Effective Prevention of Liver Fibrosis by Liver-targeted Hydrodynamic Gene Delivery of Matrix Metalloproteinase-13 in a Rat Liver Fibrosis Model

Abé, Hiroyuki; Kamimura, Kenya; Kobayashi, Yuji; Ohtsuka, Masato; Miura, Hiromi; Ohashi, Riuko; Yokoo, Takeshi; Kanefuji, Tsutomu; Suda, Takafumi; Tsuchida, Masanori; Aoyagi, Yoshinobu; Zhang, Guisheng; Liu, Dexi; Terai, Shuji

doi:10.1038/mtna.2015.49

Cited by 34 publications

(40 citation statements)

References 35 publications

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“…In our study, we further confirmed this antifibrotic effect by quantitative image analysis of liver tissue which is more effective than qualitative and semiquantitative methods [19]. Both Nilotinib and stem cell-conditioned media showed antifibrotic effect, but there was no significant difference between the Nilotinib and stem cell-conditioned medium treatment against CCl 4 -induced liver fibrosis in rats.…”

Section: Discussionsupporting

confidence: 74%

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Antifibrotic Effect of Combination of Nilotinib and Stem Cell-Conditioned Media on CCl₄-Induced Liver Fibrosis

Shiha

Nabil

Lotfy

et al. 2020

Stem Cells International

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Liver fibrosis is the excessive extracellular matrix accumulation of proteins, such as collagen, which follows the chronic liver diseases. Advanced liver fibrosis leads to cirrhosis and liver failure. Nilotinib is a second-generation tyrosine kinase inhibitor, which showed antifibrotic efficacy. Stem cell therapy still has some limitations such as oncogenesis, unexpected differentiation, and ethical consideration. Stem cells secrete cytokines and growth factors that showed paracrine-mediated antifibrotic and antiinflammatory effects in vivo and in vitro. Thus, stem cell-conditioned medium (SC-CM), which contains the secretory proteins of stem cells, may have an antifibrotic role. This study was carried out to examine the antifibrotic effect of Nilotinib and stem cell exosomes on CCl 4 -induced liver fibrosis in rats. Male Wistar rats were injected intraperitoneally with CCl 4 twice a week for 9 weeks and given daily treatments of Nilotinib (20 mg/kg), stem cell exosomes (0.5 ml/rat), and the combination treatment of Nilotinib and stem cell exosomes during the last 5 weeks of CCl 4 intoxication. Liver fibrosis and also antifibrotic efficacy of the treatments were estimated with liver function tests, oxidative stress parameters, apoptotic parameters, histopathological examination, and hydroxyproline contents. Results showed that the combination of Nilotinib and stem cell-conditioned media had more antifibrotic effects than each one alone (P value < 0.001).

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Section: Discussionsupporting

confidence: 74%

“…Then, slides were stained with Masson trichrome as routine connective tissue stain. Images were captured from each section randomly, and a quantitative analysis of fibrotic area was performed using the ImageJ software (version 1.6.0_20, National Institutes of Health, Bethesda, MD) as previously reported [19].…”

Section: Hepatic Histopathological Evaluationmentioning

confidence: 99%

Antifibrotic Effect of Combination of Nilotinib and Stem Cell-Conditioned Media on CCl₄-Induced Liver Fibrosis

Shiha

Nabil

Lotfy

et al. 2020

Stem Cells International

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“…Liver-targeted hydrodynamic delivery of MMP-13 gene could be useful in prevention of liver fibrosis. 90 …”

Section: Special Attributes Of Specific Mmpsmentioning

confidence: 99%

Biochemical and Biological Attributes of Matrix Metalloproteinases

Cui

Khalil

2017

Progress in Molecular Biology and Translational Science

952

891

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Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that are involved in the degradation of various proteins in the extracellular matrix (ECM). Typically, MMPs have a propeptide sequence, a catalytic metalloproteinase domain with catalytic zinc, a hinge region or linker peptide, and a hemopexin domain. MMPs are commonly classified on the basis of their substrates and the organization of their structural domains into collagenases, gelatinases, stromelysins, matrilysins, membrane-type (MT)-MMPs, and other MMPs. MMPs are secreted by many cells including fibroblasts, vascular smooth muscle (VSM) and leukocytes. MMPs are regulated at the level of mRNA expression and by activation of their latent zymogen form. MMPs are often secreted as inactive proMMP form which is cleaved to the active form by various proteinases including other MMPs. MMPs cause degradation of ECM proteins such as collagen and elastin, but could influence endothelial cell function as well as VSM cell migration, proliferation, Ca2+ signaling and contraction. MMPs play a role in tissue remodeling during various physiological processes such as angiogenesis, embryogenesis, morphogenesis and wound repair, as well as in pathological conditions such as myocardial infarction, fibrotic disorders, osteoarthritis, and cancer. Increases in specific MMPs could play a role in arterial remodeling, aneurysm formation, venous dilation and lower extremity venous disorders. MMPs also play a major role in leukocyte infiltration and tissue inflammation. MMPs have been detected in cancer, and elevated MMP levels have been associated with tumor progression and invasiveness. MMPs can be regulated by endogenous tissue inhibitors of metalloproteinases (TIMPs), and the MMP/TIMP ratio often determines the extent of ECM protein degradation and tissue remodeling. MMPs have been proposed as biomarkers for numerous pathological conditions and are being examined as potential therapeutic targets in various cardiovascular and musculoskeletal disorders as well as cancer.

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“…Such genetic alterations are quite common in many human genetic disease 25,26 and our strategy can be applicable to human germline gene therapy to correct disease causing mutations. Insertion of long sequences will be also useful as one of the gene therapy strategies based on the addition of a functional gene 27 . Considering that human germline gene therapy will often be coupled with ex vivo handling of embryos, including an in vitro cell culture step that could cause 20 epigenetic changes of gene expression and affect fetal development 28,29 , i-GONAD, which does not require ex vivo handling or sacrifice of GONAD-treated females, can offer a highly promising approach as a human germline gene therapy tool in the future.…”

Section: Discussionmentioning

confidence: 99%

In situgenome editing method suitable for routine generation of germline modified animal models

Ohtsuka

Miura

Arifin

et al. 2017

Preprint

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Animal genome engineering experimental procedures involve three major steps: isolation of zygotes from pregnant females; microinjection of zygotes, and; transfer of injected zygotes into recipient females, that have been practiced for over three decades. The laboratory set ups intending to performing these procedures require to have sophisticated equipment as well as highly skilled technical personnel. Because of these reasons, animal transgenesis experiments are typically performed at centralized core facilities in most research organizations. We recently showed that all three steps, of animal transgensis, can be bypassed using a method termed GONAD (Genome-editing via Oviductal Nucleic Acids Delivery), by directly electroporating genome editing components into zygotes in situ. Although our first report demonstrated the genome-editing capability, its efficiency was lower than the standard methods using microinjection.Here we investigated critical parameters of GONAD to make it suitable for creating animal models of large genomic deletions, single nucleotide corrections and long sequence insertions. The efficiency of genome editing in the improved GONAD (i-GONAD) method reached to the levels comparable to traditional microinjection methods. The streamlined parameters, and the simplified experimental steps, in the i-GONAD method makes it suitable for routine genome editing applications performed both at centralized facilities as well as at the laboratories that lack highly skilled personnel and the sophisticated equipment.

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Effective Prevention of Liver Fibrosis by Liver-targeted Hydrodynamic Gene Delivery of Matrix Metalloproteinase-13 in a Rat Liver Fibrosis Model

Cited by 34 publications

References 35 publications

Antifibrotic Effect of Combination of Nilotinib and Stem Cell-Conditioned Media on CCl₄-Induced Liver Fibrosis

Antifibrotic Effect of Combination of Nilotinib and Stem Cell-Conditioned Media on CCl₄-Induced Liver Fibrosis

Biochemical and Biological Attributes of Matrix Metalloproteinases

In situgenome editing method suitable for routine generation of germline modified animal models

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Effective Prevention of Liver Fibrosis by Liver-targeted Hydrodynamic Gene Delivery of Matrix Metalloproteinase-13 in a Rat Liver Fibrosis Model

Cited by 34 publications

References 35 publications

Antifibrotic Effect of Combination of Nilotinib and Stem Cell-Conditioned Media on CCl4-Induced Liver Fibrosis

Antifibrotic Effect of Combination of Nilotinib and Stem Cell-Conditioned Media on CCl4-Induced Liver Fibrosis

Biochemical and Biological Attributes of Matrix Metalloproteinases

In situgenome editing method suitable for routine generation of germline modified animal models

Contact Info

Product

Resources

About

Antifibrotic Effect of Combination of Nilotinib and Stem Cell-Conditioned Media on CCl₄-Induced Liver Fibrosis

Antifibrotic Effect of Combination of Nilotinib and Stem Cell-Conditioned Media on CCl₄-Induced Liver Fibrosis