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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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SLIT3-ROBO4 Activation Promotes Vascular Network Formation in Human Engineered Tissue and Angiogenesis in Vivo

ABSTRACT: Successful implantation and long-term survival of engineered tissue grafts hinges on adequate vascularization of the implant. Endothelial cells are essential for patterning vascular structures, but they require supportive mural cells such as pericytes/mesenchymal stem cells (MSCs) to generate stable, functional blood vessels.1-5 While there is evidence that the angiogenic effect of MSCs is mediated via the secretion of paracrine signals,6,7 the identity of these signals is unknown. Here, by utilizing two functionally distinct human MSC clones, we found that so-called “pericytic” MSCs secrete the pro-angiogenic neurovascular guidance molecule SLIT3,8 which guides vascular development by directing ROBO4-positive endothelial cells to form networks in engineered tissue. In contrast, “non-pericytic” MSCs exhibit reduced activation of the SLIT3/ROBO4 pathway and do not support vascular networks. Using live cell imaging of organizing 3D vascular networks, we show that knockdown of SLIT3 in MSCs leads to disorganized clustering of ECs, and knockdown of its receptor ROBO4 in ECs abolishes the generation of functional human blood vessels in an in vivo xenogenic implant. These data suggest that the SLIT3/ROBO4 pathway regulates MSC-guided vascularization in engineered tissues. Heterogeneity of SLIT3 expression may underlie the variable clinical success of MSCs for tissue repair applications. 4 samples with 2 replicates each

ORGANISM(S): Homo sapiens

SUBMITTER: Kareen Kreutziger

PROVIDER: E-GEOD-48302 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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SLIT3-ROBO4 Activation Promotes Vascular Network Formation in Human Engineered Tissue and Angiogenesis in Vivo

Project description:Successful implantation and long-term survival of engineered tissue grafts hinges on adequate vascularization of the implant. Endothelial cells are essential for patterning vascular structures, but they require supportive mural cells such as pericytes/mesenchymal stem cells (MSCs) to generate stable, functional blood vessels.1-5 While there is evidence that the angiogenic effect of MSCs is mediated via the secretion of paracrine signals,6,7 the identity of these signals is unknown. Here, by utilizing two functionally distinct human MSC clones, we found that so-called “pericytic” MSCs secrete the pro-angiogenic neurovascular guidance molecule SLIT3,8 which guides vascular development by directing ROBO4-positive endothelial cells to form networks in engineered tissue. In contrast, “non-pericytic” MSCs exhibit reduced activation of the SLIT3/ROBO4 pathway and do not support vascular networks. Using live cell imaging of organizing 3D vascular networks, we show that knockdown of SLIT3 in MSCs leads to disorganized clustering of ECs, and knockdown of its receptor ROBO4 in ECs abolishes the generation of functional human blood vessels in an in vivo xenogenic implant. These data suggest that the SLIT3/ROBO4 pathway regulates MSC-guided vascularization in engineered tissues. Heterogeneity of SLIT3 expression may underlie the variable clinical success of MSCs for tissue repair applications.

2013-08-18 | GSE48302 | GEO

Patterned human microvascular grafts enable rapid vascularization and increase perfusion in infarcted hearts

Project description:Vascularization and efficient perfusion are long-standing challenges in cardiac tissue engineering. Here, we engineer perfusable microvascular constructs, wherein human embryonic stem cell-derived endothelial cells (hESC-ECs) are seeded both into patterned microchannels and the surrounding collagen matrix. In vitro, the hESC-ECs lining the luminal walls readily sprout and anastomose with de novo-formed endothelial tubes in the matrix under flow. When implanted on infarcted rat hearts, the perfusable microvessel grafts integrate with coronary vasculature to a greater degree than non-perfusable self-assembled constructs at 5 days post-implantation. Optical microangiography imaging reveal that perfusable grafts have 6-fold greater vascular density, 2.5-fold higher vascular velocities and >20-fold higher volumetric perfusion rates. Implantation of perfusable grafts containing additional hESC-derived cardiomyocytes show higher cardiomyocyte and vascular density. Thus, pre-patterned vascular networks enhance vascular remodeling and accelerate coronary perfusion, potentially supporting cardiac tissues after implantation. These findings should facilitate the next generation of cardiac tissue engineering design.

2018-12-24 | GSE124314 | GEO

CD146 expression in mesenchymal stem cells is associated with vascular smooth muscle commitment

Project description:Bone-marrow mesenchymal stem cells (MSCs) are plastic adherent cells that can differentiate into various tissue lineages, including osteoblasts, adipocytes and chondrocytes. However, this progenitor property is not shared by all cells within the MSC population. In addition, MSCs vary in their proliferation capacities and expression of markers. Because of heterogeneity of CD146 expression in the MSC population, we compared CD146-/Low and CD146High cells under clonal and non-clonal (sorted MSCs) conditions to determine whether this expression is associated with specific functions. CD146-/Low and CD146High MSCs did not differ in colony-forming unit-fibroblast number, osteogenic and adipogenic differentiation or in vitro hematopoietic supportive activity. However, CD146-/Low clones proliferated slightly but significantly faster than did CD146High clones. In addition, a strong expression of CD146 molecule was associated with a commitment towards a vascular smooth muscle cell lineage with upregulation of calponin-1 expression. Thus, within a bone-marrow MSC population, certain subpopulations characterized by high expression of CD146, are committed toward a vascular smooth muscle cell lineage. Clonal MSC were selected on the basis of CD146 level at their surface (CD146Low and CD146 High) and non-clonal MSC were compared from 4 different donors.

2013-07-04 | E-GEOD-48540 | biostudies-arrayexpress

Translating transcriptome of cancer cells in situ in mesenchymal-rich tumor microenvironment

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2013-11-01 | E-GEOD-43306 | biostudies-arrayexpress

Surface topography enhances differentiation of mesenchymal stem cells towards osteogenic and adipogenic lineages

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2018-09-20 | E-MTAB-7177 | biostudies-arrayexpress

Biogenerated oxygen-related environmental stressed apoptotic body targets endothelial cells

Project description:he dynamic balance of hypoxia and oxidative stress constitutes the oxygen-related microenvironment in injured tissues. Oxygen homeostasis is highly variable; therefore, it is not a therapeutic target for injured tissue repair. We found an enrichment and extensive apoptosis of mesenchymal stem cells (MSCs) infused intravenously in the wound microenvironment with co-existing hypoxia and oxidative stress. Apoptotic bodies (ABs), generated from in situ apoptosis, significantly promotes angiogenesis. We improved the derivation pathway of ABs by simulating oxygen homeostasis in injured tissues, with cobalt chloride-induced hypoxia or hydrogen peroxide-induced oxidative stress in MSCs. Oxygen-related environmental stressed ABs, derived from environments of hypoxic and oxidative stress, were identified and loaded onto hydrogel microspheres for accurate regulation of endothelial cells (ECs) vascularization. These ABs directly targeted ECs; oxidative stress ABs (Oxi-ABs) have a 2.5- and 4-fold higher tube-forming ability than hypoxic and normoxic ABs, respectively. miRNA microarray analysis revealed that different oxygen-stressed ABs deliver similar miRNAs, which leads to the broad upregulation of EC phosphokinase activity. Finally, local delivery of Oxi-ABs-loaded hydrogel microspheres promotes wound healing. Oxi-ABs-loaded hydrogel microspheres achieved controlled AB release, targeting EC by reducing the consumption of early inflammatory cells and adapting to the proliferative phase of wound healing. Thus, the biogenerated apoptotic bodies responding to oxygen-related environmental stress can target ECs to promote vascularization.

2024-01-01 | GSE240216 | GEO

Gene Expression Patterns of Endothelial Cell Network Formation

Project description:Lamellar co-cultures of human aorta-derived smooth muscle cells (SMCs) cultured with cord-blood derived endothelial cells (ECs) are an in vitro model for tissue engineered blood vessels and in-growth of endothelial cells into cardiovascular repair devices. The ratio of endothelial cells to smooth muscle cells can control the EC pattern of growth and differentiation. Low density ECs form capillary-like networks in co-culture with SMCs whereas high density ECs become confluent across the top surface of the SMCs. To understand the molecular mechanisms that govern network formation, used microarray analysis of ECs purified from 1) networks, 2) confluent layers compared to 3) ECs in monoculture.

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Quantitative phosphoproteomics reveals the temporal phosphorylation network regulated via mesenchymal stem cells in the tumor microenvironment

Project description:The tumor microenvironment (TME), which comprises cellular and noncellular components, is involved in the complex process of cancer development. Emerging evidence suggests that mesenchymal stem cells (MSCs), one of the vital regulators of the TME, foster tumor progression through paracrine secretion. However, the comprehensive phospho-signaling pathways that are mediated by MSCs-secreting factors have not yet been fully established. In this study, we attempt to dissect the MSCs-triggered mechanism in lung cancer using quantitative phosphoproteomics. A total of 1958 phosphorylation sites are identified in lung cancer cells stimulated with MSCs-conditioned medium (MSC-CM). Integrative analysis of the identified phosphoproteins and predicted kinases demonstrates that MSC-CM functionally promotes the proliferation and migration of lung cancer via the ERK/phospho-c-Fos-S374 pathway. Recent studies have reported that extracellular ATP accumulates in the tumor microenvironment and stimulates the P2X7 receptor on the cancer cell membrane via purinergic signaling. We observe that ectopic ATP synthase is located on the surface of MSCs and excreted extracellular ATP into the lung cancer microenvironment to trigger the ERK/phospho-c-Fos-Ser374 pathway, which is consistent with these previous findings. Our results suggest that ectopic ATP synthase on the surface of MSCs releases extracellular ATP into the tumor microenvironment, which promotes cancer progression via activation of the ERK/phospho-c-Fos-Ser374 pathway.

2022-06-09 | PXD029288 | Pride

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