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Nature Communications Jun 2023While the generation of many lineages from pluripotent stem cells has resulted in basic discoveries and clinical trials, the derivation of tissue-specific mesenchyme via...
While the generation of many lineages from pluripotent stem cells has resulted in basic discoveries and clinical trials, the derivation of tissue-specific mesenchyme via directed differentiation has markedly lagged. The derivation of lung-specific mesenchyme is particularly important since this tissue plays crucial roles in lung development and disease. Here we generate a mouse induced pluripotent stem cell (iPSC) line carrying a lung-specific mesenchymal reporter/lineage tracer. We identify the pathways (RA and Shh) necessary to specify lung mesenchyme and find that mouse iPSC-derived lung mesenchyme (iLM) expresses key molecular and functional features of primary developing lung mesenchyme. iLM recombined with engineered lung epithelial progenitors self-organizes into 3D organoids with juxtaposed layers of epithelium and mesenchyme. Co-culture increases yield of lung epithelial progenitors and impacts epithelial and mesenchymal differentiation programs, suggesting functional crosstalk. Our iPSC-derived population thus provides an inexhaustible source of cells for studying lung development, modeling diseases, and developing therapeutics.
Topics: Animals; Mice; Pluripotent Stem Cells; Cell Differentiation; Induced Pluripotent Stem Cells; Thorax; Mesoderm
PubMed: 37311756
DOI: 10.1038/s41467-023-39099-9 -
Current Opinion in Cell Biology Dec 2019The three germ layers - mesoderm, endoderm and ectoderm - constituting the cellular blueprint for the tissues and organs that will form during embryonic development, are... (Review)
Review
The three germ layers - mesoderm, endoderm and ectoderm - constituting the cellular blueprint for the tissues and organs that will form during embryonic development, are specified at gastrulation. Cells of mesodermal origin are the most abundant in the human body, representing a great variety of cell types, including the musculoskeletal system (bone, cartilage and muscle), cardiovascular system (heart, blood and blood vessels), as well as the connective tissues found throughout our bodies. A long-standing question pertains how this panoply of mesodermal cell types arises in a stereotypical fashion in time and space. This review discusses the events associated with mesoderm specification, highlighting the reconstruction of putative developmental trajectories facilitated by recent single-cell 'omic' data. We will also discuss the potential of emergent organoid systems to emulate and interrogate the dynamics of lineage specification at cellular resolution.
Topics: Animals; Cell Differentiation; Cell Lineage; Ectoderm; Embryonic Development; Endoderm; Gastrulation; Humans; Mesoderm
PubMed: 31476530
DOI: 10.1016/j.ceb.2019.07.012 -
Developmental Cell Feb 2023Organogenesis requires the orchestrated development of multiple cell lineages that converge, interact, and specialize to generate coherent functional structures,... (Review)
Review
Organogenesis requires the orchestrated development of multiple cell lineages that converge, interact, and specialize to generate coherent functional structures, exemplified by transformation of the cardiac crescent into a four-chambered heart. Cardiomyocytes originate from the first and second heart fields, which make different regional contributions to the definitive heart. In this review, a series of recent single-cell transcriptomic analyses, together with genetic tracing experiments, are discussed, providing a detailed panorama of the cardiac progenitor cell landscape. These studies reveal that first heart field cells originate in a juxtacardiac field adjacent to extraembryonic mesoderm and contribute to the ventrolateral side of the cardiac primordium. In contrast, second heart field cells are deployed dorsomedially from a multilineage-primed progenitor population via arterial and venous pole pathways. Refining our knowledge of the origin and developmental trajectories of cells that build the heart is essential to address outstanding challenges in cardiac biology and disease.
Topics: Heart; Myocytes, Cardiac; Cell Lineage; Mesoderm; Cell Differentiation
PubMed: 36809764
DOI: 10.1016/j.devcel.2023.01.010 -
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 -
Neuro-mesodermal assembloids recapitulate aspects of peripheral nervous system development in vitro.Stem Cell Reports May 2023Here we describe a novel neuro-mesodermal assembloid model that recapitulates aspects of peripheral nervous system (PNS) development such as neural crest cell (NCC)...
Here we describe a novel neuro-mesodermal assembloid model that recapitulates aspects of peripheral nervous system (PNS) development such as neural crest cell (NCC) induction, migration, and sensory as well as sympathetic ganglion formation. The ganglia send projections to the mesodermal as well as neural compartment. Axons in the mesodermal part are associated with Schwann cells. In addition, peripheral ganglia and nerve fibers interact with a co-developing vascular plexus, forming a neurovascular niche. Finally, developing sensory ganglia show response to capsaicin indicating their functionality. The presented assembloid model could help to uncover mechanisms of human NCC induction, delamination, migration, and PNS development. Moreover, the model could be used for toxicity screenings or drug testing. The co-development of mesodermal and neuroectodermal tissues and a vascular plexus along with a PNS allows us to investigate the crosstalk between neuroectoderm and mesoderm and between peripheral neurons/neuroblasts and endothelial cells.
Topics: Humans; Endothelial Cells; Neural Stem Cells; Schwann Cells; Axons; Mesoderm; Neural Crest
PubMed: 37084722
DOI: 10.1016/j.stemcr.2023.03.012 -
Philosophical Transactions of the Royal... Dec 2022The amnion is an extraembryonic tissue that evolutionarily allowed embryos of all amniotes to develop in a transient and local aquatic environment. Despite the... (Review)
Review
The amnion is an extraembryonic tissue that evolutionarily allowed embryos of all amniotes to develop in a transient and local aquatic environment. Despite the importance of this tissue, very little is known about its formation and its molecular characteristics. In this review, we have compared the basic organization of the extraembryonic membranes in amniotes and describe the two types of amniogenesis, folding and cavitation. We then zoom in on the atypical development of the amnion in mice that occurs via the formation of a single posterior amniochorionic fold. Moreover, we consolidate lineage tracing data to better understand the spatial and temporal origin of the progenitors of amniotic ectoderm, and visualize the behaviour of their descendants in the extraembryonic-embryonic junctional region. This analysis provides new insight on amnion development and expansion. Finally, using an online-available dataset of single-cell transcriptomics during the gastrulation period in mice, we provide bioinformatic analysis of the molecular signature of amniotic ectoderm and amniotic mesoderm. The amnion is a tissue with unique biomechanical properties that deserves to be better understood. This article is part of the theme issue 'Extraembryonic tissues: exploring concepts, definitions and functions across the animal kingdom'.
Topics: Amnion; Animals; Gastrulation; Mesoderm; Mice
PubMed: 36252226
DOI: 10.1098/rstb.2021.0258 -
The Journal of Clinical Investigation Sep 2021Hypoxia-induced pulmonary hypertension (PH) is one of the most common and deadliest forms of PH. Fibroblast growth factor receptors 1 and 2 (FGFR1/2) are elevated in...
Hypoxia-induced pulmonary hypertension (PH) is one of the most common and deadliest forms of PH. Fibroblast growth factor receptors 1 and 2 (FGFR1/2) are elevated in patients with PH and in mice exposed to chronic hypoxia. Endothelial FGFR1/2 signaling is important for the adaptive response to several injury types and we hypothesized that endothelial FGFR1/2 signaling would protect against hypoxia-induced PH. Mice lacking endothelial FGFR1/2, mice with activated endothelial FGFR signaling, and human pulmonary artery endothelial cells (HPAECs) were challenged with hypoxia. We assessed the effect of FGFR activation and inhibition on right ventricular pressure, vascular remodeling, and endothelial-mesenchymal transition (EndMT), a known pathologic change seen in patients with PH. Hypoxia-exposed mice lacking endothelial FGFRs developed increased PH, while mice overexpressing a constitutively active FGFR in endothelial cells did not develop PH. Mechanistically, lack of endothelial FGFRs or inhibition of FGFRs in HPAECs led to increased TGF-β signaling and increased EndMT in response to hypoxia. These phenotypes were reversed in mice with activated endothelial FGFR signaling, suggesting that FGFR signaling inhibits TGF-β pathway-mediated EndMT during chronic hypoxia. Consistent with these observations, lung tissue from patients with PH showed activation of FGFR and TGF-β signaling. Collectively, these data suggest that activation of endothelial FGFR signaling could be therapeutic for hypoxia-induced PH.
Topics: Animals; Endothelium; Female; Fibroblast Growth Factors; Humans; Hypertension, Pulmonary; Hypoxia; Male; Mesoderm; Mice; Mice, Knockout; Receptors, Fibroblast Growth Factor; Signal Transduction; Vascular Remodeling
PubMed: 34623323
DOI: 10.1172/JCI141467 -
International Journal of Molecular... Mar 2022Cardiovascular development is initiated soon after gastrulation as bilateral precardiac mesoderm is progressively symmetrically determined at both sides of the... (Review)
Review
Cardiovascular development is initiated soon after gastrulation as bilateral precardiac mesoderm is progressively symmetrically determined at both sides of the developing embryo. The precardiac mesoderm subsequently fused at the embryonic midline constituting an embryonic linear heart tube. As development progress, the embryonic heart displays the first sign of left-right asymmetric morphology by the invariably rightward looping of the initial heart tube and prospective embryonic ventricular and atrial chambers emerged. As cardiac development progresses, the atrial and ventricular chambers enlarged and distinct left and right compartments emerge as consequence of the formation of the interatrial and interventricular septa, respectively. The last steps of cardiac morphogenesis are represented by the completion of atrial and ventricular septation, resulting in the configuration of a double circuitry with distinct systemic and pulmonary chambers, each of them with distinct inlets and outlets connections. Over the last decade, our understanding of the contribution of multiple growth factor signaling cascades such as Tgf-beta, Bmp and Wnt signaling as well as of transcriptional regulators to cardiac morphogenesis have greatly enlarged. Recently, a novel layer of complexity has emerged with the discovery of non-coding RNAs, particularly microRNAs and lncRNAs. Herein, we provide a state-of-the-art review of the contribution of non-coding RNAs during cardiac development. microRNAs and lncRNAs have been reported to functional modulate all stages of cardiac morphogenesis, spanning from lateral plate mesoderm formation to outflow tract septation, by modulating major growth factor signaling pathways as well as those transcriptional regulators involved in cardiac development.
Topics: Gene Expression Regulation, Developmental; Heart; Heart Atria; Mesoderm; MicroRNAs; Morphogenesis; Prospective Studies; RNA, Long Noncoding; Transcription Factors; Transforming Growth Factor beta
PubMed: 35269981
DOI: 10.3390/ijms23052839 -
Nature Jun 2023The development of paired appendages was a key innovation during evolution and facilitated the aquatic to terrestrial transition of vertebrates. Largely derived from the...
The development of paired appendages was a key innovation during evolution and facilitated the aquatic to terrestrial transition of vertebrates. Largely derived from the lateral plate mesoderm (LPM), one hypothesis for the evolution of paired fins invokes derivation from unpaired median fins via a pair of lateral fin folds located between pectoral and pelvic fin territories. Whilst unpaired and paired fins exhibit similar structural and molecular characteristics, no definitive evidence exists for paired lateral fin folds in larvae or adults of any extant or extinct species. As unpaired fin core components are regarded as exclusively derived from paraxial mesoderm, any transition presumes both co-option of a fin developmental programme to the LPM and bilateral duplication. Here, we identify that the larval zebrafish unpaired pre-anal fin fold (PAFF) is derived from the LPM and thus may represent a developmental intermediate between median and paired fins. We trace the contribution of LPM to the PAFF in both cyclostomes and gnathostomes, supporting the notion that this is an ancient trait of vertebrates. Finally, we observe that the PAFF can be bifurcated by increasing bone morphogenetic protein signalling, generating LPM-derived paired fin folds. Our work provides evidence that lateral fin folds may have existed as embryonic anlage for elaboration to paired fins.
Topics: Animals; Animal Fins; Biological Evolution; Larva; Mesoderm; Zebrafish; Bone Morphogenetic Proteins
PubMed: 37225983
DOI: 10.1038/s41586-023-06100-w -
Frontiers in Immunology 2021Fibrocytes are hematopoietic-derived cells that directly contribute to tissue fibrosis by producing collagen following injury, during disease, and with aging. The lack... (Review)
Review
Fibrocytes are hematopoietic-derived cells that directly contribute to tissue fibrosis by producing collagen following injury, during disease, and with aging. The lack of a fibrocyte-specific marker has led to the use of multiple strategies for identifying these cells . This review will detail how past studies were performed, report their findings, and discuss their strengths and limitations. The motivation is to identify opportunities for further investigation and promote the adoption of best practices during future study design.
Topics: Animals; Cells, Cultured; Collagen Type I; Disease Models, Animal; Fibrosis; Humans; Mesoderm; Primary Cell Culture; Stromal Cells
PubMed: 34975874
DOI: 10.3389/fimmu.2021.784401