species chimeras are both fantastic and monstrous creatures from Greek or Egyptian mythology, and a long-established research tool. Recent advances in the field of pluripotent stem cells have made it possible to extend the repertoire of inter-species chimeras to "systemic" chimeras, in which the mixing of cells from both species involves all organs including the germline. These chimeric embryos and fetuses open up new research avenues and potential medical applications. We will review the latest advances in the field. We will discuss the concepts of developmental complementation and developmental equivalence. We will discuss the methodological hurdles to be unlocked, as well as the biological and ethical limits of these new technologies.
Topics: Chimera; Germ Cells; Immunotherapy; Mythology; Pluripotent Stem Cells
PubMed: 34647874
DOI: 10.1051/medsci/2021145 -
Nature Methods Aug 2022The study of human–animal chimeras is fraught with technical and ethical challenges. In this Comment, we discuss the importance and future of human–monkey chimera...
The study of human–animal chimeras is fraught with technical and ethical challenges. In this Comment, we discuss the importance and future of human–monkey chimera research within the context of current scientific and regulatory obstacles.
Topics: Animals; Chimera; Embryo, Mammalian; Haplorhini; Humans
PubMed: 35879609
DOI: 10.1038/s41592-022-01571-7 -
Journal of Plant Research Jan 2018For millennia, people have cut and joined different plant tissues together through a process known as grafting. By creating a chimeric organism, desirable properties... (Review)
Review
For millennia, people have cut and joined different plant tissues together through a process known as grafting. By creating a chimeric organism, desirable properties from two plants combine to enhance disease resistance, abiotic stress tolerance, vigour or facilitate the asexual propagation of plants. In addition, grafting has been extremely informative in science for studying and identifying the long-distance movement of molecules. Despite its increasing use in horticulture and science, how plants undertake the process of grafting remains elusive. Here, we discuss specifically the role of eight major plant hormones during the wound healing and vascular formation process, two phenomena involved in grafting. We furthermore present the roles of these hormones during graft formation and highlight knowledge gaps and future areas of interest for the field of grafting biology.
Topics: Chimera; Plant Breeding; Plant Growth Regulators; Transplants
PubMed: 29181647
DOI: 10.1007/s10265-017-0994-5 -
Developmental Biology Nov 2016Chimeras - organisms that are composed of cells of more than one genotype - captured the human imagination long before they were formally described and used in the... (Review)
Review
Chimeras - organisms that are composed of cells of more than one genotype - captured the human imagination long before they were formally described and used in the laboratory. These organisms owe their namesake to a fire-breathing monster from Greek mythology that has the head of a lion, the body of a goat, and the tail of a serpent. The first description of a non-fictional chimera dates back to the middle of the seventeenth century when the Florentine gardener Pietro Nati discovered an adventitious shoot growing from the graft junction between sour orange (Citrus aurantium) and citron (Citrus medica). This perplexing chimera that grows with sectors phenotypically resembling each of the citrus progenitors inspired discussion and wonder from the scientific community and was fittingly named the 'Bizzaria'. Initially, the 'Bizzaria' was believed to be an asexual hybrid that formed from a cellular fusion between the grafted parents; however, in-depth cellular analyses carried out centuries later demonstrated that the 'Bizzaria', along with other chimeras, owe their unique sectored appearance to a conglomeration of cells from the two donors. Since this pivotal discovery at the turn of the twentieth century, chimeras have served both as tools and as unique biological phenomena that have contributed to our understanding of plant development at the cellular, tissue, and organismal level. Rapid advancements in genome sequencing technologies have enabled the establishment of new model species with novel morphological and developmental features that enable the generation of chimeric organisms. In this review, we show that genetic mosaic and chimera studies provide a technologically simple way to delve into the organismal, genetic, and genomic inner workings underlying the development of diverse model organisms. Moreover, we discuss the unique opportunity that chimeras present to explore universal principles governing intercellular communication and the coordination of organismal biology in a heterogenomic landscape.
Topics: Chimera; Chromosomal Instability; Chromosomes, Plant; Citrus; History, 17th Century; Hybrid Vigor; Meristem; Models, Biological; Mosaicism; Phenotype; Plant Breeding; Plant Shoots; Plants; Plants, Genetically Modified; Species Specificity; Transplants
PubMed: 27381079
DOI: 10.1016/j.ydbio.2016.07.003 -
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