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Trends in Cell Biology Jan 2024Pericytes are known as the mural cells in small-caliber vessels that interact closely with the endothelium. Pericytes play a key role in vasculature formation and... (Review)
Review
Pericytes are known as the mural cells in small-caliber vessels that interact closely with the endothelium. Pericytes play a key role in vasculature formation and homeostasis, and when dysfunctional contribute to vasculature-related diseases such as diabetic retinopathy and neurodegenerative conditions. In addition, significant extravascular roles of pathological pericytes are being discovered with relevant implications for cancer and fibrosis. Pericyte research is challenged by the lack of consistent molecular markers and clear discrimination criteria versus other (mural) cells. However, advances in single-cell approaches are uncovering and clarifying mural cell identities, biological functions, and ontogeny across organs. We discuss the latest developments in pericyte pathobiology to inform future research directions and potential outcomes.
Topics: Humans; Pericytes; Biomarkers; Endothelium, Vascular; Homeostasis
PubMed: 37474376
DOI: 10.1016/j.tcb.2023.06.001 -
Nature Oct 2023The ability to study human post-implantation development remains limited owing to ethical and technical challenges associated with intrauterine development after...
The ability to study human post-implantation development remains limited owing to ethical and technical challenges associated with intrauterine development after implantation. Embryo-like models with spatially organized morphogenesis and structure of all defining embryonic and extra-embryonic tissues of the post-implantation human conceptus (that is, the embryonic disc, the bilaminar disc, the yolk sac, the chorionic sac and the surrounding trophoblast layer) remain lacking. Mouse naive embryonic stem cells have recently been shown to give rise to embryonic and extra-embryonic stem cells capable of self-assembling into post-gastrulation structured stem-cell-based embryo models with spatially organized morphogenesis (called SEMs). Here we extend those findings to humans using only genetically unmodified human naive embryonic stem cells (cultured in human enhanced naive stem cell medium conditions). Such human fully integrated and complete SEMs recapitulate the organization of nearly all known lineages and compartments of post-implantation human embryos, including the epiblast, the hypoblast, the extra-embryonic mesoderm and the trophoblast layer surrounding the latter compartments. These human complete SEMs demonstrated developmental growth dynamics that resemble key hallmarks of post-implantation stage embryogenesis up to 13-14 days after fertilization (Carnegie stage 6a). These include embryonic disc and bilaminar disc formation, epiblast lumenogenesis, polarized amniogenesis, anterior-posterior symmetry breaking, primordial germ-cell specification, polarized yolk sac with visceral and parietal endoderm formation, extra-embryonic mesoderm expansion that defines a chorionic cavity and a connecting stalk, and a trophoblast-surrounding compartment demonstrating syncytium and lacunae formation. This SEM platform will probably enable the experimental investigation of previously inaccessible windows of human early post implantation up to peri-gastrulation development.
Topics: Humans; Embryo Implantation; Embryo, Mammalian; Embryonic Development; Fertilization; Gastrulation; Germ Layers; Human Embryonic Stem Cells; Trophoblasts; Yolk Sac; Giant Cells
PubMed: 37673118
DOI: 10.1038/s41586-023-06604-5 -
Nature Oct 2023The human embryo undergoes morphogenetic transformations following implantation into the uterus, but our knowledge of this crucial stage is limited by the inability to...
The human embryo undergoes morphogenetic transformations following implantation into the uterus, but our knowledge of this crucial stage is limited by the inability to observe the embryo in vivo. Models of the embryo derived from stem cells are important tools for interrogating developmental events and tissue-tissue crosstalk during these stages. Here we establish a model of the human post-implantation embryo, a human embryoid, comprising embryonic and extraembryonic tissues. We combine two types of extraembryonic-like cell generated by overexpression of transcription factors with wild-type embryonic stem cells and promote their self-organization into structures that mimic several aspects of the post-implantation human embryo. These self-organized aggregates contain a pluripotent epiblast-like domain surrounded by extraembryonic-like tissues. Our functional studies demonstrate that the epiblast-like domain robustly differentiates into amnion, extraembryonic mesenchyme and primordial germ cell-like cells in response to bone morphogenetic protein cues. In addition, we identify an inhibitory role for SOX17 in the specification of anterior hypoblast-like cells. Modulation of the subpopulations in the hypoblast-like compartment demonstrates that extraembryonic-like cells influence epiblast-like domain differentiation, highlighting functional tissue-tissue crosstalk. In conclusion, we present a modular, tractable, integrated model of the human embryo that will enable us to probe key questions of human post-implantation development, a critical window during which substantial numbers of pregnancies fail.
Topics: Female; Humans; Pregnancy; Bone Morphogenetic Proteins; Cell Differentiation; Embryo Implantation; Embryo, Mammalian; Embryoid Bodies; Embryonic Development; Germ Layers; Human Embryonic Stem Cells; Models, Biological; Transcription Factors; Pluripotent Stem Cells
PubMed: 37369347
DOI: 10.1038/s41586-023-06368-y -
Cell Dec 2023Embryogenesis necessitates harmonious coordination between embryonic and extraembryonic tissues. Although stem cells of both embryonic and extraembryonic origins have...
Embryogenesis necessitates harmonious coordination between embryonic and extraembryonic tissues. Although stem cells of both embryonic and extraembryonic origins have been generated, they are grown in different culture conditions. In this study, utilizing a unified culture condition that activates the FGF, TGF-β, and WNT pathways, we have successfully derived embryonic stem cells (FTW-ESCs), extraembryonic endoderm stem cells (FTW-XENs), and trophoblast stem cells (FTW-TSCs) from the three foundational tissues of mouse and cynomolgus monkey (Macaca fascicularis) blastocysts. This approach facilitates the co-culture of embryonic and extraembryonic stem cells, revealing a growth inhibition effect exerted by extraembryonic endoderm cells on pluripotent cells, partially through extracellular matrix signaling. Additionally, our cross-species analysis identified both shared and unique transcription factors and pathways regulating FTW-XENs. The embryonic and extraembryonic stem cell co-culture strategy offers promising avenues for developing more faithful embryo models and devising more developmentally pertinent differentiation protocols.
Topics: Animals; Coculture Techniques; Macaca fascicularis; Embryonic Stem Cells; Cell Differentiation; Embryo, Mammalian; Endoderm; Cell Lineage
PubMed: 38052213
DOI: 10.1016/j.cell.2023.11.008 -
Physiological Reviews Jul 2023The teeth are vertebrate-specific, highly specialized organs performing fundamental functions of mastication and speech, the maintenance of which is crucial for... (Review)
Review
The teeth are vertebrate-specific, highly specialized organs performing fundamental functions of mastication and speech, the maintenance of which is crucial for orofacial homeostasis and is further linked to systemic health and human psychosocial well-being. However, with limited ability for self-repair, the teeth can often be impaired by traumatic, inflammatory, and progressive insults, leading to high prevalence of tooth loss and defects worldwide. Regenerative medicine holds the promise to achieve physiological restoration of lost or damaged organs, and in particular an evolving framework of developmental engineering has pioneered functional tooth regeneration by harnessing the odontogenic program. As a key event of tooth morphogenesis, mesenchymal condensation dictates dental tissue formation and patterning through cellular self-organization and signaling interaction with the epithelium, which provides a representative to decipher organogenetic mechanisms and can be leveraged for regenerative purposes. In this review, we summarize how mesenchymal condensation spatiotemporally assembles from dental stem cells (DSCs) and sequentially mediates tooth development. We highlight condensation-mimetic engineering efforts and mechanisms based on ex vivo aggregation of DSCs, which have achieved functionally robust and physiologically relevant tooth regeneration after implantation in animals and in humans. The discussion of this aspect will add to the knowledge of development-inspired tissue engineering strategies and will offer benefits to propel clinical organ regeneration.
Topics: Tooth; Odontogenesis; Tissue Engineering; Humans; Animals; Mesoderm; Tooth Loss; Bone Regeneration
PubMed: 36656056
DOI: 10.1152/physrev.00019.2022 -
Metabolism: Clinical and Experimental Aug 2023Acute kidney injury (AKI) is associated with high morbidity and mortality and is recognized as a long-term risk factor for progression to chronic kidney disease (CKD)....
BACKGROUND AND AIMS
Acute kidney injury (AKI) is associated with high morbidity and mortality and is recognized as a long-term risk factor for progression to chronic kidney disease (CKD). The AKI to CKD transition is characterized by interstitial fibrosis and the proliferation of collagen-secreting myofibroblasts. Pericytes are the major source of myofibroblasts in kidney fibrosis. However, the underlying mechanism of pericyte-myofibroblast transition (PMT) is still unclear. Here we investigated the role of metabolic reprogramming in PMT.
METHODS
Unilateral ischemia/reperfusion-induced AKI to CKD mouse model and TGF-β-treated pericyte-like cells were used to detect the levels of fatty acid oxidation (FAO) and glycolysis, and the critical signaling pathways during PMT under the treatment of drugs regulating metabolic reprogramming.
RESULTS
PMT is characterized by a decrease in FAO and an increase in glycolysis. Enhancement of FAO by the peroxisome proliferator-activated receptor gamma coactivator-1α (PGC1α) activator ZLN-005 or suppression of glycolysis by the hexokinase 2 (HK2) inhibitor 2-DG can inhibit PMT, preventing the transition of AKI to CKD. Mechanistically, AMPK modulates various pathways involved in the metabolic switch from glycolysis to FAO. Specifically, the PGC1α-CPT1A pathway activates FAO, while inhibition of the HIF1α-HK2 pathway drives glycolysis inhibition. The modulations of these pathways by AMPK contribute to inhibiting PMT.
CONCLUSIONS
Metabolic reprogramming controls the fate of pericyte transdifferentiation and targets the abnormal metabolism of pericytes can effectively prevent AKI to CKD transition.
Topics: Mice; Animals; Pericytes; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; AMP-Activated Protein Kinases; Renal Insufficiency, Chronic; Acute Kidney Injury; Fibrosis; Kidney
PubMed: 37230215
DOI: 10.1016/j.metabol.2023.155592 -
Cell Jun 2023The hourglass model describes the convergence of species within the same phylum to a similar body plan during development; however, the molecular mechanisms underlying...
The hourglass model describes the convergence of species within the same phylum to a similar body plan during development; however, the molecular mechanisms underlying this phenomenon in mammals remain poorly described. Here, we compare rabbit and mouse time-resolved differentiation trajectories to revisit this model at single-cell resolution. We modeled gastrulation dynamics using hundreds of embryos sampled between gestation days 6.0 and 8.5 and compared the species using a framework for time-resolved single-cell differentiation-flows analysis. We find convergence toward similar cell-state compositions at E7.5, supported by the quantitatively conserved expression of 76 transcription factors, despite divergence in surrounding trophoblast and hypoblast signaling. However, we observed noticeable changes in specification timing of some lineages and divergence of primordial germ cell programs, which in the rabbit do not activate mesoderm genes. Comparative analysis of temporal differentiation models provides a basis for studying the evolution of gastrulation dynamics across mammals.
Topics: Animals; Rabbits; Mice; Gastrulation; Mesoderm; Cell Differentiation; Mammals; Trophoblasts; Gene Expression Regulation, Developmental
PubMed: 37209682
DOI: 10.1016/j.cell.2023.04.037 -
Cancer Cell Sep 2023Brain metastasis of lung cancer causes high mortality, but the exact mechanisms underlying the metastasis remain unclear. Here we report that vascular pericytes derived...
Brain metastasis of lung cancer causes high mortality, but the exact mechanisms underlying the metastasis remain unclear. Here we report that vascular pericytes derived from CD44 lung cancer stem cells (CSCs) in lung adenocarcinoma (ADC) potently cause brain metastases through the G-protein-coupled receptor 124 (GPR124)-enhanced trans-endothelial migration (TEM). CD44 CSCs in perivascular niches generate the majority of vascular pericytes in lung ADC. CSC-derived pericyte-like cells (Cd-pericytes) exhibit remarkable TEM capacity to effectively intravasate into the vessel lumina, survive in the circulation, extravasate into the brain parenchyma, and then de-differentiate into tumorigenic CSCs to form metastases. Cd-pericytes uniquely express GPR124 that activates Wnt7-β-catenin signaling to enhance TEM capacity of Cd-pericytes for intravasation and extravasation, two critical steps during tumor metastasis. Furthermore, selective disruption of Cd-pericytes, GPR124, or the Wnt7-β-catenin signaling markedly reduces brain and liver metastases of lung ADC. Our findings uncover an unappreciated cellular and molecular paradigm driving tumor metastasis.
Topics: Humans; Adenocarcinoma of Lung; beta Catenin; Brain Neoplasms; Cadmium; Hyaluronan Receptors; Lung; Lung Neoplasms; Pericytes; Receptors, G-Protein-Coupled
PubMed: 37595587
DOI: 10.1016/j.ccell.2023.07.012 -
Nature Oct 2023Clostridioides difficile infection (CDI) is a major cause of healthcare-associated gastrointestinal infections. The exaggerated colonic inflammation caused by...
Clostridioides difficile infection (CDI) is a major cause of healthcare-associated gastrointestinal infections. The exaggerated colonic inflammation caused by C. difficile toxins such as toxin B (TcdB) damages tissues and promotes C. difficile colonization, but how TcdB causes inflammation is unclear. Here we report that TcdB induces neurogenic inflammation by targeting gut-innervating afferent neurons and pericytes through receptors, including the Frizzled receptors (FZD1, FZD2 and FZD7) in neurons and chondroitin sulfate proteoglycan 4 (CSPG4) in pericytes. TcdB stimulates the secretion of the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) from neurons and pro-inflammatory cytokines from pericytes. Targeted delivery of the TcdB enzymatic domain, through fusion with a detoxified diphtheria toxin, into peptidergic sensory neurons that express exogeneous diphtheria toxin receptor (an approach we term toxogenetics) is sufficient to induce neurogenic inflammation and recapitulates major colonic histopathology associated with CDI. Conversely, mice lacking SP, CGRP or the SP receptor (neurokinin 1 receptor) show reduced pathology in both models of caecal TcdB injection and CDI. Blocking SP or CGRP signalling reduces tissue damage and C. difficile burden in mice infected with a standard C. difficile strain or with hypervirulent strains expressing the TcdB2 variant. Thus, targeting neurogenic inflammation provides a host-oriented therapeutic approach for treating CDI.
Topics: Animals; Mice; Bacterial Toxins; Calcitonin Gene-Related Peptide; Clostridioides difficile; Clostridium Infections; Neurogenic Inflammation; Pericytes; Receptors, Neurokinin-1; Substance P; Neurons, Afferent; Inflammation Mediators; Cecum; Signal Transduction
PubMed: 37699522
DOI: 10.1038/s41586-023-06607-2