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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 -
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 -
Cell Research Sep 2023Studies of cultured embryos have provided insights into human peri-implantation development. However, detailed knowledge of peri-implantation lineage development as well...
Studies of cultured embryos have provided insights into human peri-implantation development. However, detailed knowledge of peri-implantation lineage development as well as underlying mechanisms remains obscure. Using 3D-cultured human embryos, herein we report a complete cell atlas of the early post-implantation lineages and decipher cellular composition and gene signatures of the epiblast and hypoblast derivatives. In addition, we develop an embryo-like assembloid (E-assembloid) by assembling naive hESCs and extraembryonic cells. Using human embryos and E-assembloids, we reveal that WNT, BMP and Nodal signaling pathways synergistically, but functionally differently, orchestrate human peri-implantation lineage development. Specially, we dissect mechanisms underlying extraembryonic mesoderm and extraembryonic endoderm specifications. Finally, an improved E-assembloid is developed to recapitulate the epiblast and hypoblast development and tissue architectures in the pre-gastrulation human embryo. Our findings provide insights into human peri-implantation development, and the E-assembloid offers a useful model to disentangle cellular behaviors and signaling interactions that drive human embryogenesis.
Topics: Humans; Germ Layers; Embryo, Mammalian; Embryo Implantation; Endoderm; Mesoderm; Embryonic Development
PubMed: 37460804
DOI: 10.1038/s41422-023-00846-8 -
Circulation Sep 2023Pericytes have been implicated in tissue repair, remodeling, and fibrosis. Although the mammalian heart contains abundant pericytes, their fate and involvement in...
BACKGROUND
Pericytes have been implicated in tissue repair, remodeling, and fibrosis. Although the mammalian heart contains abundant pericytes, their fate and involvement in myocardial disease remains unknown.
METHODS
We used NG2;PDGFRα pericyte:fibroblast dual reporter mice and inducible NG2 mice to study the fate and phenotypic modulation of pericytes in myocardial infarction. The transcriptomic profile of pericyte-derived cells was studied using polymerase chain reaction arrays and single-cell RNA sequencing. The role of transforming growth factor-β (TGF-β) signaling in regulation of pericyte phenotype was investigated in vivo using pericyte-specific TGF-β receptor 2 knockout mice and in vitro using cultured human placental pericytes.
RESULTS
In normal hearts, neuron/glial antigen 2 (NG2) and platelet-derived growth factor receptor α (PDGFRα) identified distinct nonoverlapping populations of pericytes and fibroblasts, respectively. After infarction, a population of cells expressing both pericyte and fibroblast markers emerged. Lineage tracing demonstrated that in the infarcted region, a subpopulation of pericytes exhibited transient expression of fibroblast markers. Pericyte-derived cells accounted for ~4% of PDGFRα+ infarct fibroblasts during the proliferative phase of repair. Pericyte-derived fibroblasts were overactive, expressing higher levels of extracellular matrix genes, integrins, matricellular proteins, and growth factors, when compared with fibroblasts from other cellular sources. Another subset of pericytes contributed to infarct angiogenesis by forming a mural cell coat, stabilizing infarct neovessels. Single-cell RNA sequencing showed that NG2 lineage cells diversify after infarction and exhibit increased expression of matrix genes, and a cluster with high expression of fibroblast identity markers emerges. Trajectory analysis suggested that diversification of infarct pericytes may be driven by proliferating cells. In vitro and in vivo studies identified TGF-β as a potentially causative mediator in fibrogenic activation of infarct pericytes. However, pericyte-specific TGF-β receptor 2 disruption had no significant effects on infarct myofibroblast infiltration and collagen deposition. Pericyte-specific TGF-β signaling was involved in vascular maturation, mediating formation of a mural cell coat investing infarct neovessels and protecting from dilative remodeling.
CONCLUSIONS
In the healing infarct, cardiac pericytes upregulate expression of fibrosis-associated genes, exhibiting matrix-synthetic and matrix-remodeling profiles. A fraction of infarct pericytes exhibits expression of fibroblast identity markers. Pericyte-specific TGF-β signaling plays a central role in maturation of the infarct vasculature and protects from adverse dilative remodeling, but it does not modulate fibrotic remodeling.
Topics: Pregnancy; Mice; Female; Humans; Animals; Pericytes; Receptor, Platelet-Derived Growth Factor alpha; Placenta; Myocardial Infarction; Fibrosis; Mice, Knockout; Phenotype; Transforming Growth Factor beta; Receptors, Transforming Growth Factor beta; Mammals
PubMed: 37350296
DOI: 10.1161/CIRCULATIONAHA.123.064155 -
Cells Jul 2023Pericytes are specialized cells located in close proximity to endothelial cells within the microvasculature. They play a crucial role in regulating blood flow,... (Review)
Review
Pericytes are specialized cells located in close proximity to endothelial cells within the microvasculature. They play a crucial role in regulating blood flow, stabilizing vessel walls, and maintaining the integrity of the blood-brain barrier. The loss of pericytes has been associated with the development and progression of various diseases, such as diabetes, Alzheimer's disease, sepsis, stroke, and traumatic brain injury. This review examines the detection of pericyte loss in different diseases, explores the methods employed to assess pericyte coverage, and elucidates the potential mechanisms contributing to pericyte loss in these pathological conditions. Additionally, current therapeutic strategies targeting pericytes are discussed, along with potential future interventions aimed at preserving pericyte function and promoting disease mitigation.
Topics: Humans; Pericytes; Endothelial Cells; Blood-Brain Barrier; Stroke; Brain Injuries, Traumatic
PubMed: 37566011
DOI: 10.3390/cells12151931