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MSCs-encapsulated porous microparticle eye drops for autoimmune dry eye disease treatment

ABSTRACT: Dry eye disease (DED) characterizes by chronic inflammation and an unstable tear film. Stem cells have shown potential for DED treatment, but the main challenge lies in improving the effectiveness of cell delivery. Here, we developed novel eye drops for DED treatment by employing porous microcarriers with mesenchymal stem cells. The microcarriers were created by electrospraying the solution of Arginine-Glycine-Aspartic Acid (RGD) peptides-modified sodium alginate with polyethylene oxide and mesenchymal stem/stromal cells (MSCs) into the calcium chloride solution. In vitro experiments based on a hyperosmotic corneal epithelial cell model indicated that porous microcarriers encapsulated with MSCs (RGD-Alg@MSCs) demonstrated notable enhancements in cell viability, reductions in apoptosis and reactive oxygen species (ROS), and diminished expression of pro-inflammatory cytokines. In the DED model using non-obese diabetic (NOD) mice, RGD-Alg@MSCs effectively enhanced tear production, promoted corneal healing, and alleviated inflammation. Additionally, RGD-Alg@MSCs modulated the immune environment in DED by inhibiting dendritic cell (DC) activation and suppressing Th17 differentiation in vitro, effectively disrupting the inflammatory feedback loop characteristic of DED. This immune modulation strategy was further validated through in vivo experiments, confirming its therapeutic potential. Thus, the designed MSCs-encapsulated porous microcarrier system can improve stem cell delivery and DED treatment efficiency.

ORGANISM(S): Homo sapiens

PROVIDER: GSE295017 | GEO | 2025/04/23

REPOSITORIES: GEO

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MSCs-encapsulated porous microparticle eye drops for autoimmune dry eye disease treatment

Project description:MSCs-encapsulated porous microparticle eye drops for autoimmune dry eye disease treatment

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α7 Nicotinic Acetylcholine Receptor Regulates Macrophage-Mediated Neuroinflammation in Dry Eye Disease

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2024-04-07 | GSE263136 | GEO

Long non-coding RNAs Gabarapl2 and Chrnb2 positively regulate inflammatory signaling in a mouse model of dry eye

Project description:Purpose: To elucidate the expression profile and the potential role of long non-coding ribonucleic acids (RNAs; lncRNAs) in a dry eye disease (DED) model. Methods: A DED model was established in C57BL/6J mice with 0.2% benzalkonium chloride (BAC) twice a day for 14 days. The differentially expressed lncRNAs were detected by RNA-seq technology and the aberrantly expressed lncRNAs were further verified by RT-qPCR. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted to predicate the related candidate genes and potential pathological pathways. Cells from a human corneal epithelial cell line (HCECs) were cultured under hyperosmolarity. The regulation of inflammatory factors by silencing potential targeted lncRNAs was verified in vitro in HCECs. Results: In our study, a significant increase in corneal fluorescence staining and a reduction in tear production were observed in DED mice at all follow-ups compared with the controls, and the differences were increasing over time. In total, 2649 upregulated and 704 downregulated lncRNAs were identified in DED mice. We selected six aberrantly expressed and most abundant lncRNAs and performed RT-qPCR using the samples for RNA-seq. Chrnb2, Gabarapl2, and Usp31 were thereby confirmed as the most significantly altered lncRNAs. Pathway analysis revealed that the neuroactive ligand–receptor interaction signaling pathway was the most enriched, followed by the calcium signaling pathway and cytokine–cytokine receptor interaction. Following treatment of Gabarapl2 siRNA and Chrnb2 siRNA, tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and interleukin (IL)-6 were significantly downregulated in the HCECs. Conclusion: Our study suggests that Chrnb2 and Gabarapl2 may be involved in the inflammation response by regulating TNF-α, IL-1β, and IL-6 in DED. These candidate lncRNAs may be both potential biomarkers and therapeutic targets for DED.

2021-11-09 | GSE186450 | GEO

Interleukin-12 sustained release system promotes hematopoietic recovery after radiation injury

Project description:The continuous production of all mature blood cell lineages is maintained by Hematopoietic stem cells (HSCs), but they are highly susceptible to damage by ionizing radiation (IR) that induces death. Therefore, devising the therapeutic strategies that can mitigate hematopoietic toxicity caused by IR would benefit acute radiation syndrome (ARS) victims and radiation therapy patients. Here, we prepared an injectable hydrogel based on RGD-alginate and Laponite by a simple mixing method to release IL-12 (RGD-Alg/Laponite@IL-12) slowly and locally. The localization administration of RGD-Alg/Laponite@IL-12 substantially increased the survival and promoted the hematopoietic recovery of mice following sublethal-dose irradiation. These results suggested that local intra-bone marrow injection of RGD-Alg/Laponite@IL-12 hydrogel can effectively stimulate IL12R-PI3K/AKT signaling axis, which promotes proliferation and hematopoietic growth factors (HGFs) secretion of bone marrow mesenchymal stem/stromal cells (BM-MSCs). This signaling axis facilitates hematopoietic microenvironment repair and plays a pivotal role in hematopoietic reconstitution. In conclusion, our study attempted a biomaterial-sustained release of IL-12 for the treatment of irradiated hematopoietic injury and provided a new therapeutic strategy for hematopoietic acute radiation syndrome (H-ARS).

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Lacripep promotes corneal regeneration in autoimmune mediated dry eye disease

Project description:Corneal architecture is essential for vision and is greatly perturbed by the absence of tears due to the highly prevalent disorder dry eye. With no regenerative therapies available, pathological alterations of the ocular surface in response to dryness, including persistent epithelial defects and poor wound healing, result in lifelong morbidity. Here, using a mouse model of aqueous-deficient dry eye, we reveal that topical application of the synthetic tear protein lacripep reverses the pathological outcomes of dry eye through restoring the extensive network of corneal nerves that are essential for tear secretion, barrier function, epithelial homeostasis and wound healing. Intriguingly, the restorative effects of lacripep occur despite extensive immune cell infiltration, suggesting tissue reinnervation and regeneration can be achieved under chronic inflammatory conditions. In summary, our data highlight lacripep as a first-in-class regenerative therapy for returning the cornea to a near homeostatic state in individuals who suffer from dry eye.

2022-07-18 | GSE208297 | GEO

microRNA expression data from human corneal epithelial cells exposed to media, human tear, media + P. aeruginosa antigens, tear + P. aeruginosa antigens

Project description:Exposure to tear fluid can enhance corneal epithelial cells' ability to resist bacterial virulence mechanisms by upregulating epithelial-derived innate defense genes. The aim of this study was to further elucidate the mechanisms by which tear fluid modulates epithelial cell susceptibility to P. aeruginosa internalization and the relationship to known to be upregulated genes with tear fluid exposure. The hypothesis tested was that tear fluid effects on epithelial cells involve the induction of microRNA expression to modify innate defense gene responses to bacterial challenge. Human corneal epithelial cells were incubated in either 40 ul of fresh human tear fluid or high calcium KGM without antibiotics for 16 hours before extraction or before incubation with P. aeruginosa antigens for 3 h then extraction.

2012-07-13 | E-GEOD-39341 | biostudies-arrayexpress

The transcriptome of rabbit conjunctiva in dry eye disease: Large-scale changes and similarity to the human dry eye

Project description:Rabbit Dry Eye Diesease model induced with 3 weekly injections of Concanavalin A into the periorbital lacrimal glands Male Dutch-Belted rabbits. The pathophysiology of dry eye disease (DED) remains largely unknown, accounting in part for the lack of successful treatments. The transcriptome of full-thickness’s conjunctival tissue from rabbits with DED and from normal controls was determined using microarrays. DED induced large-scale changes in gene transcription involving 5,184 genes (22% of the total). Differentially expressed genes could be segregated into: functional modules and clusters; altered pathways; functionally linked genes; and groups of individual genes of known or suspected pathophysiological relevance to DED. A common feature of these subgroups is the breadth and magnitude of the changes that encompass ocular immunology and essentially all aspects of cell biology. Prominent changes concerned innate and adaptive immune responses; ocular surface inflammation; at least 25 significantly altered signaling pathways; a large number of chemokines; cell cycle; and apoptosis. Comparison of our findings to the limited extant transcriptomic data from DED patients associated with either Sjogren’s syndrome or non-Sjogren’s etiologies revealed a significant correlation between human and rabbit DED transcriptomes. Our data, establishing the large-scale transcriptomic changes of DED and their potential similarity to the human, underscore the enormous complexity of DED; establish a robust animal model of DED; will help expand our understanding of its pathophysiology; and could guide the development of successful therapeutic strategies.

2021-03-30 | GSE171043 | GEO

Modeling dry eye with an air-liquid interface in corneal epithelium-on-a-chip

Project description:Dry eye syndrome (DES) is a complex ocular condition characterized by an unstable tear film and inadequate tear production, leading to tissue damage. Despite its common occurrence, there is currently no comprehensive in vitro model that accurately reproduce the cellular characteristics of DES. Here we modified a corneal epithelium-on-a-chip (CEpOC) model to recapitulate DES by subjecting HCE-T human corneal epithelial cells to an air-liquid (AL) interface stimulus. We then assessed the effects of AL stimulation both in the presence and absence of diclofenac (DCF). Transcriptomic analysis revealed distinct gene expression changes in response to AL and AL_DCF, affecting pathways related to development, epithelial structure, inflammation, and extracellular matrix remodeling. Both treatments upregulated PIEZO2, linked to corneal damage signaling, while downregulating OCLN, involved in cell-cell junctions. They increased the expression of inflammatory genes (e.g., IL6) and reduced mucin production genes (e.g., MUC16), reflecting dry eye characteristics. TGFB1, crucial for corneal wound healing, was slightly downregulated in AL_DCF, potentially affecting wound healing processes rather than reducing inflammation by DCF. Metabolomic analysis showed increased secretion of metabolites associated with cell damage and inflammation (e.g., methyl-2-oxovaleric acid, 3-methyl-2-oxobutanoic acid, lauroyl-carnitine) in response to AL and even more with AL_DCF, indicating a shift in cellular metabolism. This study showcases the utilization of AL stimulus within the CEpOC as a comprehensive approach to faithfully reproduce the cellular characteristics of DES.

2023-10-11 | GSE244787 | GEO

TFAM deficiency promotes mitochondrial dysfunction to drive inflammation in the corneas of dry eye disease through mtDNA stress-mediated AIM2 inflammasome activation

Project description:Background & Aims Mitochondrial dysfunction and mtDNA stress-mediated inflammasome activation play critical roles in the pathogenesis of dry eye disease (DED). Mitochondrial transcription factor A (TFAM) is essential for regulating mtDNA stability and mitochondrial homeostasis. However, the mechanism underling TFAM to infuence DED progression is largely unknown. As a cytosolic DNA sensor, absent in melanoma 2 (AIM2) may contribute to the development of DED. Therefore, we aimed to explore whether the role of TFAM is associated with AIM2 inflammasome activation in DED. Methods The changes in inflammation, mitochondrial function, mtDNA homeostasis and TFAM expression were analyzed in the corneas of DED mice in vivo and in HCECs under oxidative stress in vitro. The effects of TFAM knockout on mtDNA homeostasis, mitochondrial respiration and cytokine release were also investigated in HCECs. The mechanism was analyzed by RNA sequencing in the corneas of DED mice, which was further verified by the HCECs with TFAM depletion. Results We found that the corneas of DED mice and HCECs under oxidative stress exhibited inflammation, mitochondrial damage and mtDNA maintenance disruption , which were highly associated with significantly reduced TFAM protein levels. Furthermore, we demonstrated that silencing of TFAM in HCECs suppressed mitochondrial respiratory capacity, induced mtDNA released into the cytosol and triggered cytokine release. Mechanistically, cytosolic mtDNA accumulation caused by TFAM depletion activated the AIM2 inflammasome and facilitated inflammation, thereby driving DED progression. Conclusions Our findings elucidate that TFAM deficiency induces mitochondrial dysfunction and cytosolic mtDNA stress, which subsequently activates the AIM2 inflammasome, triggers inflammatory responses and promotes DED progression. TFAM pathway may provide a novel therapeutic strategy for DED.

2024-06-18 | GSE252984 | GEO

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