Gene Expression Changes in Soleus Muscle in Mice after Pericytes-Deletion
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE229364 | GEO | 2023/04/26
REPOSITORIES: GEO
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Project description:Pericytes (PCs) are microvascular mural cells which constituent the embryonic blood brain barrier (BBB) along with endothelial cells (ECs). During brain development, germinal matrix (GM) - a highly vascularized region rich in neuronal-glial precursors, is selectively vulnerable to hemorrhage in premature infants. The transforming growth factor β (TGFβ) pathway plays a crucial role in barrier development by regulating cellular cross talk between PCs and ECs. Indeed, murine embryos lacking TGFβ receptor activin receptor-like kinase 5 (Alk5) in brain PCs (mutants) develop gross germinal matrix hemorrhage-intraventricular hemorrhage (GMH-IVH) and culminate in perinatal lethality. Mutant GM vessels display reduced PC and collagen coverage, abnormal vessel dilation and EC hyperproliferation. However, the mechanistic link between PC-specific deletion of ALK5 and aberrant EC behavior remains elusive. Herein, using bulk RNA sequencing from human brain PCs lacking ALK5 (siALK5) as well as murine vascular cells [PCs and ECs] isolated from embryonic brain at embryonic days E11.5 and E13.5 we establish that angiopoietin 2 (ANGPT2), a secreted angiogenic growth factor, is robustly repressed by the TGFβ pathway in PCs. Conversely, mutants lacking PC-ALK5 secrete higher levels of ANGPT2 resulting in overactivation of tyrosine protein kinase receptor (TIE2) and culminating in EC hyperproliferation, vessel dilation, BBB breakdown and GMH. PC-specific Angpt2 deletion or pharmacological inhibition in mutants improves GM vessel morphology, reduces EC proliferation and attenuates GMH pathogenesis. Taken together, we demonstrate that loss of TGFβ-mediated ANGPT2 repression in PCs is detrimental for BBB integrity and identify ANGPT2 as an important pathological target for GMH-IVH.
2024-06-30 | GSE269066 | GEO
Project description:Pericytes (PCs) are microvascular mural cells which constituent the embryonic blood brain barrier (BBB) along with endothelial cells (ECs). During brain development, germinal matrix (GM) - a highly vascularized region rich in neuronal-glial precursors, is selectively vulnerable to hemorrhage in premature infants. The transforming growth factor β (TGFβ) pathway plays a crucial role in barrier development by regulating cellular cross talk between PCs and ECs. Indeed, murine embryos lacking TGFβ receptor activin receptor-like kinase 5 (Alk5) in brain PCs (mutants) develop gross germinal matrix hemorrhage-intraventricular hemorrhage (GMH-IVH) and culminate in perinatal lethality. Mutant GM vessels display reduced PC and collagen coverage, abnormal vessel dilation and EC hyperproliferation. However, the mechanistic link between PC-specific deletion of ALK5 and aberrant EC behavior remains elusive. Herein, using bulk RNA sequencing from human brain PCs lacking ALK5 (siALK5) as well as murine vascular cells [PCs and ECs] isolated from embryonic brain at embryonic days E11.5 and E13.5 we establish that angiopoietin 2 (ANGPT2), a secreted angiogenic growth factor, is robustly repressed by the TGFβ pathway in PCs. Conversely, mutants lacking PC-ALK5 secrete higher levels of ANGPT2 resulting in overactivation of tyrosine protein kinase receptor (TIE2) and culminating in EC hyperproliferation, vessel dilation, BBB breakdown and GMH. PC-specific Angpt2 deletion or pharmacological inhibition in mutants improves GM vessel morphology, reduces EC proliferation and attenuates GMH pathogenesis. Taken together, we demonstrate that loss of TGFβ-mediated ANGPT2 repression in PCs is detrimental for BBB integrity and identify ANGPT2 as an important pathological target for GMH-IVH.
2024-06-30 | GSE268575 | GEO
Project description:Early acute rejection of human allografts is mediated by circulating alloreactive host effector memory T cells (TEM). TEM infiltration typically occurs across graft post-capillary venules and involves sequential interactions with graft-derived endothelial cells (ECs) and pericytes (PCs). While the role of ECs in allograft rejection has been extensively studied, contributions of PCs to this process are largely unknown. This study aimed to characterize the effects and mechanisms of interactions between human PCs and allogeneic TEM. We report that unstimulated PCs, like ECs, can directly present alloantigen to TEM but while IFN-γ-activated ECs (γ-ECs) show increased ability to stimulate alloreactive T cells, IFN-γ-activated PCs (γ-PCs) instead suppress TEM proliferation but not cytokine production or signaling. RNA sequencing analysis of PCs, γ-PCs, ECs, and γ-ECs reveal induction of indoleamine 2,3-dioxygenase 1 (IDO1) in γ-PCs to significantly higher levels than in γ-ECs that correlates with tryptophan depletion in vitro. Consistently, shRNA knockdown of IDO1 markedly reduces -PC-mediated immunoregulatory effects. Adoptively transferred T cells induced PC expression of IDO1 in allogeneic human skin grafts on immunodeficient mice. We conclude that immunosuppressive properties of human PCs are not intrinsic but instead result from IFN-γ-induced IDO1-mediated tryptophan depletion.
2018-05-09 | GSE109322 | GEO
Project description:Pericytes (PCs) are a subset of perivascular cells that can give rise to mesenchymal stromal cells (MSCs) when culture-expanded, and are postulated to give rise to MSC-like cells during tissue repair in vivo. PCs have been suggested to behave as stem cells (SCs) in situ in animal models, although evidence for this role in humans is lacking. Here, we analyzed the transcriptomes of highly purified, non-cultured adipose tissue (AT)-derived PCs (ATPCs) to detect gene expression changes that occur as they acquire MSC characteristics in vitro, and evaluated the hypothesis that human ATPCs exhibit a gene expression profile compatible with an AT SC phenotype. The results showed ATPCs are non-proliferative and express genes characteristic not only of PCs (e.g., PDGFRB, NGFR, CSPG4, ACTA2, ALPL, NESTIN, LEPR, CXCL12, SEPT4, and GLI1), but also of AT stem/progenitor cells previously described in mice (BHLHE22, ZNF423, CYP7B1, FABP4, PPARG, and CD34). Additional analyses defined a gene expression signature for AT PCs, and revealed putative novel AT PC markers (e.g., APOD, ARC, SPARCL1, OMD, IGF1, EDNRB, and TNMD). Various transcripts, including NGFR, LEPR, and almost all AT stem/progenitor cell genes differentially expressed by ATPCs were not expressed by ATMSCs or culture-expanded PCs. Genes expressed by ATMSCs but not by ATPCs (e.g., CDH2, SSTR1, and FGF1) were also identified. These findings strengthen the hypothesis that PCs are SCs in vascularized tissues, highlight gene expression changes they undergo as they assume an MSC phenotype, and provide new insights into PC biology.
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Project description:Comparison of transcript levels after diphtheria-toxin deletion of the Nav1.8-expressing cells using the cre/loxP system.<br> Pain requires input from nociceptors which are specialised peripheral sensory neurons in dorsal root ganglia (DRG). To explore the nociceptor-specific mRNA profiles, we used microarray analysis to examine the altered repertoire of genes expressed in DRG from mice depleted of Nav1.8-expressing neurons which are mainly nociceptors. To generate the animal, a Nav1.8 knock-in Cre-expressing mouse (Nav1.8-Cre) was used to excise a floxed stop upstream of globally expressed diphtheria toxin A-subunit gene (ROSA26-eGFP-DTA). By crossing heterozygous Cre mice with homozygous toxin-expressing floxed mice, experimental toxin-expressing (DTA) mice, in which DTA expressing nociceptors had been deleted, were generated. 6 DTA mice and 6 litter mate controls were used for microarray analysis. 3 Affymetrix Mouse Genome 430 2.0 Array chips were employed for analysis of the gene transcripts of each conditions.
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Project description:We demonstrated that deletion of the p53 tumor suppressor gene in NG2 expressing cells resulted in the development of bone and soft tissue sarcomas that closely resemble human tumors. To determine gene expression differences between NG2 expressing pericytes lacking p53 and sarcomas that arose from deletion of p53 in NG2 expressing cells, RNA sequencing analysis was implemented.
2016-08-27 | GSE63679 | GEO
Project description:Nociceptors play an essential role in both acute pain and chronic pain conditions. In this study, we examined the proteome of mouse dorsal root ganglia and compared NaV1.8Cre+/-; ROSA26-flox-stop-flox-DTA (Diphtheria toxin fragment A) mutant mice (NaV1.8Cre-DTA), in which NaV1.8-positive neurons (mainly nociceptors) in dorsal root ganglia (DRG) were ablated, with respective littermate wildtype controls.
2022-10-03 | PXD034447 | Pride
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Project description:Pericytes (PCs) are multipotent contractile cells that wrap around the endothelial cells to maintain the blood vessel's functionality and integrity. The hyperglycemia associated with Type 2 diabetes mellitus (T2DM) was shown to impair the function of PCs and increase the risk of diabetes complications. In this study, we aimed to investigate the deleterious effect of the diabetic microenvironment on the regenerative capacities of human PCs. PCs isolated from human adipose tissue were cultured in the presence or absence of serum collected from diabetic patients (DS). The functionality of PCs was analysed after 6, 14, and 30 days. Microscopic examination of PCs cultured in DS (DS-PCs) showed increased aggregate formation and altered surface topography with hyperbolic invaginations. Compared to PCs cultured in normal serum (NS-PCs), DS-PCs showed more fragmented mitochondria and thicker nuclear membrane. DS caused impaired angiogenic differentiation of PCs as confirmed by tube formation, decreased VEGF-A and IGF-1 gene expression, upregulated TSP1, PF4, actin related protein 2/3 complex and downregulated COL21A1 protein expression. These cells suffered higher apoptotis and showed higher expression of Clic4, apoptosis facilitator BCl-2-like protein serine/threonine protein phosphatase, and Caspase-7 proteins. DS-PCs showed dysregulated DNA repair genes CDKN1A, SIRT1, XRCC5 and TERF2 and up-regulation of the pro-inflammatory genes ICAM1, IL-6, and TNF-α. DS treated cells also showed disruption in the expression of the focal adhesion and binding proeins TSP1, TGF- β, fibronectin and PCDH7. DS-PCs showed resistance mechanisms upon exposure to diabetic microenvironment by maitining the intracellular ROS level and upregulation of ECM organizing proteins vinculin, IQGAP1, and tubulin beta chain.These data show that the diabetic microenvironment exert a deleterious effect on the regenerative capacities of human adipose tissue-derived PCs, and may thus have possible implications on the vascular complications of type-2 diabetes mellitus. Nevertheless, their protective mechanisms when initially exposed to DS could provide a promising cellular therapy for T2DM.
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