Diminished Immune Cell Adhesion in Hypoimmune ICAM-1 Knockout Human Pluripotent Stem Cells
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PROVIDER: PRJNA1234521 | ENA |
REPOSITORIES: ENA
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Project description:Gene edited human pluripotent stem cells (hPSCs) are a promising platform for developing reparative cellular therapies that evade immune rejection. Existing first-generation hypoimmune strategies have used CRISPR/Cas9 editing to modulate genes associated with adaptive immune responses, but have largely not addressed the innate immune cells, such as neutrophils, that mediate inflammation and rejection processes occurring early after graft transplantation. We identified the adhesion molecule ICAM-1 as a hypoimmune target that plays multiple critical roles in both adaptive and innate immune responses post-transplantation. In our experiments, we found that ICAM-1 blocking or knock-out (KO) in hPSC-derived cardiovascular therapies imparted significantly diminished binding of multiple immune cell types. ICAM-1 KO resulted in diminished T cell proliferation responses in vitro and in longer in vivo retention/protection of KO grafts following immune cell encounter in NeoThy humanized mice. The ICAM-1 KO edit was also introduced into existing first-generation hypoimmune hPSCs and prevented immune cell binding. This promising hypoimmune editing strategy has the potential to improve transplantation outcomes for regenerative therapies in the setting of cardiovascular pathologies and several other diseases.
2025-07-07 | GSE291617 | GEO
Project description:Hypoimmune gene edited human pluripotent stem cells (hPSCs) are a promising platform for developing reparative cellular therapies that evade immune rejection. Existing first-generation hypoimmune strategies have used CRISPR/Cas9 editing to modulate genes associated with adaptive (e.g., T cell) immune responses, but have largely not addressed the innate immune cells (e.g., monocytes, neutrophils) that mediate inflammation and rejection processes occurring early after graft transplantation. We identified the adhesion molecule ICAM-1 as a novel hypoimmune target that plays multiple critical roles in both adaptive and innate immune responses post-transplantation. In a series of studies, we found that ICAM-1 blocking or knock-out (KO) in hPSC-derived cardiovascular therapies imparted significantly diminished binding of multiple immune cell types. ICAM-1 KO resulted in diminished T cell proliferation responses in vitro and in longer in vivo retention/protection of KO grafts following immune cell encounter in NeoThy humanized mice. The ICAM-1 KO edit was also introduced into existing first-generation hypoimmune hPSCs and prevented immune cell binding, thereby enhancing the overall hypoimmune capacity of the cells. This novel hypoimmune editing strategy has the potential to improve the long-term efficacy and safety profiles of regenerative therapies for cardiovascular pathologies and a number of other diseases.
| S-EPMC11185752 | biostudies-literature
Project description:Pulmonary hypertension (PH) patients typically present with a diminished platelet count, but the role of platelets in the development and progression of PH remains unclear.Transcriptomic analysis revealed that platelets from PH patients exhibited an upregulation of genes associated with cellular adhesion, platelet activation, and adhesion. Notably, the hub genes, glycoprotein IIb/IIIa (GP IIb/IIIa), were implicated in mediating platelet-endothelium adhesion through their interaction with intercellular adhesion molecule-1 (ICAM-1) on pulmonary artery endothelial cells, triggering platelet activation and the subsequent release of platelet-derived growth factor BB (PDGF-BB).
2024-12-09 | GSE283520 | GEO
Project description:GP IIb/IIIa-ICAM-1 Mediated Platelet-Endothelial Adhesion Exacerbates Pulmonary Hypertension
| PRJNA1194190 | ENA
Project description:The bone marrow niche plays a critical role in controlling the fate of hematopoietic stem cells (HSCs) by integrating intrinsic and extrinsic signals. However, the molecular events in the HSC niche remain to be investigated. Here, we report that intercellular adhesion molecule-1 (ICAM-1) maintains HSC quiescence and repopulation capacity in the niche. ICAM-1-deficient mice (ICAM-1-/-) displayed significant expansion of phenotypic long-term HSCs with impaired quiescence, as well as favors myeloid cell expansion. ICAM-1-deficient HSCs presented normal reconstitution capacity during serial transplantation; however, reciprocal transplantation experiments showed that ICAM-1 deficiency in the niche impaired HSCs quiescence and repopulation capacity. In addition, ICAM-1 deletion caused failure to retain HSCs in the bone marrow and changed the expression profile of stroma cell-derived factors, possibly representing the mechanism for defective HSCs in ICAM-1-/- mice. Collectively, these observations identify ICAM-1 as a regulator in the bone marrow niche.
2018-06-21 | GSE114836 | GEO
Project description:Streptococcus pneumoniae is a leading cause of community-acquired pneumonia. Intercellular adhesion molecule-1 (ICAM-1) is an adhesion molecule that is highly expressed on the pulmonary capillary endothelium, alveolar epithelium and other cell types within the lung. ICAM-1 is known to play important roles in leukocyte adhesion, migration, and motility. To determine the contributions of ICAM-1 to bacterial clearance and leukocyte kinetics during pneumonia, mice were inoculated with S. pneumoniae and evaluated 1, 4 and 7 days later. Our results show that Icam1-/- mice have a greater number of viable bacteria within the lung at each time point. The impaired clearance observed in Icam1-/- mice was not due to an impediment in leukocyte recruitment. In fact, Icam1-/- mice had a greater number of neutrophils and recruited inflammatory macrophages in the lung tissue and the alveoli/airways on day 7. In contrast, fewer alveolar macrophages were present in the BAL of Icam1-/- mice. The loss of body weight and the concentrations of inflammatory mediators in the BAL were also significantly greater in Icam1-/- mice. Mechanistic studies to understand the defect in clearance show that neutrophils and macrophage subpopulations had no defect in phagocytosis or acidification of phagosomes. RNA sequencing reveals many differences in gene expression, but does not suggest° a defect in phagocytosis. Thus, ICAM-1 is necessary for the clearance of S. pneumoniae and for the resolution of pneumonia, but is not required for the recruitment of neutrophils or inflammatory macrophages into the pneumonic lung parenchyma or the alveoli/airways during S. pneumoniae-induced pneumonia.
2024-10-16 | GSE270761 | GEO
Project description:Background：Atherosclerosis is the major cause of cardiovascular disease. Endothelial injury is one of the initiating factors of atherosclerosis. Injured endothelial cells overexpress adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), facilitating the binding and accumulation of monocytes-macrophages into the vascular wall via the ligands. Adipose-derived stem cells (ADSCs) have been extensively researched for their anti-inflammatory properties and therapeutic potential in various diseases. Targeting atherosclerotic regions with ADSCs may offer a promising therapeutic strategy to alleviate local inflammation associated with atherosclerosis.Methods：The ligands of very late antigen-4 (VLA-4) and lymphocyte function-associated antigen-1 (LFA-1) were expressed in the ADSC to construct the Macrophage (Mφ)-mimicking ADSCs. Cell proliferation, adhesion, and migration assays were used to characterize the Mφ-mimicking ADSCs. An atherosclerosis model was established in ApoE-/- mice via partial carotid artery ligation. Mφ-mimicking ADSCs were administered through tail vein injection. Distribution of these cells was tracked by far-red fluorescent probe. Histological analyses, including H&E staining, Oil Red O staining, and immunofluorescence were conducted to assess the impact on plaque size, composition, and macrophage polarization.Results：Mφ-mimicking ADSCs were successfully constructed and characterized. These cells exhibited enhanced adhesion and migration capabilities. The culture medium from Mφ-mimicking ADSCs increased the proportion of M2 macrophages and decreased the lipid uptake capacity. In the atherosclerosis mouse model, fluorescently labeled Mφ-mimicking ADSCs specifically adhered to and accumulated in atherosclerotic regions, demonstrating targeted localization. Mφ-mimicking ADSC treatment resulted in a reduction in plaque size and a decrease in the number of M1 macrophages within the arterial wall.Conclusions：Mφ-mimicking ADSCs confirmed their preserved anti-inflammatory properties and enhanced adhesion and migration abilities. In vivo, Mφ-mimicking ADSCs exhibited targeted localization ability to regions of endothelial dysfunction in atherosclerosis and attenuate plaque progression. These findings suggest that Mφ-mimicking ADSCs may serve as a potential therapeutic strategy for alleviating atherosclerosis and reducing inflammation.
2024-11-30 | GSE276970 | GEO
Project description:The human pluripotent stem cells cultured on Low-adhesion substrates formed two morphologically different subtypes (Monolayer and Domed). The dome-like cells showed higher proliferation capacity and KLF4/5 expression than the monolayer cells. A serum response factor based regulatory double loop was proposed to explain how cell-matrix adhesion mediates the interaction between cell morphology and pluripotency genes
2018-06-11 | GSE115256 | GEO
Project description:The adhesion of monocytic cells to the M-^SdysfunctionalM-^T endothelium constitutes a critical step in the initiation of atherosclerotic plaque formation. Cigarette smoke (CS) has been shown to contribute to the monocyte-endothelial adhesion process. Yet, the complex mechanisms underlying this event remain to be discovered. In the systemic compartment, monocytes and endothelial cells are exposed primarily to soluble constituents originating from the inhaled CS and absorbed through the lung alveolar epithelium and the adjacent microvascular endothelium. Considering this rationale, we developed an in vitro adhesion assay, intending to mimic the in vivo situation, to deeply investigate the impact of CS on the adhesion of monocytic cell to the endothelium. Using a transcriptomics approach followed by confirmation experiments, we were able to identify a key mechanism by which aqueous extract of CS (smoke-bubbled Phosphate Buffered Saline, sbPBS) promotes the adhesion of monocytic Mono Mac 6 (MM6) cells to the human umbilical vein endothelial cells (HUVECs). While CS-derived constituents directly provoke a strong oxidative stress response in both cell types, the induced expression of E-selectin, VCAM-1 and ICAM-1 adhesion molecules, responsible for the binding of MM6 cells to HUVECs, occurs through a proinflammatory paracrine effect. We demonstrate that this effect is mainly driven by TNF? produced by MM6 cells exposed to sbPBS. In conclusion, the development of our in vitro adhesion assay, intending to mimic the in vivo conditions, enabled to show that the adhesion of monocytic cells to endothelial cells is promoted through an indirect effect of the sbPBS.
2014-04-24 | E-MTAB-1173 | biostudies-arrayexpress
Project description:Low Cell-Matrix Adhesion Reveals Two Subtypes of Human Pluripotent Stem Cells
| PRJNA474380 | ENA