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Cells Nov 2020Pancreatic ductal adenocarcinoma (PDA) is characterized by an extensive fibroinflammatory microenvironment that accumulates from the onset of disease progression.... (Review)
Review
Pancreatic ductal adenocarcinoma (PDA) is characterized by an extensive fibroinflammatory microenvironment that accumulates from the onset of disease progression. Cancer-associated fibroblasts (CAFs) are a prominent cellular component of the stroma, but their role during carcinogenesis remains controversial, with both tumor-supporting and tumor-restraining functions reported in different studies. One explanation for these contradictory findings is the heterogeneous nature of the fibroblast populations, and the different roles each subset might play in carcinogenesis. Here, we review the current literature on the origin and function of pancreatic fibroblasts, from the developing organ to the healthy adult pancreas, and throughout the initiation and progression of PDA. We also discuss clinical approaches to targeting fibroblasts in PDA.
Topics: Animals; Cancer-Associated Fibroblasts; Embryonic Development; Fibroblasts; Humans; Mesoderm; Pancreas; Pancreatic Neoplasms
PubMed: 33198201
DOI: 10.3390/cells9112464 -
FEBS Letters Dec 2019The haematopoietic system is established during embryonic life through a series of developmental steps that culminates with the generation of haematopoietic stem cells.... (Review)
Review
The haematopoietic system is established during embryonic life through a series of developmental steps that culminates with the generation of haematopoietic stem cells. Characterisation of the transcriptional network that regulates blood cell emergence has led to the identification of transcription factors essential for this process. Among the many factors wired within this complex regulatory network, ETV2, SCL and RUNX1 are the central components. All three factors are absolutely required for blood cell generation, each one controlling a precise step of specification from the mesoderm germ layer to fully functional blood progenitors. Insight into the transcriptional control of blood cell emergence has been used for devising protocols to generate blood cells de novo, either through reprogramming of somatic cells or through forward programming of pluripotent stem cells. Interestingly, the physiological process of blood cell generation and its laboratory-engineered counterpart have very little in common.
Topics: Blood Cells; Cell Differentiation; Cellular Reprogramming; Core Binding Factor Alpha 2 Subunit; Hematopoietic Stem Cells; Humans; Mesoderm; Pluripotent Stem Cells; T-Cell Acute Lymphocytic Leukemia Protein 1; Transcription Factors; Transcriptional Activation
PubMed: 31432499
DOI: 10.1002/1873-3468.13585 -
Current Topics in Developmental Biology 2024The Segmentation Clock is a tissue-level patterning system that enables the segmentation of the vertebral column precursors into transient multicellular blocks called... (Review)
Review
The Segmentation Clock is a tissue-level patterning system that enables the segmentation of the vertebral column precursors into transient multicellular blocks called somites. This patterning system comprises a set of elements that are essential for correct segmentation. Under the so-called "Clock and Wavefront" model, the system consists of two elements, a genetic oscillator that manifests itself as traveling waves of gene expression, and a regressing wavefront that transforms the temporally periodic signal encoded in the oscillations into a permanent spatially periodic pattern of somite boundaries. Over the last twenty years, every new discovery about the Segmentation Clock has been tightly linked to the nomenclature of the "Clock and Wavefront" model. This constrained allocation of discoveries into these two elements has generated long-standing debates in the field as what defines molecularly the wavefront and how and where the interaction between the two elements establishes the future somite boundaries. In this review, we propose an expansion of the "Clock and Wavefront" model into three elements, "Clock", "Wavefront" and signaling gradients. We first provide a detailed description of the components and regulatory mechanisms of each element, and we then examine how the spatiotemporal integration of the three elements leads to the establishment of the presumptive somite boundaries. To be as exhaustive as possible, we focus on the Segmentation Clock in zebrafish. Furthermore, we show how this three-element expansion of the model provides a better understanding of the somite formation process and we emphasize where our current understanding of this patterning system remains obscure.
Topics: Animals; Body Patterning; Gene Expression Regulation, Developmental; Somites; Mesoderm; Zebrafish; Signal Transduction; Biological Clocks
PubMed: 38729682
DOI: 10.1016/bs.ctdb.2023.11.001 -
Developmental Biology Oct 2021To date, the role of miRNAs on pluripotency and differentiation of ESCs into specific lineages has been studied extensively. However, the specific role of miRNAs during...
To date, the role of miRNAs on pluripotency and differentiation of ESCs into specific lineages has been studied extensively. However, the specific role of miRNAs during lateral and paraxial mesoderm cell fate decision is still unclear. To address this, we firstly determined miRNA profile of mouse ESCs differentiating towards lateral and paraxial lineages which were detected using Flk1 and PDGFαR antibodies, and of myogenic and hematopoietic differentiation potential of purified paraxial and lateral mesodermal cells within these populations. miRNAs associated with lateral and paraxial mesoderm, and their targets were identified using bioinformatics tools. The targets of the corresponding miRNAs were validated after transfection into mouse ESCs. The roles of the selected miRNAs in lateral, and paraxial mesoderm formation were assessed along with hematopoietic and myogenic differentiation capacity. Among the miRNAs, mmu-miR-126a-3p, mmu-miR-335-5p and mmu-miR-672-5p, upregulated in lateral mesoderm cells, and mmu-miR-10b-5p, mmu-miR-196a-5p and mmu-miR-615-3p, upregulated in paraxial mesoderm cells. While transient co-transfection of mmu-miR-126a-3p, mmu-miR-335-5p and mmu-miR-672-5p increased the number of lateral mesodermal cells, co-transfection of mmu-miR-10b-5p, mmu-miR-196a-5p and mmu-miR-615-3p increased the number of paraxial mesodermal cells. Moreover, differentiation potential of the lateral mesodermal cells into hematopoietic cell lineage increased upon co-transfection of mmu-miR-126a-3p, mmu-miR-335-5p and mmu-miR-672-5p and differentiation potential of the paraxial mesodermal cells into skeletal muscle lineage were increased upon co-transfection of mmu-miR-10b-5p, mmu-miR-196a-5p and mmu-miR-615-3p. In conclusion, we determined the miRNA profile of lateral and paraxial mesodermal cells and co-transfection of miRNAs increased differentiation potential of both lateral and paraxial mesodermal cells transiently.
Topics: Animals; Cell Differentiation; Computational Biology; Embryoid Bodies; Embryonic Stem Cells; Hematopoiesis; Mesoderm; Mice; MicroRNAs; Muscle Development; Transfection; Up-Regulation
PubMed: 34245726
DOI: 10.1016/j.ydbio.2021.07.002 -
ELife Jan 2022During the development of the vertebrate embryo, segmented structures called somites are periodically formed from the presomitic mesoderm (PSM) and give rise to the...
During the development of the vertebrate embryo, segmented structures called somites are periodically formed from the presomitic mesoderm (PSM) and give rise to the vertebral column. While somite formation has been studied in several animal models, it is less clear how well this process is conserved in humans. Recent progress has made it possible to study aspects of human paraxial mesoderm (PM) development such as the human segmentation clock using human pluripotent stem cells (hPSCs); however, somite formation has not been observed in these monolayer cultures. Here, we describe the generation of human PM organoids from hPSCs (termed Somitoids), which recapitulate the molecular, morphological, and functional features of PM development, including formation of somite-like structures . Using a quantitative image-based screen, we identify critical parameters such as initial cell number and signaling modulations that reproducibly yielded formation of somite-like structures in our organoid system. In addition, using single-cell RNA-sequencing and 3D imaging, we show that PM organoids both transcriptionally and morphologically resemble their counterparts and can be differentiated into somite derivatives. Our organoid system is reproducible and scalable, allowing for the systematic and quantitative analysis of human spine development and disease .
Topics: Animals; Cell Differentiation; Humans; Mesoderm; Organoids; Pluripotent Stem Cells; Somites
PubMed: 35088712
DOI: 10.7554/eLife.68925 -
Current Topics in Developmental Biology 2024In avian and mammalian embryos the "organizer" property associated with neural induction of competent ectoderm into a neural plate and its subsequent patterning into... (Review)
Review
In avian and mammalian embryos the "organizer" property associated with neural induction of competent ectoderm into a neural plate and its subsequent patterning into rostro-caudal domains resides at the tip of the primitive streak before neurulation begins, and before a morphological Hensen's node is discernible. The same region and its later derivatives (like the notochord) also have the ability to "dorsalize" the adjacent mesoderm, for example by converting lateral plate mesoderm into paraxial (pre-somitic) mesoderm. Both neural induction and dorsalization of the mesoderm involve inhibition of BMP, and the former also requires other signals. This review surveys the key experiments done to elucidate the functions of the organizer and the mechanisms of neural induction in amniotes. We conclude that the mechanisms of neural induction in amniotes and anamniotes are likely to be largely the same; apparent differences are likely to be due to differences in experimental approaches dictated by embryo topology and other practical constraints. We also discuss the relationships between "neural induction" assessed by grafts of the organizer and normal neural plate development, as well as how neural induction relates to the generation of neuronal cells from embryonic and other stem cells in vitro.
Topics: Animals; Mesoderm; Somites; Embryonic Induction; Birds; Mammals
PubMed: 38556458
DOI: 10.1016/bs.ctdb.2024.02.004 -
Advances in Experimental Medicine and... 2020The Apelin receptor (Aplnr) is a G-protein coupled receptor which has a wide body distribution and various physiological roles including homeostasis, angiogenesis,...
The Apelin receptor (Aplnr) is a G-protein coupled receptor which has a wide body distribution and various physiological roles including homeostasis, angiogenesis, cardiovascular and neuroendocrine function. Apelin and Elabela are two peptide components of the Aplnr signaling and are cleaved to give different isoforms which are active in different tissues and organisms.Aplnr signaling is related to several pathologies including obesity, heart disases and cancer in the adult body. However, the developmental role in mammalian embryogenesis is crucial for migration of early cardiac progenitors and cardiac function. Aplnr and peptide components have a role in proliferation, differentiation and movement of endodermal precursors. Although expression of Aplnr signaling is observed in endodermal lineages, the main function is the control of mesoderm cell movement and cardiac development. Mutant of the Aplnr signaling components results in the malformations, defects and lethality mainly due to the deformed heart function. This developmental role share similarity with the cardiovascular functions in the adult body.Determination of Aplnr signaling and underlying mechanisms during mammalian development might enable understanding of regulatory molecular mechanisms which not only control embryonic development process but also control tissue function and disease pathology in the adult body.
Topics: Animals; Apelin; Apelin Receptors; Female; Mesoderm; Pregnancy; Signal Transduction
PubMed: 32648246
DOI: 10.1007/5584_2020_567 -
Current Topics in Developmental Biology 2021Branching morphogenesis generates epithelial trees which facilitate gas exchange, filtering, as well as secretion processes with their large surface to volume ratio. In... (Review)
Review
Branching morphogenesis generates epithelial trees which facilitate gas exchange, filtering, as well as secretion processes with their large surface to volume ratio. In this review, we focus on the developmental mechanisms that control the early stages of lung branching morphogenesis. Lung branching morphogenesis involves the stereotypic, recurrent definition of new branch points, subsequent epithelial budding, and lung tube elongation. We discuss current models and experimental evidence for each of these steps. Finally, we discuss the role of the mesenchyme in determining the organ-specific shape.
Topics: Cell Division; Lung; Mesoderm; Morphogenesis; Organogenesis
PubMed: 33820622
DOI: 10.1016/bs.ctdb.2021.02.002 -
Developmental Cell Mar 2022Human pluripotent stem cells (hPSCs) can self-renew indefinitely or can be induced to differentiate. We previously showed that exogenous glutamine (Gln) withdrawal...
Human pluripotent stem cells (hPSCs) can self-renew indefinitely or can be induced to differentiate. We previously showed that exogenous glutamine (Gln) withdrawal biased hPSC differentiation toward ectoderm and away from mesoderm. We revealed that, although all three germ lineages are capable of de novo Gln synthesis, only ectoderm generates sufficient Gln to sustain cell viability and differentiation, and this finding clarifies lineage fate restrictions under Gln withdrawal. Furthermore, we found that Gln acts as a signaling molecule for ectoderm that supersedes lineage-specifying cytokine induction. In contrast, Gln in mesoderm and endoderm is the preferred precursor of α-ketoglutarate without a direct signaling role. Our work raises a question about whether the nutrient environment functions directly in cell differentiation during development. Interestingly, transcriptome analysis of a gastrulation-stage human embryo shows that unique Gln enzyme-encoding gene expression patterns may also distinguish germ lineages in vivo. Together, our study suggests that intracellular Gln may help coordinate differentiation of the three germ layers.
Topics: Cell Differentiation; Cell Lineage; Endoderm; Germ Layers; Glutamine; Humans; Mesoderm; Pluripotent Stem Cells
PubMed: 35216682
DOI: 10.1016/j.devcel.2022.02.003 -
Cold Spring Harbor Protocols Nov 2022Marginal zone explants from embryos can be used to expose cell behaviors and tissue movements that normally operate in dorsal tissues. Dorsal explants comprise the...
Marginal zone explants from embryos can be used to expose cell behaviors and tissue movements that normally operate in dorsal tissues. Dorsal explants comprise the diverse set of progenitor cells found in dorsal tissues including mesendoderm, head mesoderm, prechordal mesoderm, endoderm with bottle cells, axial mesoderm of the prospective notochord, paraxial mesoderm of the somites, lateral plate mesoderm, neural ectoderm, and ectoderm. Unlike an organoid, the dorsal marginal zone (DMZ) explant is "organotypic" in that microsurgery does not disrupt native tissue organization beyond manipulations needed to dissect the tissue from the embryo. An organotypic early gastrula DMZ explant preserves boundaries and close tissue associations in the native marginal zone. Depending on the stage, patterning and cell identities can be maintained in explants and tissue isolates. Local cell movements and behaviors may also be preserved; however, the large-scale biomechanical impact of their collective movements may be altered from those in the native marginal zone. For instance, involution is typically inhibited in the DMZ explant, precluding the two-layer association of mesoderm and prospective neural ectoderm normally achieved during gastrulation. DMZ explants may be mounted and imaged in a variety of ways, exposing interesting cell behaviors or collective movements such as mediolateral cell intercalation in the axial and paraxial mesoderm, apical constriction of bottle cells, and directional migration of mesendoderm. The flattened DMZ explant can also be used to study emergence of new tissue-defining boundaries such as the notochord-somite boundary, the ectoderm-mesoderm boundary, and the mesendoderm-mesoderm boundary.
Topics: Animals; Gastrula; Prospective Studies; Mesoderm; Xenopus laevis; Ectoderm
PubMed: 35577522
DOI: 10.1101/pdb.prot097360