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Nature Feb 2019Mammalian organogenesis is a remarkable process. Within a short timeframe, the cells of the three germ layers transform into an embryo that includes most of the major...
Mammalian organogenesis is a remarkable process. Within a short timeframe, the cells of the three germ layers transform into an embryo that includes most of the major internal and external organs. Here we investigate the transcriptional dynamics of mouse organogenesis at single-cell resolution. Using single-cell combinatorial indexing, we profiled the transcriptomes of around 2 million cells derived from 61 embryos staged between 9.5 and 13.5 days of gestation, in a single experiment. The resulting 'mouse organogenesis cell atlas' (MOCA) provides a global view of developmental processes during this critical window. We use Monocle 3 to identify hundreds of cell types and 56 trajectories, many of which are detected only because of the depth of cellular coverage, and collectively define thousands of corresponding marker genes. We explore the dynamics of gene expression within cell types and trajectories over time, including focused analyses of the apical ectodermal ridge, limb mesenchyme and skeletal muscle.
Topics: Animals; Ectoderm; Embryo, Mammalian; Female; Gene Expression Regulation, Developmental; Genetic Markers; Male; Mesoderm; Mice; Muscle Development; Muscle, Skeletal; Organ Specificity; Organogenesis; Sequence Analysis, RNA; Single-Cell Analysis; Time Factors; Transcriptome
PubMed: 30787437
DOI: 10.1038/s41586-019-0969-x -
Development (Cambridge, England) Jun 2017Skeletal muscle is the largest tissue in the body and loss of its function or its regenerative properties results in debilitating musculoskeletal disorders.... (Review)
Review
Skeletal muscle is the largest tissue in the body and loss of its function or its regenerative properties results in debilitating musculoskeletal disorders. Understanding the mechanisms that drive skeletal muscle formation will not only help to unravel the molecular basis of skeletal muscle diseases, but also provide a roadmap for recapitulating skeletal myogenesis from pluripotent stem cells (PSCs). PSCs have become an important tool for probing developmental questions, while differentiated cell types allow the development of novel therapeutic strategies. In this Review, we provide a comprehensive overview of skeletal myogenesis from the earliest premyogenic progenitor stage to terminally differentiated myofibers, and discuss how this knowledge has been applied to differentiate PSCs into muscle fibers and their progenitors .
Topics: Animals; Cell Differentiation; Cellular Reprogramming; Humans; Mesoderm; Mice; Models, Biological; Muscle Development; Muscle Fibers, Skeletal; Muscle, Skeletal; Myoblasts, Skeletal; Pluripotent Stem Cells; Somites
PubMed: 28634270
DOI: 10.1242/dev.151035 -
Science (New York, N.Y.) Apr 2017Mammalian embryogenesis requires intricate interactions between embryonic and extraembryonic tissues to orchestrate and coordinate morphogenesis with changes in...
Mammalian embryogenesis requires intricate interactions between embryonic and extraembryonic tissues to orchestrate and coordinate morphogenesis with changes in developmental potential. Here, we combined mouse embryonic stem cells (ESCs) and extraembryonic trophoblast stem cells (TSCs) in a three-dimensional scaffold to generate structures whose morphogenesis is markedly similar to that of natural embryos. By using genetically modified stem cells and specific inhibitors, we show that embryogenesis of ESC- and TSC-derived embryos-ETS-embryos-depends on cross-talk involving Nodal signaling. When ETS-embryos develop, they spontaneously initiate expression of mesoderm and primordial germ cell markers asymmetrically on the embryonic and extraembryonic border, in response to Wnt and BMP signaling. Our study demonstrates the ability of distinct stem cell types to self-assemble in vitro to generate embryos whose morphogenesis, architecture, and constituent cell types resemble those of natural embryos.
Topics: Animals; Embryo Implantation; Embryo, Mammalian; Embryonic Development; Embryonic Stem Cells; Gastrulation; Germ Layers; In Vitro Techniques; Mesoderm; Mice; Models, Biological; Tissue Scaffolds; Trophoblasts; Wnt Signaling Pathway
PubMed: 28254784
DOI: 10.1126/science.aal1810 -
Nature Nov 2017Acquired drug resistance prevents cancer therapies from achieving stable and complete responses. Emerging evidence implicates a key role for non-mutational drug...
Acquired drug resistance prevents cancer therapies from achieving stable and complete responses. Emerging evidence implicates a key role for non-mutational drug resistance mechanisms underlying the survival of residual cancer 'persister' cells. The persister cell pool constitutes a reservoir from which drug-resistant tumours may emerge. Targeting persister cells therefore presents a therapeutic opportunity to impede tumour relapse. We previously found that cancer cells in a high mesenchymal therapy-resistant cell state are dependent on the lipid hydroperoxidase GPX4 for survival. Here we show that a similar therapy-resistant cell state underlies the behaviour of persister cells derived from a wide range of cancers and drug treatments. Consequently, we demonstrate that persister cells acquire a dependency on GPX4. Loss of GPX4 function results in selective persister cell ferroptotic death in vitro and prevents tumour relapse in mice. These findings suggest that targeting of GPX4 may represent a therapeutic strategy to prevent acquired drug resistance.
Topics: Animals; Antioxidants; Apoptosis; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Female; Glutathione Peroxidase; Humans; Iron; Male; Mesoderm; Mice; Molecular Targeted Therapy; Neoplasms; Phospholipid Hydroperoxide Glutathione Peroxidase; Recurrence; Xenograft Model Antitumor Assays
PubMed: 29088702
DOI: 10.1038/nature24297 -
Seminars in Cell & Developmental Biology Jul 2019The intermediate mesoderm is located between the somites and the lateral plate mesoderm and gives rise to renal progenitors that contribute to the three mammalian kidney... (Review)
Review
The intermediate mesoderm is located between the somites and the lateral plate mesoderm and gives rise to renal progenitors that contribute to the three mammalian kidney types (pronephros, mesonephros and metanephros). In this review, focusing largely on murine kidney development, we examine how the intermediate mesoderm forms during gastrulation/axis elongation and how it progressively gives rise to distinct renal progenitors along the rostro-caudal axis. We highlight some of the potential signalling cues and core transcription factor circuits that direct these processes, up to the point of early metanephric kidney formation.
Topics: Animals; Body Patterning; Gene Expression Regulation, Developmental; Kidney; Mesoderm; Mesonephros; Mice; Organogenesis; Somites; Transcription Factors
PubMed: 30172050
DOI: 10.1016/j.semcdb.2018.08.016 -
Current Topics in Developmental Biology 2020In birds as in all amniotes, the site of gastrulation is a midline structure, the primitive streak. This appears as cells in the one cell-thick epiblast undergo... (Review)
Review
In birds as in all amniotes, the site of gastrulation is a midline structure, the primitive streak. This appears as cells in the one cell-thick epiblast undergo epithelial-to-mesenchymal transition to ingress and form definitive mesoderm and endoderm. Global movements involving tens of thousands of cells in the embryonic epiblast precede gastrulation. They position the primitive streak precursors from a marginal position (equivalent to the situation in anamniotes) along the future antero-posterior axis (typical for amniotes). These epithelial movements continue in modified form during gastrulation, when they are accompanied by collective movements of different class in the forming mesoderm and endoderm. Here I discuss the nature of these collective cell movements shaping the embryo, their interplay with signaling events controlling fate specification and significance in an evolutionary perspective.
Topics: Animals; Cell Movement; Chick Embryo; Chickens; Endoderm; Gastrula; Gastrulation; Gene Expression Regulation, Developmental; Mesoderm; Signal Transduction; Zebrafish Proteins; Zygote
PubMed: 31959297
DOI: 10.1016/bs.ctdb.2019.11.015 -
Cell Feb 2023Axial development of mammals involves coordinated morphogenetic events, including axial elongation, somitogenesis, and neural tube formation. To gain insight into the...
Axial development of mammals involves coordinated morphogenetic events, including axial elongation, somitogenesis, and neural tube formation. To gain insight into the signals controlling the dynamics of human axial morphogenesis, we generated axially elongating organoids by inducing anteroposterior symmetry breaking of spatially coupled epithelial cysts derived from human pluripotent stem cells. Each organoid was composed of a neural tube flanked by presomitic mesoderm sequentially segmented into somites. Periodic activation of the somite differentiation gene MESP2 coincided in space and time with anteriorly traveling segmentation clock waves in the presomitic mesoderm of the organoids, recapitulating critical aspects of somitogenesis. Timed perturbations demonstrated that FGF and WNT signaling play distinct roles in axial elongation and somitogenesis, and that FGF signaling gradients drive segmentation clock waves. By generating and perturbing organoids that robustly recapitulate the architecture of multiple axial tissues in human embryos, this work offers a means to dissect mechanisms underlying human embryogenesis.
Topics: Animals; Humans; Body Patterning; Embryonic Development; Gene Expression Regulation, Developmental; Mammals; Mesoderm; Morphogenesis; Somites; Wnt Signaling Pathway; Organoids
PubMed: 36657441
DOI: 10.1016/j.cell.2022.12.042 -
Nature Communications Sep 2020Understanding cell types and mechanisms of dental growth is essential for reconstruction and engineering of teeth. Therefore, we investigated cellular composition of...
Understanding cell types and mechanisms of dental growth is essential for reconstruction and engineering of teeth. Therefore, we investigated cellular composition of growing and non-growing mouse and human teeth. As a result, we report an unappreciated cellular complexity of the continuously-growing mouse incisor, which suggests a coherent model of cell dynamics enabling unarrested growth. This model relies on spatially-restricted stem, progenitor and differentiated populations in the epithelial and mesenchymal compartments underlying the coordinated expansion of two major branches of pulpal cells and diverse epithelial subtypes. Further comparisons of human and mouse teeth yield both parallelisms and differences in tissue heterogeneity and highlight the specifics behind growing and non-growing modes. Despite being similar at a coarse level, mouse and human teeth reveal molecular differences and species-specific cell subtypes suggesting possible evolutionary divergence. Overall, here we provide an atlas of human and mouse teeth with a focus on growth and differentiation.
Topics: Adolescent; Adult; Animals; Cell Differentiation; Epithelial Cells; Female; Gene Expression Regulation, Developmental; Genetic Heterogeneity; Humans; Incisor; Male; Mesoderm; Mice; Mice, Inbred C57BL; Models, Animal; Molar; Odontoblasts; Stem Cells; Tooth; Young Adult
PubMed: 32968047
DOI: 10.1038/s41467-020-18512-7 -
Cell Jul 2016Stem-cell differentiation to desired lineages requires navigating alternating developmental paths that often lead to unwanted cell types. Hence, comprehensive...
Stem-cell differentiation to desired lineages requires navigating alternating developmental paths that often lead to unwanted cell types. Hence, comprehensive developmental roadmaps are crucial to channel stem-cell differentiation toward desired fates. To this end, here, we map bifurcating lineage choices leading from pluripotency to 12 human mesodermal lineages, including bone, muscle, and heart. We defined the extrinsic signals controlling each binary lineage decision, enabling us to logically block differentiation toward unwanted fates and rapidly steer pluripotent stem cells toward 80%-99% pure human mesodermal lineages at most branchpoints. This strategy enabled the generation of human bone and heart progenitors that could engraft in respective in vivo models. Mapping stepwise chromatin and single-cell gene expression changes in mesoderm development uncovered somite segmentation, a previously unobservable human embryonic event transiently marked by HOPX expression. Collectively, this roadmap enables navigation of mesodermal development to produce transplantable human tissue progenitors and uncover developmental processes. VIDEO ABSTRACT.
Topics: Bone Morphogenetic Proteins; Bone and Bones; Heart; Homeodomain Proteins; Humans; Mesoderm; Myocytes, Cardiac; Pluripotent Stem Cells; Primitive Streak; Signal Transduction; Single-Cell Analysis; Somites; Stem Cells; Tumor Suppressor Proteins; Wnt Proteins
PubMed: 27419872
DOI: 10.1016/j.cell.2016.06.011 -
Current Topics in Developmental Biology 2015
Topics: Animals; Craniofacial Abnormalities; Gene Expression Regulation, Developmental; Humans; Mesoderm; Morphogenesis; Neural Crest; Signal Transduction; Skull; Transcription Factors
PubMed: 26589940
DOI: 10.1016/S0070-2153(15)00137-4