Genetically‑modified stem cells in treatment of human diseases: Tissue kallikrein (KLK1)‑based targeted therapy (Review)

Devetzi, Marina; Goulielmaki, Maria; Khoury, Nicolas; Spandidos, Demetrios Α.; Sotiropoulou, Georgia; Christodoulou, Ioannis; Zoumpourlis, Vassilis

doi:10.3892/ijmm.2018.3361

Cited by 20 publications

(26 citation statements)

References 143 publications

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“…Thus far, new strategy, such as genetic modification, has been developed and has showed promising outcomes in MSC therapy. Recently, increasing evidence indicates that the genetically modified MSCs always have a better outcome than wild-type MSCs due to the expression of the function genes after transfection [55]. The functions of the gene targeted for MSC modification are classified as follows: firstly, enhance proliferation and antiapoptosis capacity; secondly, improve homing and migration ability; and thirdly, increase paracrine effects or transdifferentiation capacity.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic effect of integrin-linked kinase gene-modified bone marrow-derived mesenchymal stem cells for streptozotocin-induced diabetic cystopathy in a rat model

et al. 2020

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Background: Diabetic cystopathy (DCP) is a chronic complication of diabetes mainly within the submucosal and muscular layers of the bladder due to the hyperglycemia-induced ischemia. As no effective therapies are currently available, the administration of optimized mesenchymal stem cells (MSCs) provides a potential treatment of DCP. Thus far, new strategy, such as genetic modification of MSCs, has been developed and has shown promising outcomes of various disorders. Methods: This study was conducted using integrin-linked kinase (ILK) gene-modified bone marrow-derived stem cells (BMSCs) for streptozotocin (STZ)-induced diabetic cystopathy in a rat model. In total, 68 male Sprague-Dawley rats were randomized into five groups: sham control (control group, n = 10); DCP model alone (DM group, n = 10); DCP rats intravenously treated with BMSCs (BMSC group, n = 16); DCP rats accepted adenoviral vector-infected BMSCs (Ad-null-BMSC group, n = 16) and DCP rats accepted ILK adenoviral vector-infected BMSCs (Ad-ILK-BMSC group, n = 16). Diabetic rats accepted cell transplantation in the experimental group (2 rats per group) were sacrificed for the bladder tissue on the third day, 7th day, and 14th day of treatment respectively ahead of schedule. At 4 weeks after treatment, all rats in five groups accepted urodynamic studies to evaluate bladder function and were sacrificed for bladder tissue. Results: Our data showed that the underactive bladder function was significantly improved in DCP rats intravenously treated with ILK gene-modified BMSCs compared to those in the DM, BMSCs, and Ad-null-BMSC group. Meanwhile, we found that gene-modified BMSC treatment significantly promoted the activation of the AKT/ GSK-3β pathway by increasing phosphorylation and led to the enhancement of survival. In addition, the expression levels of angiogenesis-related protein vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and stromal cell-derived factor-1 (SDF-1) were significantly higher in the Ad-ILK-BMSC group than that in the DM, BMSCs, and Ad-null-BMSC group as assessed by enzyme-linked immunosorbent assay and western blot. As two indicators of vascular endothelial cell markers, the expression of von Willebrand factor (vWF) and CD31 by

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Section: Discussionmentioning

confidence: 99%

Therapeutic effect of integrin-linked kinase gene-modified bone marrow-derived mesenchymal stem cells for streptozotocin-induced diabetic cystopathy in a rat model

et al. 2020

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“…In rodent and in vitro studies, KLK1 is constitutively expressed by endothelial cells, and endothelial activation leads to release of active protease, matrix degradation, smooth muscle cell migration and vascular sprouting 32 , processes relevant to PAH. Gene delivery of tissue KLK1 via adenoviral vectors, protein infusion or genetically-modified stem cells has shown beneficial effects in multiple models of vascular diseases 40 . KLK1 is part of a highly-conserved, serine protease subfamily.…”

Section: Discussionmentioning

confidence: 99%

Novel risk genes and mechanisms implicated by exome sequencing of 2,572 individuals with pulmonary arterial hypertension

Zhu

Pauciulo

Welch

et al. 2019

Preprint

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Group 1 pulmonary arterial hypertension (PAH) is a rare disease with high mortality despite recent therapeutic advances. Pathogenic remodeling of pulmonary arterioles leads to increased pulmonary pressures, right ventricular hypertrophy and heart failure. Mutations in bone morphogenetic protein receptor type 2 and other risk genes predispose to disease, but the vast majority of non-familial cases remain genetically undefined. To identify new risk genes, we performed exome sequencing in a large cohort from the National Biological Sample and Data Repository for PAH. By statistical association of rare deleterious variants, we found tissue kallikrein 1 and gamma glutamyl carboxylase as new candidate risk genes for idiopathic PAH associated with a later age-of-onset and relatively moderate disease phenotype compared to bone morphogenetic receptor type 2. Both genes play important roles in vascular hemodynamics and inflammation but have not been implicated in PAH previously. These data suggest new genes, pathogenic mechanisms and therapeutic targets for this lethal vasculopathy.Word count: 154

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“…KLK1 74 is a component of the kallikrein-kinin system (KKS) implicated in the homeostasis of the cardiovascular, renal and central nervous system 75, 76 . The KKS comprises kallikreins, kininogens, kinins, kinin receptors and kininases (angiotensin-converting enzyme, ACE is the most important kinin-degrading enzyme in the cardiovascular system) 77 .…”

Section: The New Kids On the Blockmentioning

confidence: 99%

The role of genomics and genetics in pulmonary arterial hypertension

Swietlik¹,

Gräf²,

Morrell³

2020

gcsp

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[No abstract. Showing first paragraph of article]Although pulmonary hypertension (PH) had been recognised for centuries, it was not until the invention of cardiac catheterisation in the 1950s that enabled an accurate gene encoding bone morphogenetic protein receptor type 2, in patients with familial and clinical diagnosis. The discovery of heterozygous germline mutations in BMPR2, the idiopathic forms of pulmonary arterial hypertension (PAH) was another breakthrough in understanding the disease and initiated a new era in care of patients with this condition.

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Genetically‑modified stem cells in treatment of human diseases: Tissue kallikrein (KLK1)‑based targeted therapy (Review)

Cited by 20 publications

References 143 publications

Therapeutic effect of integrin-linked kinase gene-modified bone marrow-derived mesenchymal stem cells for streptozotocin-induced diabetic cystopathy in a rat model

Therapeutic effect of integrin-linked kinase gene-modified bone marrow-derived mesenchymal stem cells for streptozotocin-induced diabetic cystopathy in a rat model

Novel risk genes and mechanisms implicated by exome sequencing of 2,572 individuals with pulmonary arterial hypertension

The role of genomics and genetics in pulmonary arterial hypertension

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