Valve organoids recapitulate human in vivo organogenesis and pathological processes
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE328065 | GEO | 2026/08/10
REPOSITORIES: GEO
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Project description:Valve organoids recapitulate human in vivo organogenesis and pathological processes
| PRJNA1453601 | ENA
Project description:Valve remodeling is a complex process involving extracellular matrix organization, development of trilaminar structures, and physical elongation of valve leaflets. However, the cellular and molecular mechanisms regulating valve remodeling and their roles in congenital valve disorders remain poorly understood. Semilunar valves and atrioventricular valves from healthy and age-matched human fetal hearts with pulmonary stenosis (PS) were collected. Single-Cell RNA-sequencing (scRNA-seq) was performed to determine the transcriptomic landscape of multiple valvular cell subtypes in valve remodeling and disease. Spatial localization of newly-identified cell subtypes was determined via immunofluorescence and RNA in situ hybridization. The molecular mechanisms mediating valve development was investigated utilizing primary human fetal valve interstitial cells (VICs) and endothelial cells (VECs). scRNA-seq analysis of healthy human fetal valves identified a novel APOE+ elastin-producing VIC subtype (Elastin-VIC) spatially located underneath VECs sensing the unidirectional flow. Knockdown of APOE in fetal VICs resulted in significant elastogenesis defects. In pulmonary valve with PS, we observed decreased expression of APOE and other genes regulating elastogenesis such as EMILIN1 and LOXL1, as well as elastin fragmentation. These findings suggested the crucial role of APOE in regulating elastogenesis during valve remodeling. Furthermore, cell-cell interaction analysis revealed that JAG1 from unidirectional VECs activates NOTCH signaling in Elastin-VICs through NOTCH3. In vitro Jag1 treatment in VICs increased the expression of elastogenesis-related genes and enhanced contractile functions with related gene expression. This was accompanied by activation of NOTCH signaling and elastogenesis observed in VICs co-cultured with VECs in the presence of unidirectional flow. Notably, we found that the JAG1-NOTCH3 signaling pair was drastically reduced in the PS valves. Lastly, we demonstrated that APOE is indispensable for JAG1-induced NOTCH activation in VICs, reinforcing the presence of a synergistic intrinsic and external regulatory network involving APOE and NOTCH signaling that is responsible for regulating elastogenesis during human valve remodeling. scRNA-seq analysis of human fetal valves identified a novel Elastin-VIC subpopulation, and revealed mechanism of intrinsic APOE and external NOTCH signaling from VECs sensing unidirectional flow in regulating elastogenesis during valve remodeling. These mechanisms may contribute to the pathogenesis of elastic malformation in congenital valve disease.
2024-01-10 | GSE228638 | GEO
Project description:Introduction: Renal failure is associated with aortic valve calcification. Using our rat model of uraemia-induced reversible aortic valve calcification, we assessed the role of apoptosis and survival pathways in aortic valve calcification. We also explored the effects of raloxifene - an estrogen receptor modulator on valvular calcification. Methods: Gene array analysis was performed in aortic valves obtained from 3 groups of rats (n=7 each): calcified valves from rats fed with uremic diet -high-adenine (0.75%), high-phosphate diet (1.5%), valves after calcification resolution following diet cessation (reversibility) and control. In addition, four groups of rats (n=10 each) were used in order to evaluate the effect of raloxifene in aortic valve calcification: three groups as mentioned above and a fourth group fed with the uremic diet which also received daily raloxifene. Evaluation of these groups included imaging, histology and antigen expression analysis. Results: Gene array results showed that the majority of the expressed genes that were altered were from the diet group valves. Most apoptosis-related genes were changed in a pro-apoptotic direction in calcified valves. Apoptosis and decrease in several survival pathways were confirmed in calcified valves. Resolution of aortic valve calcification was accompanied by decreased apoptosis and upregulation of these ant-apoptotic pathways. Imaging and histology demonstrated that raloxifene significantly decreased aortic valve calcification. Conclusion: Downregulation of several survival pathways and apoptosis are involved in the pathogenesis of aortic valve calcification. The beneficial effect of raloxifene in valve calcification is related to apoptosis modulation. This novel observation is important for developing remedies for aortic valve calcification in patients with renal failure. Introduction: Renal failure is associated with aortic valve calcification. Using our rat model of uraemia-induced reversible aortic valve calcification, we assessed the role of apoptosis and survival pathways in aortic valve calcification. We also explored the effects of raloxifene - an estrogen receptor modulator on valvular calcification. Methods: Gene array analysis was performed in aortic valves obtained from 3 groups of rats (n=7 each): calcified valves from rats fed with uremic diet -high-adenine (0.75%), high-phosphate diet (1.5%), valves after calcification resolution following diet cessation (reversibility) and control. In addition, four groups of rats (n=10 each) were used in order to evaluate the effect of raloxifene in aortic valve calcification: three groups as mentioned above and a fourth group fed with the uremic diet which also received daily raloxifene. Evaluation of these groups included imaging, histology and antigen expression analysis. Results: Gene array results showed that the majority of the expressed genes that were altered were from the diet group valves. Most apoptosis-related genes were changed in a pro-apoptotic direction in calcified valves. Apoptosis and decrease in several survival pathways were confirmed in calcified valves. Resolution of aortic valve calcification was accompanied by decreased apoptosis and upregulation of these ant-apoptotic pathways. Imaging and histology demonstrated that raloxifene significantly decreased aortic valve calcification. Conclusion: Downregulation of several survival pathways and apoptosis are involved in the pathogenesis of aortic valve calcification. The beneficial effect of raloxifene in valve calcification is related to apoptosis modulation. This novel observation is important for developing remedies for aortic valve calcification in patients with renal failure.
2010-05-11 | GSE21771 | GEO
Project description:E12.5 AV cushion and E17.5 AV valve from wild-type FVB/N mice and in vitro cultured MC3T3 cells In the study we demonstrated shared gene expression in embryonic heart valve development and Osteoblast progenitor cells. The atrioventricular (AV) valves of the heart develop from undifferentiated mesenchymal endocardial cushions, that later remodel into stratified valves with diversified extracellular matrix (ECM). Because the mature valves express genes associated with osteogenesis and exhibit disease-associated calcification, we hypothesized the existence of shared regulatory pathways active in the remodeling AV valves and in bone progenitor cells. In order to define gene regulatory programs of valvulogenesis relative to osteoblast progenitors, we undertook Affymetrix gene expression profiling analysis of murine embryonic day (E)12.5 AV cushions compared to E17.5 remodeled AV valves (mitral and tri-cuspid) and to pre-osteoblast MC3T3-E1 (subclone4) cells. Overall MC3T3 cells were significantly more similar to E17.5 valves than to E12.5 cushions, supporting the hypothesis that valve remodeling involves the expression of many genes also expressed in osteoblasts. Several transcription factors characteristic of mesenchymal and osteoblast precursor cells, including Twist1 are predominant in E12.5 cushion. Valve remodeling also includes differential regulation of matrix metalloproteinases and their inhibitors as well as characteristic collagen isoform switching. Among the most highly enriched genes during valvulogenesis were members of the small leucine-rich proteoglycan (SLRP) family including Asporin, a known negative regulator of osteoblast differentiation and mineralization. Together, these data support shared gene expression profiles of the remodeling valves and osteoblast bone precursor cells in normal valve development and homeostasis with potential functions in calcific valve disease. Keywords: Embryonic valve development time point
2008-07-11 | GSE11040 | GEO
Project description:Therapeutic management of heart valve disease is currently hampered by a lack of mechanistic understanding of human valve development and pathobiology. Here, we develop a protocol to generate 3-dimensional human heart valve tissues from pluripotent stem cells with enhanced maturational properties closely mirroring the valve interstitial cell, resident myeloid cells and protein expression profile of native heart valves. Importantly, bioengineered heart valves transplanted subcutaneously in rats did not calcify, highlighting potential clinical utility as a cellular therapy. In parallel, using a high-throughput 96-well platform, we demonstrate that bioengineered human heart valves can be used for modelling valve disease. Treatment with inflammatory cytokines augmented tissue passive tension and upregulated molecular markers associated with valve calcification and fibrosis. Thus, bioengineered human heart valve tissues provide a platform to understand human heart valve development, disease pathogenesis and offer a potential regenerative therapy for heart valve disease.
2026-08-07 | GSE294124 | GEO
Project description:Therapeutic management of heart valve disease is currently hampered by a lack of mechanistic understanding of human valve development and pathobiology. Here, we develop a protocol to generate 3-dimensional human heart valve tissues from pluripotent stem cells with enhanced maturational properties closely mirroring the valve interstitial cell, resident myeloid cells and protein expression profile of native heart valves. Importantly, bioengineered heart valves transplanted subcutaneously in rats did not calcify, highlighting potential clinical utility as a cellular therapy. In parallel, using a high-throughput 96-well platform, we demonstrate that bioengineered human heart valves can be used for modelling valve disease. Treatment with inflammatory cytokines augmented tissue passive tension and upregulated molecular markers associated with valve calcification and fibrosis. Thus, bioengineered human heart valve tissues provide a platform to understand human heart valve development, disease pathogenesis and offer a potential regenerative therapy for heart valve disease.
2026-08-24 | GSE294442 | GEO
Project description:Heart valve formation initiates when endothelial cells of the heart transform into mesenchyme and populate the cardiac cushions. The transcription factor, SOX9, is highly expressed in the cardiac cushion mesenchyme, and is essential for heart valve development. Loss of Sox9 in mouse cardiac cushion mesenchyme alters cell proliferation, embryonic survival, and disrupts valve formation. Despite this important role, little is known regarding how SOX9 regulates heart valve formation or its transcriptional targets. Therefore, we mapped putative SOX9 binding sites by ChIP-Seq in embryonic day (E) 12.5 heart valves, a stage at which the valve mesenchyme is actively proliferating and initiating differentiation. Embryonic heart valves have been shown to express a high number of genes that are associated with chondrogenesis, including several extracellular matrix proteins and transcription factors that regulate chondrogenesis. Consequently, we compared regions of putative SOX9 DNA-binding between E12.5 heart valves and E12.5 limb buds. We identified context-dependent and contextâindependent SOX9 interacting regions throughout the genome. Analysis of context-independent SOX9 binding suggests an extensive role for SOX9 across tissues in regulating proliferation-associated genes including key components of the AP-1 complex. Integrative analysis of tissue-specific SOX9 interacting regions and gene expression profiles on Sox9-deficient heart valves demonstrated that SOX9 controls the expression of several transcription factors with previously identified roles in heart valve development, including Twist1, Sox4, Mecom/Evi1 and Pitx2. Together, our data identifies SOX9 coordinated transcriptional hierarchies that control cell proliferation and differentiation during valve formation. Examination of SOX9 binding sites in E12.5 atrioventricular canal (AVC) and E12.5 embryonic limb and mRNA expression profiling in E12.5 WT and Sox9 mutant AVCs, in duplicate.
2015-11-05 | E-GEOD-73225 | biostudies-arrayexpress
Project description:Although calcific aortic valve stenosis (CAVS) is the most prevalent valvular heart disease, the molecular mechanisms underlying aortic valve calcification remain unknown. Here, we found a significant elevation in stanniocalcin-1 (STC1) expression in the valve interstitial cells (VICs) of calcific aortic valves by combined analysis of our comprehensive gene expression data and microarray datasets reported previously. Immunohistochemical staining showed that STC1 was located around the calcific area in the aortic valves of patients with CAVS. In vitro experiments using inhibitors and siRNA targeting osteoblast differentiation signaling revealed that activation of the Akt/STC1 axis was essential for runt-related transcription factor 2 (RUNX2) induction in the VICs. RNA sequencing and bioinformatics analysis of STC1-knocked down VICs in osteoblast differentiation medium resulted in silencing of the induction of osteoarthritis signaling-related genes, including RUNX2 and COL10A1. STC1 depletion in the murine CAVS model improved aortic valve dysfunction with high peak velocity and valve thickening and suppressed the appearance of osteochondrocytes. STC1-deficient mice also exhibited complete calcification abolishment, although partial valve thickening by aortic valve injury was observed. Our findings suggest that STC1 may be a critical factor in determining valve calcification and a novel target for preventing the transition to severe CAVS with calcification. We analyzed the gene expression profiles of the valve interstitial cells (VICs) isolated from noncalcific and calcific areas in calcific aortic valve stenosis (CAVS) donors using a gene microarray.
2023-12-31 | GSE226781 | GEO
Project description:E12.5 AV cushion and E17.5 AV valve from wild-type FVB/N mice and in vitro cultured MC3T3 cells; In the study we demonstrated shared gene expression in embryonic heart valve development and Osteoblast progenitor cells. The atrioventricular (AV) valves of the heart develop from undifferentiated mesenchymal endocardial cushions, that later remodel into stratified valves with diversified extracellular matrix (ECM). Because the mature valves express genes associated with osteogenesis and exhibit disease-associated calcification, we hypothesized the existence of shared regulatory pathways active in the remodeling AV valves and in bone progenitor cells. In order to define gene regulatory programs of valvulogenesis relative to osteoblast progenitors, we undertook Affymetrix gene expression profiling analysis of murine embryonic day (E)12.5 AV cushions compared to E17.5 remodeled AV valves (mitral and tri-cuspid) and to pre-osteoblast MC3T3-E1 (subclone4) cells. Overall MC3T3 cells were significantly more similar to E17.5 valves than to E12.5 cushions, supporting the hypothesis that valve remodeling involves the expression of many genes also expressed in osteoblasts. Several transcription factors characteristic of mesenchymal and osteoblast precursor cells, including Twist1 are predominant in E12.5 cushion. Valve remodeling also includes differential regulation of matrix metalloproteinases and their inhibitors as well as characteristic collagen isoform switching. Among the most highly enriched genes during valvulogenesis were members of the small leucine-rich proteoglycan (SLRP) family including Asporin, a known negative regulator of osteoblast differentiation and mineralization. Together, these data support shared gene expression profiles of the remodeling valves and osteoblast bone precursor cells in normal valve development and homeostasis with potential functions in calcific valve disease. Experiment Overall Design: In the study, we hybridized RNA from E12.5 AV cushion and E17.5 AV valve from wild-type FVB/N mice and in vitro cultured MC3T3 cells to Affymetrix MOE430 2 GeneChip® arrays.
2008-10-21 | E-GEOD-11040 | biostudies-arrayexpress
Project description:Heart valve formation initiates when endothelial cells of the heart transform into mesenchyme and populate the cardiac cushions. The transcription factor, SOX9, is highly expressed in the cardiac cushion mesenchyme, and is essential for heart valve development. Loss of Sox9 in mouse cardiac cushion mesenchyme alters cell proliferation, embryonic survival, and disrupts valve formation. Despite this important role, little is known regarding how SOX9 regulates heart valve formation or its transcriptional targets. Therefore, we mapped putative SOX9 binding sites by ChIP-Seq in embryonic day (E) 12.5 heart valves, a stage at which the valve mesenchyme is actively proliferating and initiating differentiation. Embryonic heart valves have been shown to express a high number of genes that are associated with chondrogenesis, including several extracellular matrix proteins and transcription factors that regulate chondrogenesis. Consequently, we compared regions of putative SOX9 DNA-binding between E12.5 heart valves and E12.5 limb buds. We identified context-dependent and context–independent SOX9 interacting regions throughout the genome. Analysis of context-independent SOX9 binding suggests an extensive role for SOX9 across tissues in regulating proliferation-associated genes including key components of the AP-1 complex. Integrative analysis of tissue-specific SOX9 interacting regions and gene expression profiles on Sox9-deficient heart valves demonstrated that SOX9 controls the expression of several transcription factors with previously identified roles in heart valve development, including Twist1, Sox4, Mecom/Evi1 and Pitx2. Together, our data identifies SOX9 coordinated transcriptional hierarchies that control cell proliferation and differentiation during valve formation.
2015-11-05 | GSE73225 | GEO