Abstract 256: Rbp-j Controls the Fate of the Kidney Vasculature

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Eugene Lin ◽  
Maria Luisa S Sequeira Lopez ◽  
Roberto A Gomez
Keyword(s):  
Stromal Cells ◽  
Mesangial Cells ◽  
Notch Signaling Pathway ◽  
Renal Vasculature ◽  
Arterial Tree ◽  
Mural Cells ◽  
Vascular Markers ◽  
Renal Abnormalities ◽  
Glomerular Tuft

Proper assembly of the renal vasculature is essential for post-natal life, and alterations to the renal vasculature are at the root of many types of cardiovascular disease. However, the mechanisms underlying the establishment, assembly and maintenance of the renal blood vessels are poorly understood. We have identified a population of renal stromal cells (marked by their expression of the transcription factor Foxd1) that differentiate to form the mural cells of the kidney arterial tree (excluding endothelial cells) and the glomerular mesangium. We previously demonstrated that RBP-J, the final transcriptional effector of the Notch signaling pathway, controls the phenotype of renin cells which are also derived from the Foxd1 lineage. We therefore hypothesized that RBP-J regulates the differentiation of stromal cells into the mural cells of the kidney arterioles. To answer this question, we deleted RBP-J in the metanephric stromal precursor cells, and found that mutant mice displayed striking kidney abnormalities in early life. Staining for vascular markers showed a significant decrease in the number of arteries and arterioles. Vessel walls were thinner due to a decrease in both the size and number of smooth muscle cells. We also noted a near absence of renin cells, supporting our earlier findings regarding the key role of RBP-J in establishing the differentiated renin cell endowment. These findings were accompanied by delayed nephrogenesis and other renal abnormalities including tubular dilation. In addition, mutant kidneys lacked Foxd1-lineage cells within the glomeruli, resulting in a depletion of mesangial cells and glomerular aneurysms. Thus, we conclude that RBP-J in Foxd1+ stromal cells plays a key role in the development of the kidney vasculature, and regulates the fate of cells that compose the arterial tree and the glomerular tuft.

Abstract 23: Foxd1+ Stromal Cells, the Required Progenitors for Kidney Vascular Development

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Eugene E Lin ◽  
Roberto A Gomez ◽  
Maria-Luisa S Sequeira-Lopez
Keyword(s):  
Stromal Cells ◽  
Mesangial Cells ◽  
Cell Types ◽  
Lineage Tracing ◽  
Arterial Tree ◽  
Mural Cell ◽  
Mural Cells ◽  
Selective Ablation ◽  
Similar Phenotype

The mechanisms underlying the establishment, assembly and maintenance of the renal blood vessels are poorly understood. We have previously suggested using detailed lineage tracing that renal stromal cells, characterized by their early and transient expression of the transcription factor Foxd1 , give rise to the entirety of the mural cell layer of the renal arterial tree and mesangial cells. Mural cells as defined here exclude endothelial cells, which we identified as having a separate precursor, the renal hemangioblast. To define whether Foxd1 cells are the required essential progenitor or whether their role as such could be assumed by other cell types, we used the cre-lox system to generate mice expressing diphtheria toxin subunit A in Foxd1+ cells ( Foxd1-DTA mice ) which resulted in animals with selective ablation of Foxd1+ cells. Kidneys from Foxd1-DTA embryos had a significantly reduced complement of arterial mural cells, lacking smooth muscle cells, perivascular fibroblasts, renin cells and mesangial cells. Interestingly, the few vessels that remained were also abnormal: they originated underneath the kidney capsule and elongated towards the center of the kidney rather than radiating outward from the center of the kidney. In addition, ablation of Foxd1 cells resulted in significantly delayed nephrogenesis and reduction in glomerular number. In conjunction with our previous data showing a similar phenotype upon global deletion of the Foxd1 ,gene, this illustrates the central role of Foxd1 and the cells that express it during early development. We conclude that Foxd1 stromal cells are the required progenitors for the establishment of the mural cells of the kidney arterioles and (via Foxd1 expression) for the proper origin and orientation of the kidney vessels.

scholarly journals RBP-J in FOXD1+ renal stromal progenitors is crucial for the proper development and assembly of the kidney vasculature and glomerular mesangial cells

2014 ◽  
Vol 306 (2) ◽  
pp. F249-F258 ◽  
Author(s):  
E. E. Lin ◽  
M. L. S. Sequeira-Lopez ◽  
R. A. Gomez
Keyword(s):  
Stromal Cells ◽  
Mesangial Cells ◽  
Complete Loss ◽  
Interior Structure ◽  
Glomerular Mesangial Cells ◽  
Renal Vasculature ◽  
Immunoglobulin Kappa ◽  
Mural Cells ◽  
Forkhead Box ◽  
Kidney Malformations

The mechanisms underlying the establishment, development, and maintenance of the renal vasculature are poorly understood. Here, we propose that the transcription factor “recombination signal binding protein for immunoglobulin kappa J region” (RBP-J) plays a key role in the differentiation of the mural cells of the kidney arteries and arterioles, as well as the mesangial cells of the glomerulus. Deletion of RBP-J in renal stromal cells of the forkhead box D1 (FOXD1) lineage, which differentiate into all the mural cells of the kidney arterioles along with mesangial cells and pericytes, resulted in significant kidney abnormalities and mortality by day 30 postpartum ( P30). In newborn mutant animals, we observed a decrease in the total number of arteries and arterioles, along with thinner vessel walls, and depletion of renin cells. Glomeruli displayed striking abnormalities, including a failure of FOXD1-descendent cells to populate the glomerulus, an absence of mesangial cells, and in some cases complete loss of glomerular interior structure and the development of aneurysms. By P30, the kidney malformations were accentuated by extensive secondary fibrosis and glomerulosclerosis. We conclude that RBP-J is essential for proper formation and maintenance of the kidney vasculature and glomeruli.

Epithelial Cells and Their Neighbors I. Role of intestinal myofibroblasts in development, repair, and cancer

2005 ◽  
Vol 289 (1) ◽  
pp. G2-G7 ◽  
Author(s):  
D. W. Powell ◽  
P. A. Adegboyega ◽  
J. F. Di Mari ◽  
R. C. Mifflin
Keyword(s):  
Lamina Propria ◽  
Information Flow ◽  
Stromal Cells ◽  
Smooth Muscle Actin ◽  
Distant Metastases ◽  
Muscle Actin ◽  
Mural Cells ◽  
Intestinal Neoplasms ◽  
Extracellular Matrix Molecules

Intestinal myofibroblasts are α-smooth muscle actin-positive stromal cells that exist as a syncytium with fibroblasts and mural cells in the lamina propria of the gut. Through expression and secretion of cytokines, chemokines, growth factors, prostaglandins, and basal lamina/extracellular matrix molecules, as well as expression of adhesion molecules and receptors for many of the same soluble factors and matrix, myofibroblasts mediate information flow between the epithelium and the mesenchymal elements of the lamina propria. With the use of these factors and receptors, they play a fundamental role in intestinal organogenesis and in the repair of wounding or disease. Intestinal neoplasms enlist and conscript myofibroblast factors and matrix molecules to promote neoplastic growth, carcinoma invasion, and distant metastases.

Abstract MP25: Defining The Role Of Renin Lineage Cells During Regeneration After Release Of Partial Ureteral Obstruction In Neonatal Mice.

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Vidya Nagalakshmi Kusma Harinathan ◽  
Minghong Li ◽  
Ariel R Gomez ◽  
Maria Luisa S Sequeira-Lopez
Keyword(s):  
Ureteral Obstruction ◽  
Unilateral Ureteral Obstruction ◽  
Lineage Tracing ◽  
Kidney Damage ◽  
Regeneration Capacity ◽  
Renal Vasculature ◽  
Dynamic Changes ◽  
Mural Cells ◽  
Neonatal Mice

Our previous study on a partial unilateral ureteral obstruction (pUUO) model in neonatal mice showed that the release of obstruction halts the progression of kidney damage and leads to a remarkable repair of the kidney with improvement in renal blood flow. In the current study, we aim to understand the role of mural cells of the renin lineage during kidney damage and repair in the neonatal pUUO model. Our results show a marked increase in renin-positive areas in kidneys obstructed for 3W (Sham-3W: 0.70±0.10%, n=3; Obstructed-3W: 1.82±0.43%, n=3). However, relief of obstruction at 1W restored the renin-positive areas to sham levels (Post-release-2W: 0.70±0.09%; n=3). Lineage tracing using Ren1 d Cre;mTmG mice revealed a significant increase in GFP+ cells in the obstructed kidneys, with a decrease post-release. To understand further the dynamic changes in cells of renin lineage due to obstruction, we ablated the renin cells using DTA (Diphtheria toxin subunit A). We crossed the DTA fl/fl mice with Ren1 d -DTA het ;Ren1 d Cre;mTmG mice and performed pUUO in the resultant pups with DTA in the renin cells (DTA+). DTA+ animals showed thinning of the renal vasculature and a 90% reduction in renin-positive area compared to controls [Control: 0.70±0.10% (n=3); DTA+: 0.06±0.03% (n=3)]. In addition, there was no significant increase in the renin-positive area post-obstruction [Sham-3W: 0.06±0.04% (n=3); Obstructed-3W: 0.12±0.05% (n=4); Post-release-2W: 0.08±0.03% (n=4)]. These results indicate that ablation of renin cells abolished the obstruction-mediated surge in the renin expression. However, measurement of interstitial collagen positive area indicated that despite the absence of renin cells, the fibrotic damage due to obstruction recovered remarkably post-release [Collagen positive area: Sham-3W: 3.38±0.67% (n=3) Obstructed-3W: 62.98±31.50% (n=3); Post-release-2W: 10.93±5.46% (n=4)]. Similarly, vascular damage induced by persistent obstruction and recovery following the relief of obstruction was similar between the DTA+ and non-DTA animals. Our results imply that though the renin and renin lineage cells increase in obstructed kidneys, ablation of renin cells does not affect the regeneration capacity of kidneys following the relief of obstruction.

scholarly journals The earliest metanephric arteriolar progenitors and their role in kidney vascular development

2015 ◽  
Vol 308 (2) ◽  
pp. R138-R149 ◽  
Author(s):  
Maria Luisa S. Sequeira-Lopez ◽  
Eugene E. Lin ◽  
Minghong Li ◽  
Yan Hu ◽  
Curt D. Sigmund ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Cell Types ◽  
Forkhead Transcription Factor ◽  
Arterial Tree ◽  
Mural Cells ◽  
Vascular Morphogenesis ◽  
Distinct Cell ◽  
Series Of Experiments ◽  
Renal Vascular

The development of the kidney arterioles is poorly understood. Mature arterioles contain several functionally and morphologically distinct cell types, including smooth muscle, endothelial, and juxtaglomerular cells, and they are surrounded by interconnected pericytes, fibroblasts, and other interstitial cells. We have shown that the embryonic kidney possesses all of the necessary precursors for the development of the renal arterial tree, and those precursors assemble in situ to form the kidney arterioles. However, the identity of those precursors was unclear. Within the embryonic kidney, several putative progenitors marked by the expression of either the winged-forkhead transcription factor 1 (Foxd1+ progenitor), the aspartyl-protease renin (Ren+ progenitor), and/or hemangioblasts (Scl+ progenitor) are likely to differentiate and endow most of the cells of the renal arterial tree. However, the lineage relationships and the role of these distinct progenitors in renal vascular morphogenesis have not been delineated. We, therefore, designed a series of experiments to ascertain the hierarchical lineage relationships between Foxd1+ and Ren+ progenitors and the role of these two precursors in the morphogenesis and patterning of the renal arterial tree. Results show that 1) Foxd1+ cells are the precursors for all the mural cells (renin cells, smooth muscle cells, perivascular fibroblasts, and pericytes) of the renal arterial tree and glomerular mesangium, and 2) Foxd1 per se directs the origin, number, orientation, and cellular composition of the renal vessels.

Notch-3 and Notch-4 signaling rescue from apoptosis human B-ALL cells in contact with human bone marrow–derived mesenchymal stromal cells

Blood ◽  
2011 ◽  
Vol 118 (2) ◽  
pp. 380-389 ◽  
Author(s):  
Armel Hervé Nwabo Kamdje ◽  
Federico Mosna ◽  
Francesco Bifari ◽  
Veronica Lisi ◽  
Giulio Bassi ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Cell Survival ◽  
Stromal Cells ◽  
Stromal Cell ◽  
Lymphoblastic Leukemia ◽  
Notch Signaling Pathway ◽  
Notch 3 ◽  
Secretase Inhibitor ◽  
B Lineage

Abstract Although many literature data are available on the role of Notch signaling in T-cell acute lymphoblastic leukemia (ALL) biology, the importance of this molecular pathway in the development of B-lineage ALL (B-ALL) cells in the BM microenvironment is unknown so far. In this study, we used anti-Notch molecules neutralizing Abs and γ-secretase inhibitor (GSI) XII to investigate the role of the Notch signaling pathway in the promotion of human B-ALL cell survival in presence of stromal cell support. The treatment with combinations of anti-Notch molecule neutralizing Abs resulted in the decrease of B-ALL cell survival, either cultured alone or cocultured in presence of stromal cells from normal donors and B-ALL patients. Interestingly, the inhibition of Notch-3 and -4 or Jagged-1/-2 and DLL-1 resulted in a dramatic increase of apoptotic B-ALL cells by 3 days, similar to what is obtained by blocking all Notch signaling with the GSI XII. Our data suggest that the stromal cell–mediated antiapoptotic effect on B- ALL cells is mediated by Notch-3 and -4 or Jagged-1/-2 and DLL-1 in a synergistic manner.

scholarly journals Estrogen- and Progesterone (P4)-Mediated Epigenetic Modifications of Endometrial Stromal Cells (EnSCs) and/or Mesenchymal Stem/Stromal Cells (MSCs) in the Etiopathogenesis of Endometriosis

2021 ◽  
Author(s):  
Dariusz Szukiewicz ◽  
Aleksandra Stangret ◽  
Carmen Ruiz-Ruiz ◽  
Enrique G. Olivares ◽  
Olga Soriţău ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Uterine Cavity ◽  
Retrograde Transport ◽  
Surrounding Tissue ◽  
Pelvic Cavity ◽  
Endometrial Stromal Cells ◽  
Endometrial Cells ◽  
Estrogen Exposure ◽  
Chronic Inflammatory Condition

AbstractEndometriosis is a common chronic inflammatory condition in which endometrial tissue appears outside the uterine cavity. Because ectopic endometriosis cells express both estrogen and progesterone (P4) receptors, they grow and undergo cyclic proliferation and breakdown similar to the endometrium. This debilitating gynecological disease affects up to 15% of reproductive aged women. Despite many years of research, the etiopathogenesis of endometrial lesions remains unclear. Retrograde transport of the viable menstrual endometrial cells with retained ability for attachment within the pelvic cavity, proliferation, differentiation and subsequent invasion into the surrounding tissue constitutes the rationale for widely accepted implantation theory. Accordingly, the most abundant cells in the endometrium are endometrial stromal cells (EnSCs). These cells constitute a particular population with clonogenic activity that resembles properties of mesenchymal stem/stromal cells (MSCs). Thus, a significant role of stem cell-based dysfunction in formation of the initial endometrial lesions is suspected. There is increasing evidence that the role of epigenetic mechanisms and processes in endometriosis have been underestimated. The importance of excess estrogen exposure and P4 resistance in epigenetic homeostasis failure in the endometrial/endometriotic tissue are crucial. Epigenetic alterations regarding transcription factors of estrogen and P4 signaling pathways in MSCs are robust in endometriotic tissue. Thus, perspectives for the future may include MSCs and EnSCs as the targets of epigenetic therapies in the prevention and treatment of endometriosis. Here, we reviewed the current known changes in the epigenetic background of EnSCs and MSCs due to estrogen/P4 imbalances in the context of etiopathogenesis of endometriosis.

scholarly journals Crosstalk between NOTCH and AKT signaling during murine megakaryocyte lineage specification

Blood ◽  
2011 ◽  
Vol 118 (5) ◽  
pp. 1264-1273 ◽  
Author(s):  
Melanie G. Cornejo ◽  
Vinciane Mabialah ◽  
Stephen M. Sykes ◽  
Tulasi Khandan ◽  
Cristina Lo Celso ◽  
...  
Keyword(s):  
Stem Cell ◽  
Notch Signaling ◽  
Signaling Pathway ◽  
Hematopoietic Stem Cell ◽  
Stem Cell Differentiation ◽  
Notch Signaling Pathway ◽  
Developmental Pathways ◽  
Lineage Specification ◽  
Hematopoietic Stem

Abstract The NOTCH signaling pathway is implicated in a broad range of developmental processes, including cell fate decisions. However, the molecular basis for its role at the different steps of stem cell lineage commitment is unclear. We recently identified the NOTCH signaling pathway as a positive regulator of megakaryocyte lineage specification during hematopoiesis, but the developmental pathways that allow hematopoietic stem cell differentiation into the erythro-megakaryocytic lineages remain controversial. Here, we investigated the role of downstream mediators of NOTCH during megakaryopoiesis and report crosstalk between the NOTCH and PI3K/AKT pathways. We demonstrate the inhibitory role of phosphatase with tensin homolog and Forkhead Box class O factors on megakaryopoiesis in vivo. Finally, our data annotate developmental mechanisms in the hematopoietic system that enable a decision to be made either at the hematopoietic stem cell or the committed progenitor level to commit to the megakaryocyte lineage, supporting the existence of 2 distinct developmental pathways.

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