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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 -
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 -
The Journal of Clinical Investigation Jul 2023Mesenchymal cells are uniquely located at the interface between the epithelial lining and the stroma, allowing them to act as a signaling hub among diverse cellular... (Review)
Review
Mesenchymal cells are uniquely located at the interface between the epithelial lining and the stroma, allowing them to act as a signaling hub among diverse cellular compartments of the lung. During embryonic and postnatal lung development, mesenchyme-derived signals instruct epithelial budding, branching morphogenesis, and subsequent structural and functional maturation. Later during adult life, the mesenchyme plays divergent roles wherein its balanced activation promotes epithelial repair after injury while its aberrant activation can lead to pathological remodeling and fibrosis that are associated with multiple chronic pulmonary diseases, including bronchopulmonary dysplasia, idiopathic pulmonary fibrosis, and chronic obstructive pulmonary disease. In this Review, we discuss the involvement of the lung mesenchyme in various morphogenic, neomorphogenic, and dysmorphogenic aspects of lung biology and health, with special emphasis on lung fibroblast subsets and smooth muscle cells, intercellular communication, and intrinsic mesenchymal mechanisms that drive such physiological and pathophysiological events throughout development, homeostasis, injury repair, regeneration, and aging.
Topics: Infant, Newborn; Humans; Lung; Pulmonary Disease, Chronic Obstructive; Fibrosis; Regeneration; Mesoderm; Epithelial Cells
PubMed: 37463440
DOI: 10.1172/JCI170498 -
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 -
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 -
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 -
Nature Reviews. Nephrology Nov 2023Perivascular niches in the kidney comprise heterogeneous cell populations, including pericytes and fibroblasts, with distinct functions. These perivascular cells have... (Review)
Review
Perivascular niches in the kidney comprise heterogeneous cell populations, including pericytes and fibroblasts, with distinct functions. These perivascular cells have crucial roles in preserving kidney homeostasis as they maintain microvascular networks by stabilizing the vasculature and regulating capillary constriction. A subset of kidney perivascular cells can also produce and secrete erythropoietin; this ability can be enhanced with hypoxia-inducible factor-prolyl hydroxylase inhibitors, which are used to treat anaemia in chronic kidney disease. In the pathophysiological state, kidney perivascular cells contribute to the progression of kidney fibrosis, partly via transdifferentiation into myofibroblasts. Moreover, perivascular cells are now recognized as major innate immune sentinels in the kidney that produce pro-inflammatory cytokines and chemokines following injury. These mediators promote immune cell infiltration, leading to persistent inflammation and progression of kidney fibrosis. The crosstalk between perivascular cells and tubular epithelial, immune and endothelial cells is therefore a key process in physiological and pathophysiological states. Here, we examine the multiple roles of kidney perivascular cells in health and disease, focusing on the latest advances in this field of research.
Topics: Humans; Pericytes; Endothelial Cells; Kidney; Renal Insufficiency, Chronic; Inflammation; Fibrosis
PubMed: 37608184
DOI: 10.1038/s41581-023-00752-7