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Extracellular vesicle therapy for retinal diseases.

ABSTRACT: Extracellular vesicles (EV), which include exosomes and microvesicles, are secreted from virtually every cell. EV contain mRNA, miRNA, lipids and proteins and can deliver this expansive cargo into nearby cells as well as over long distances via the blood stream. Great interest has been given to them for their role in cell to cell communication, disease progression, or as biomarkers, and more recent studies have interrogated their potential as a therapeutic that may replace paracrine-acting cell therapies. The retina is a conveniently accessible component of the central nervous system and the proposed paradigm for the testing of many cell therapies. Recently, several studies have been published demonstrating that the delivery of EV/exosomes into the eye can elicit significant therapeutic effects in several models of retinal disease. We summarize results from currently available studies, demonstrating their efficacy in multiple eye disease models as well as highlighting where future research efforts should be directed.

SUBMITTER: Mead B

PROVIDER: S-EPMC9460937 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Extracellular vesicle therapy for retinal diseases.

Mead Ben B Tomarev Stanislav S

Progress in retinal and eye research 20200310

Extracellular vesicles (EV), which include exosomes and microvesicles, are secreted from virtually every cell. EV contain mRNA, miRNA, lipids and proteins and can deliver this expansive cargo into nearby cells as well as over long distances via the blood stream. Great interest has been given to them for their role in cell to cell communication, disease progression, or as biomarkers, and more recent studies have interrogated their potential as a therapeutic that may replace paracrine-acting cell ...[more]

PMID: 32169632

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Project description:Autosomal dominant polycystic kidney (ADPKD) disease is the commonest genetic cause of kidney failure (affecting 1:800 individuals) and is due to heterozygous germline mutations in either of two genes, PKD1 and PKD2. Homozygous germline mutations in PKHD1 are responsible for autosomal recessive polycystic kidney (ARPKD) disease a rare (1:20,000) but severe neonatal disease. The products of these three genes, PKD1 (polycystin-1 (PC1 4302(3)aa)), PKD2 (polycystin-2 (PC2 968aa)) and PKHD1 (fibrocystin (4074aa)) are all present on extracellular vesicles (EVs) termed, PKD-exosome-like vesicles (PKD-ELVs). PKD-ELVs are defined as 100 nm PC1/PC2/CD133 and fibrocystin positive EVs which are shed into the urine from the apical plasma membrane of proximal tubule (PT) cells. PKD-ELVs are therefore ectosomes and are distinct from classical exosomes from the multivesicular body. PC1, PC2, fibrocystin and exosomal polycystin-1 interacting protein (EPIC, CU062) form a higher order ion channel complex termed the polycystin complex (PCC) on the surface of the PKD-ELV. We hypothesize that the PCC is involved in the generation of the PKD-ELV and is a structural component thereof. The PCC has also been detected on the primary cilium, a hair like 9+0 microtubule based structure present on all cells except hepatocytes. In kidney epithelial cells, the primary cilium protrudes into the lumen of the tubule where it regulates planar cell polarity (PCP) and tubule lumen diameter. Here we present a theory that explains the presence of the PCC on PKD-ELVs and primary cilia as well as other cryptic aspects of ADPKD and ARPKD. We suggest that the fundamental role of the PCC is to assemble PKD-ELVs on the plasma membrane and then shed them into the extracellular space or the lumen of the tubule. The resultant PKD-ELVs can have multiple functions in different biological contexts. One of the roles of the resultant PKD-ELVs is to generate a planar cell polarity (PCP) signaling gradient along kidney tubules in developing or regenerating kidney. This is mediated via an adhesion event between the PKD-ELV and primary cilium. Defects in the primary cilium or PKD-ELV assembly lead to cystogenesis, the major feature of ADPKD. The other important role for the PCC dependent PKD-ELV is the detection, packaging and extrusion of defective mitochondria. The PKD-ELV is also critical in the transfer of mRNA and miRNAs between cells and as a vector for extracellular proteinases and hyaluronidases involved in tissue remodeling. A PKD-ELV centric view of polycystic disease (EV theory) can explain the requirement for primary cilium function in ADPKD (where the primary cilium is the PKD-ELV receptor), the observation of defective mitochondria in the disease, the abnormalities detected in the extracellular matrix (ECM) as well as the resistance to carcinoma noted in ADPKD patients and individuals carrying PKHD1 mutations, see graphical abstract.

Dataset Information

Extracellular vesicle therapy for retinal diseases.

Publications

Extracellular vesicle therapy for retinal diseases.

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