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Nature Jun 2020The skin is a multilayered organ, equipped with appendages (that is, follicles and glands), that is critical for regulating body temperature and the retention of bodily...
The skin is a multilayered organ, equipped with appendages (that is, follicles and glands), that is critical for regulating body temperature and the retention of bodily fluids, guarding against external stresses and mediating the sensation of touch and pain. Reconstructing appendage-bearing skin in cultures and in bioengineered grafts is a biomedical challenge that has yet to be met. Here we report an organoid culture system that generates complex skin from human pluripotent stem cells. We use stepwise modulation of the transforming growth factor β (TGFβ) and fibroblast growth factor (FGF) signalling pathways to co-induce cranial epithelial cells and neural crest cells within a spherical cell aggregate. During an incubation period of 4-5 months, we observe the emergence of a cyst-like skin organoid composed of stratified epidermis, fat-rich dermis and pigmented hair follicles that are equipped with sebaceous glands. A network of sensory neurons and Schwann cells form nerve-like bundles that target Merkel cells in organoid hair follicles, mimicking the neural circuitry associated with human touch. Single-cell RNA sequencing and direct comparison to fetal specimens suggest that the skin organoids are equivalent to the facial skin of human fetuses in the second trimester of development. Moreover, we show that skin organoids form planar hair-bearing skin when grafted onto nude mice. Together, our results demonstrate that nearly complete skin can self-assemble in vitro and be used to reconstitute skin in vivo. We anticipate that our skin organoids will provide a foundation for future studies of human skin development, disease modelling and reconstructive surgery.
Topics: Animals; Ectoderm; Female; Hair; Hair Color; Hair Follicle; Head; Heterografts; Humans; Mice; Mice, Nude; Organoids; Pluripotent Stem Cells; RNA-Seq; Single-Cell Analysis; Skin; Skin Transplantation
PubMed: 32494013
DOI: 10.1038/s41586-020-2352-3 -
Orphanet Journal of Rare Diseases Oct 2022The objective of this systematic review was to determine the orthodontic and dentofacial orthopedic treatments carried out in patients with ectodermal dysplasia to... (Review)
Review
OBJECTIVE
The objective of this systematic review was to determine the orthodontic and dentofacial orthopedic treatments carried out in patients with ectodermal dysplasia to facilitate functional and aesthetic rehabilitation.
METHODS
The systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis statement. We systematically searched PubMed, Web of Science, Scopus, Scielo, LILACS, EBSCOhost and Embase databases up to 6 January 2022. We included articles describing patients with any type of ectodermal dysplasia who received orthodontic or dentofacial orthopedic treatment to facilitate functional and aesthetic oral rehabilitation. The search was not restricted by language or year of publication. The quality of the studies was assessed using the Joanna Briggs Institute Quality Assessment Scale of the University of Adelaide for case series and case reports. The review was registered at the University of York Centre for reviews (CRD42021288030).
RESULTS
Of the initial 403 studies found, 29 met the inclusion criteria. After applying the quality scale, 23 were left for review-21 case reports and 2 case series. The initial age of patients ranged from 34 months to 24 years. Thirteen studies were on hypohidrotic and/or anhidrotic ectodermal dysplasia, of which two were X-chromosome linked. In one study, the patient had Wiktop syndrome, and in nine the type of ectodermal dysplasia was not specified. The duration of treatment was 7 weeks to 10 years. The treatments described were: fixed orthodontic appliances or simple acrylic plates designed for tooth movement, including leveling and aligning, closing of diastemata, retraction of impacted teeth in the dental arch; clear aligners; fixed and/or removable appliances for the correction of skeletal and/or dentoalveolar relationships; palatal expanders in combination with face masks for orthopedic traction of the maxilla; and orthognathic surgery. Only three studies provided cephalometric data.
CONCLUSION
The level of evidence of the articles reviewed was low and most orthopedic and dentofacial orthodontic treatments described were focused on correcting dental malpositioning and jaw asymmetries and not on stimulating growth from an early age. Studies with greater scientific evidence are needed to determine the best treatment for these patients.
Topics: Child, Preschool; Ectodermal Dysplasia; Ectodermal Dysplasia 1, Anhidrotic; Humans; Tooth Movement Techniques
PubMed: 36253866
DOI: 10.1186/s13023-022-02533-0 -
Nature Nov 2021Understanding human organ formation is a scientific challenge with far-reaching medical implications. Three-dimensional stem-cell cultures have provided insights into...
Understanding human organ formation is a scientific challenge with far-reaching medical implications. Three-dimensional stem-cell cultures have provided insights into human cell differentiation. However, current approaches use scaffold-free stem-cell aggregates, which develop non-reproducible tissue shapes and variable cell-fate patterns. This limits their capacity to recapitulate organ formation. Here we present a chip-based culture system that enables self-organization of micropatterned stem cells into precise three-dimensional cell-fate patterns and organ shapes. We use this system to recreate neural tube folding from human stem cells in a dish. Upon neural induction, neural ectoderm folds into a millimetre-long neural tube covered with non-neural ectoderm. Folding occurs at 90% fidelity, and anatomically resembles the developing human neural tube. We find that neural and non-neural ectoderm are necessary and sufficient for folding morphogenesis. We identify two mechanisms drive folding: (1) apical contraction of neural ectoderm, and (2) basal adhesion mediated via extracellular matrix synthesis by non-neural ectoderm. Targeting these two mechanisms using drugs leads to morphological defects similar to neural tube defects. Finally, we show that neural tissue width determines neural tube shape, suggesting that morphology along the anterior-posterior axis depends on neural ectoderm geometry in addition to molecular gradients. Our approach provides a new route to the study of human organ morphogenesis in health and disease.
Topics: Ectoderm; Humans; Models, Biological; Morphogenesis; Neural Plate; Neural Tube; Neural Tube Defects; Organ Culture Techniques; Regeneration; Stem Cells
PubMed: 34707290
DOI: 10.1038/s41586-021-04026-9 -
Cell Stem Cell Sep 2022Despite its clinical and fundamental importance, our understanding of early human development remains limited. Stem cell-derived, embryo-like structures (or embryoids)...
Despite its clinical and fundamental importance, our understanding of early human development remains limited. Stem cell-derived, embryo-like structures (or embryoids) allowing studies of early development without using natural embryos can potentially help fill the knowledge gap of human development. Herein, transcriptome at the single-cell level of a human embryoid model was profiled at different time points. Molecular maps of lineage diversifications from the pluripotent human epiblast toward the amniotic ectoderm, primitive streak/mesoderm, and primordial germ cells were constructed and compared with in vivo primate data. The comparative transcriptome analyses reveal a critical role of NODAL signaling in human mesoderm and primordial germ cell specification, which is further functionally validated. Through comparative transcriptome analyses and validations with human blastocysts and in vitro cultured cynomolgus embryos, we further proposed stringent criteria for distinguishing between human blastocyst trophectoderm and early amniotic ectoderm cells.
Topics: Animals; Blastocyst; Cell Lineage; Ectoderm; Embryo, Mammalian; Germ Layers; Humans; Single-Cell Analysis
PubMed: 36055194
DOI: 10.1016/j.stem.2022.08.009 -
Nature Nov 2020Current understandings of cell specification in early mammalian pre-implantation development are based mainly on mouse studies. The first lineage differentiation event... (Comparative Study)
Comparative Study
Current understandings of cell specification in early mammalian pre-implantation development are based mainly on mouse studies. The first lineage differentiation event occurs at the morula stage, with outer cells initiating a trophectoderm (TE) placental progenitor program. The inner cell mass arises from inner cells during subsequent developmental stages and comprises precursor cells of the embryo proper and yolk sac. Recent gene-expression analyses suggest that the mechanisms that regulate early lineage specification in the mouse may differ in other mammals, including human and cow. Here we show the evolutionary conservation of a molecular cascade that initiates TE segregation in human, cow and mouse embryos. At the morula stage, outer cells acquire an apical-basal cell polarity, with expression of atypical protein kinase C (aPKC) at the contact-free domain, nuclear expression of Hippo signalling pathway effectors and restricted expression of TE-associated factors such as GATA3, which suggests initiation of a TE program. Furthermore, we demonstrate that inhibition of aPKC by small-molecule pharmacological modulation or Trim-Away protein depletion impairs TE initiation at the morula stage. Our comparative embryology analysis provides insights into early lineage specification and suggests that a similar mechanism initiates a TE program in human, cow and mouse embryos.
Topics: Adaptor Proteins, Signal Transducing; Animals; Biological Evolution; Blastocyst Inner Cell Mass; Cattle; Cell Lineage; Cell Polarity; Ectoderm; Embryo, Mammalian; Female; GATA3 Transcription Factor; Gene Expression Regulation, Developmental; Hippo Signaling Pathway; Humans; Mice; Morula; Placenta; Pregnancy; Protein Kinase C; Protein Serine-Threonine Kinases; SOXB1 Transcription Factors; Signal Transduction; Transcription Factors; Transcription, Genetic; Trophoblasts; YAP-Signaling Proteins; Yolk Sac
PubMed: 32968278
DOI: 10.1038/s41586-020-2759-x -
Nature Communications Feb 2021Extensive epigenetic reprogramming occurs during preimplantation embryo development. However, it remains largely unclear how the drastic epigenetic reprogramming...
Extensive epigenetic reprogramming occurs during preimplantation embryo development. However, it remains largely unclear how the drastic epigenetic reprogramming contributes to transcriptional regulatory network during this period. Here, we develop a single-cell multiomics sequencing technology (scNOMeRe-seq) that enables profiling of genome-wide chromatin accessibility, DNA methylation and RNA expression in the same individual cell. We apply this method to depict a single-cell multiomics map of mouse preimplantation development. We find that genome-wide DNA methylation remodeling facilitates the reconstruction of genetic lineages in early embryos. Further, we construct a zygotic genome activation (ZGA)-associated regulatory network and reveal coordination among multiple epigenetic layers, transcription factors and repeat elements that instruct proper ZGA. Cell fates associated cis-regulatory elements are activated stepwise in post-ZGA stages. Trophectoderm (TE)-specific transcription factors play dual roles in promoting the TE program while repressing the inner cell mass (ICM) program during the ICM/TE separation.
Topics: Alleles; Animals; Blastocyst; Cell Lineage; Chromatin; DNA Methylation; Ectoderm; Embryo, Mammalian; Female; Gene Expression Regulation, Developmental; Genomics; Male; Mice; Phylogeny; Promoter Regions, Genetic; Single-Cell Analysis; Zygote
PubMed: 33623021
DOI: 10.1038/s41467-021-21409-8