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Developmental Biology May 2022
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Frontiers in Genetics 2022In 2002 we published an article describing a population of vessel-associated progenitors that we termed mesoangioblasts (MABs). During the past decade evidence had... (Review)
Review
In 2002 we published an article describing a population of vessel-associated progenitors that we termed mesoangioblasts (MABs). During the past decade evidence had accumulated that during muscle development and regeneration things may be more complex than a simple sequence of binary choices (e.g., dorsal vs. ventral somite). LacZ expressing fibroblasts could fuse with unlabelled myoblasts but not among themselves or with other cell types. Bone marrow derived, circulating progenitors were able to participate in muscle regeneration, though in very small percentage. Searching for the embryonic origin of these progenitors, we identified them as originating at least in part from the embryonic aorta and, at later stages, from the microvasculature of skeletal muscle. While continuing to investigate origin and fate of MABs, the fact that they could be expanded (also from human muscle) and cross the vessel wall, suggested a protocol for the cell therapy of muscular dystrophies. We tested this protocol in mice and dogs before proceeding to the first clinical trial on Duchenne Muscular Dystrophy patients that showed safety but minimal efficacy. In the last years, we have worked to overcome the problem of low engraftment and tried to understand their role as auxiliary myogenic progenitors during development and regeneration.
PubMed: 36685855
DOI: 10.3389/fgene.2022.1056114 -
Nature Biotechnology Jan 2022Molecular profiling of single cells has advanced our knowledge of the molecular basis of development. However, current approaches mostly rely on dissociating cells from...
Molecular profiling of single cells has advanced our knowledge of the molecular basis of development. However, current approaches mostly rely on dissociating cells from tissues, thereby losing the crucial spatial context of regulatory processes. Here, we apply an image-based single-cell transcriptomics method, sequential fluorescence in situ hybridization (seqFISH), to detect mRNAs for 387 target genes in tissue sections of mouse embryos at the 8-12 somite stage. By integrating spatial context and multiplexed transcriptional measurements with two single-cell transcriptome atlases, we characterize cell types across the embryo and demonstrate that spatially resolved expression of genes not profiled by seqFISH can be imputed. We use this high-resolution spatial map to characterize fundamental steps in the patterning of the midbrain-hindbrain boundary (MHB) and the developing gut tube. We uncover axes of cell differentiation that are not apparent from single-cell RNA-sequencing (scRNA-seq) data, such as early dorsal-ventral separation of esophageal and tracheal progenitor populations in the gut tube. Our method provides an approach for studying cell fate decisions in complex tissues and development.
Topics: Animals; In Situ Hybridization, Fluorescence; Mice; Organogenesis; RNA, Messenger; Single-Cell Analysis; Transcriptome
PubMed: 34489600
DOI: 10.1038/s41587-021-01006-2 -
Seminars in Cell & Developmental Biology Jul 2022The discovery of mesoderm inducing signals helped usher in the era of molecular developmental biology, and today the mechanisms of mesoderm induction and patterning are... (Review)
Review
The discovery of mesoderm inducing signals helped usher in the era of molecular developmental biology, and today the mechanisms of mesoderm induction and patterning are still intensely studied. Mesoderm induction begins during gastrulation, but recent evidence in vertebrates shows that this process continues after gastrulation in a group of posteriorly localized cells called neuromesodermal progenitors (NMPs). NMPs reside within the post-gastrulation embryonic structure called the tailbud, where they make a lineage decision between ectoderm (spinal cord) and mesoderm. The majority of NMP-derived mesoderm generates somites, but also contributes to lateral mesoderm fates such as endothelium. The discovery of NMPs provides a new paradigm in which to study vertebrate mesoderm induction. This review will discuss mechanisms of mesoderm induction within NMPs, and how they have informed our understanding of mesoderm induction more broadly within vertebrates as well as animal species outside of the vertebrate lineage. Special focus will be given to the signaling networks underlying NMP-derived mesoderm induction and patterning, as well as emerging work on the significance of partial epithelial-mesenchymal states in coordinating cell fate and morphogenesis.
Topics: Animals; Body Patterning; Cell Differentiation; Gastrulation; Gene Expression Regulation, Developmental; Mesoderm; Somites
PubMed: 34840081
DOI: 10.1016/j.semcdb.2021.11.010 -
International Journal of Molecular... Aug 2021To ensure the formation of a properly patterned embryo, multiple processes must operate harmoniously at sequential phases of development. This is implemented by mutual... (Review)
Review
To ensure the formation of a properly patterned embryo, multiple processes must operate harmoniously at sequential phases of development. This is implemented by mutual interactions between cells and tissues that together regulate the segregation and specification of cells, their growth and morphogenesis. The formation of the spinal cord and paraxial mesoderm derivatives exquisitely illustrate these processes. Following early gastrulation, while the vertebrate body elongates, a population of bipotent neuromesodermal progenitors resident in the posterior region of the embryo generate both neural and mesodermal lineages. At later stages, the somitic mesoderm regulates aspects of neural patterning and differentiation of both central and peripheral neural progenitors. Reciprocally, neural precursors influence the paraxial mesoderm to regulate somite-derived myogenesis and additional processes by distinct mechanisms. Central to this crosstalk is the activity of the axial notochord, which, via sonic hedgehog signaling, plays pivotal roles in neural, skeletal muscle and cartilage ontogeny. Here, we discuss the cellular and molecular basis underlying this complex developmental plan, with a focus on the logic of sonic hedgehog activities in the coordination of the neural-mesodermal axis.
Topics: Animals; Cell Differentiation; Embryonic Stem Cells; Gene Expression Regulation, Developmental; Hedgehog Proteins; Humans; Mesoderm; Neural Tube
PubMed: 34502050
DOI: 10.3390/ijms22179141 -
Development (Cambridge, England) Aug 2019Consistent asymmetries between the left and right sides of animal bodies are common. For example, the internal organs of vertebrates are left-right (L-R) asymmetric in a... (Review)
Review
Consistent asymmetries between the left and right sides of animal bodies are common. For example, the internal organs of vertebrates are left-right (L-R) asymmetric in a stereotyped fashion. Other structures, such as the skeleton and muscles, are largely symmetric. This Review considers how symmetries and asymmetries form alongside each other within the embryo, and how they are then maintained during growth. I describe how asymmetric signals are generated in the embryo. Using the limbs and somites as major examples, I then address mechanisms for protecting symmetrically forming tissues from asymmetrically acting signals. These examples reveal that symmetry should not be considered as an inherent background state, but instead must be actively maintained throughout multiple phases of embryonic patterning and organismal growth.
Topics: Animals; Body Patterning; Disease; Embryonic Development; Extremities; Humans; Mice; Somites
PubMed: 31416929
DOI: 10.1242/dev.170985 -
Cell Reports Apr 2023Recent advances in synthetic embryology have opened new avenues for understanding the complex events controlling mammalian peri-implantation development. Here, we show...
Recent advances in synthetic embryology have opened new avenues for understanding the complex events controlling mammalian peri-implantation development. Here, we show that mouse embryonic stem cells (ESCs) solely exposed to chemical inhibition of SUMOylation generate embryo-like structures comprising anterior neural and trunk-associated regions. HypoSUMOylation-instructed ESCs give rise to spheroids that self-organize into gastrulating structures containing cell types spatially and functionally related to embryonic and extraembryonic compartments. Alternatively, spheroids cultured in a droplet microfluidic device form elongated structures that undergo axial organization reminiscent of natural embryo morphogenesis. Single-cell transcriptomics reveals various cellular lineages, including properly positioned anterior neuronal cell types and paraxial mesoderm segmented into somite-like structures. Transient SUMOylation suppression gradually increases DNA methylation genome wide and repressive mark deposition at Nanog. Interestingly, cell-to-cell variations in SUMOylation levels occur during early embryogenesis. Our approach provides a proof of principle for potentially powerful strategies to explore early embryogenesis by targeting chromatin roadblocks of cell fate change.
Topics: Animals; Mice; Sumoylation; Embryo, Mammalian; Embryonic Stem Cells; Embryonic Development; Cell Differentiation; Mammals
PubMed: 37061916
DOI: 10.1016/j.celrep.2023.112380 -
Developmental Biology Apr 2020Multicellular animals and plants represent independent evolutionary experiments with complex multicellular bodyplans. Differences in their life history, a mobile versus... (Review)
Review
Multicellular animals and plants represent independent evolutionary experiments with complex multicellular bodyplans. Differences in their life history, a mobile versus sessile lifestyle, and predominant embryonic versus postembryonic development, have led to the evolution of highly different body plans. However, also many intriguing parallels exist. Extension of the vertebrate body axis and its segmentation into somites bears striking resemblance to plant root growth and the concomittant prepatterning of lateral root competent sites. Likewise, plant shoot phyllotaxis displays similarities with vertebrate limb and digit patterning. Additionally, both plants and animals use complex signalling systems combining systemic and local signals to fine tune and coordinate organ growth across their body. Identification of these striking examples of convergent evolution provides support for the existence of general design principles: the idea that for particular patterning demands, evolution is likely to arrive at highly similar developmental patterning mechanisms. Furthermore, focussing on these parallels may aid in identifying core mechanistic principles, often obscured by the highly complex nature of multiscale patterning processes.
Topics: Animals; Body Patterning; Developmental Biology; Embryonic Development; Gene Expression Regulation, Developmental; Mice; Models, Biological; Plant Shoots; Plants; Signal Transduction; Systems Biology
PubMed: 30395805
DOI: 10.1016/j.ydbio.2018.10.024 -
Science Advances Jan 2024Spatiotemporal patterns widely occur in biological, chemical, and physical systems. Particularly, embryonic development displays a diverse gamut of repetitive patterns... (Review)
Review
Spatiotemporal patterns widely occur in biological, chemical, and physical systems. Particularly, embryonic development displays a diverse gamut of repetitive patterns established in many tissues and organs. Branching treelike structures in lungs, kidneys, livers, pancreases, and mammary glands as well as digits and bones in appendages, teeth, and palates are just a few examples. A fascinating instance of repetitive patterning is the sequential segmentation of the primary body axis, which is conserved in all vertebrates and many arthropods and annelids. In these species, the body axis elongates at the posterior end of the embryo containing an unsegmented tissue. Meanwhile, segments sequentially bud off from the anterior end of the unsegmented tissue, laying down an exquisite repetitive pattern and creating a segmented body plan. In vertebrates, the paraxial mesoderm is sequentially divided into somites. In this review, we will discuss the most prominent models, the most puzzling experimental data, and outstanding questions in vertebrate somite segmentation.
Topics: Animals; Body Patterning; Somites; Mesoderm; Vertebrates; Embryonic Development; Gene Expression Regulation, Developmental
PubMed: 38277458
DOI: 10.1126/sciadv.adk8937 -
Journal of Anatomy Oct 2019Somites are epithelial segments of the paraxial mesoderm. Shortly after their formation, the epithelial somites undergo extensive cellular rearrangements and form...
Somites are epithelial segments of the paraxial mesoderm. Shortly after their formation, the epithelial somites undergo extensive cellular rearrangements and form specific somite compartments, including the sclerotome and the myotome, which give rise to the axial skeleton and to striated musculature, respectively. The dynamics of somite development varies along the body axis, but most research has focused on somite development at thoracolumbar levels. The development of tail somites has not yet been thoroughly characterized, even though vertebrate tail development has been intensely studied recently with respect to the termination of segmentation and the limitation of body length in evolution. Here, we provide a detailed description of the somites in the avian tail from the beginning of tail formation at HH-stage 20 to the onset of degeneration of tail segments at HH-stage 27. We characterize the formation of somite compartment formation in the tail region with respect to morphology and the expression patterns of the sclerotomal marker gene paired-box gene 1 (Pax1) and the myotomal marker genes MyoD and myogenic factor 5 (Myf5). Our study gives insight into the development of the very last segments formed in the avian embryo, and provides a basis for further research on the development of tail somite derivatives such as tail vertebrae, pygostyle and tail musculature.
Topics: Animals; Birds; Chick Embryo; Embryonic Development; Somites; Tail
PubMed: 31225912
DOI: 10.1111/joa.13032