Simultaneous Administration of ADSCs-Based Therapy and Gene Therapy Using Ad-huPA Reduces Experimental Liver Fibrosis

Meza-Ríos, Alejandra; García-Benavides, Leonel; García-Bañuelos, Jesús; Salazar-Montes, Adriana; Armendáriz‐Borunda, Juan; Sandoval-Rodríguez, Ana

doi:10.1371/journal.pone.0166849

Cited by 7 publications

(14 citation statements)

References 27 publications

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“…Rivera-Valdes et al demonstrated that ADSCs could reverse chronic kidney fibrosis through the suppression of CTGF gene expression, in addition to IL6, IL10- TNF and TGF-β1 [55]. Similarly, liver fibrosis was reversed by ADSCs intravenous injection through the down regulation of pro-collagen alpha1, CTGF and α-SMA mRNA [56].…”

Section: Discussionmentioning

confidence: 99%

Stem cell enriched lipotransfer reverses the effects of fibrosis in systemic sclerosis

et al. 2019

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Oro-facial fibrosis in systemic sclerosis (Scleroderma;SSc) has a major impact on mouth function, facial appearance, and patient quality of life. Lipotransfer is a method of reconstruction that can be used in the treatment of oro-facial fibrosis. The effect of this treatment not only restores oro-facial volume but has also been found to reverse the effects of oro-facial fibrosis. Adipose derived stem cells (ADSCs) within the engrafted adipose tissue have been shown to be anti-fibrotic in SSc and are proposed as the mechanism of the anti-fibrotic effect of lipotransfer. A cohort of 62 SSc patients with oro-facial fibrosis were assessed before and after stem cell enriched lipotransfer treatment. Clinical evaluation included assessment of mouth function using a validated assessment tool (Mouth Handicap in Systemic Sclerosis Scale-MHISS), validated psychological measurements and pre and post-operative volumetric assessment. In addition, to understand the mechanism by which the anti-fibrotic effect of ADSCs occur, SSc derived fibroblasts and ADSCs from this cohort of patients were co-cultured in direct and indirect culture systems and compared to monoculture controls. Cell viability, DNA content, protein secretion of known fibrotic mediators including growth factor- β1 (TGF β-1) and connective tissue growth factor (CTGF) using ELISA analysis and fibrosis gene expression using a fibrosis pathway specific qPCR array were evaluated. Mouth function (MHISS) was significantly improved (6.85±5.07) (p<0.0001) after treatment. All psychological measures were significantly improved: DAS 24 (12.1±9.5) (p<0.0001); HADS-anxiety (2.8±3.2) (p<0.0001), HADS-depression (2.0±3.1) (p<0.0001); BFNE (2.9 ± 4.3) (p<0.0001); VAS (3.56±4.1) (p<0.0001). Multiple treatments further improved mouth function (p<0.05), DAS (p<0.0001) and VAS (p = 0.01) scores. SSc fibroblast viability and proliferation was significantly reduced in co-culture compared to monoculture via a paracrine effect over 14 days (p < 0.0001). Protein secretion of transforming growth factor (TGF-β1) and connective tissue growth factor (CTGF) was significantly reduced in co-culture compared to monoculture (p < 0.0001). Multiple fibrosis associated genes were down regulated in SSc co-culture compared to monoculture after 14 days including Matrix metalloproteinase-8 (MMMP-8), Platelet derived growth factor-β (PDGF-β) and Integrin Subunit Beta 6 (ITG-β6). Autologous stem cell enriched lipotransfer significantly improved the effects of oro-facial fibrosis in SSc in this open cohort study. Lipotransfer may reduce dermal fibrosis through the suppression of fibroblast proliferation and key regulators of fibrogenesis including TG-β1 and CTGF. Our findings warrant further investigation in a randomised controlled trial.

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Section: Discussionmentioning

confidence: 99%

Stem cell enriched lipotransfer reverses the effects of fibrosis in systemic sclerosis

et al. 2019

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“…The function of HPC activation in liver fibrogenesis vs regeneration is controversial (Michalopoulos and Bhushan, 2021;Williams et al, 2014). Partial hepatectomy in fibrotic liver was previously reported to drive pro-fibrogenic HPC activation that impaired liver regeneration (Kuramitsu et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…MMP9 overexpression promoted a pro-resolving macrophage phenotype and improved liver regeneration in cirrhotic mice (Melgar-Lesmes et al, 2018). Urokinase plasminogen activator (Plau) therapy ameliorated fibrosis in the CCL4 model via activation of latent metalloproteinases and HGF (Bueno et al, 2006;Meza-Rios et al, 2016;Salgado et al, 2000). Fibrosis regression occurred despite high expression of the canonical profibrogenic cytokine Tgfb1 and, in some cases, the proinflammatory cytokines Il6 and Tnf, which have frequently been shown to diminish in the resolution phase of disease.…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, CSF1-Fc treated mice had substantial increases in mRNA encoding Hbegf, Tgfb1, Il6 and Tnf (Fig. 5O-R) each of which could contribute to hepatic growth (Kiso et al, 2003;Michalopoulos and Bhushan, 2021). Hgf and Brg1, a chromatin remodelling gene involved in liver regeneration (Wang et al, 2019), were more highly expressed following PHx in fibrotic liver compared to healthy liver (Fig.…”

Section: Acute Csf1-fc Treatment Is Sufficient To Eliminate Established Fibrosismentioning

confidence: 99%

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Therapeutic potential of macrophage colony-stimulating factor (CSF1) in chronic liver disease

Keshvari

Genz

Teakle

et al. 2021

Preprint

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Resident and recruited macrophages control the development and proliferation of the liver. We showed previously in multiple species that treatment with a macrophage colony stimulating factor (CSF1)-Fc fusion protein initiated hepatocyte proliferation and promoted repair in models of acute hepatic injury in mice. Here we investigated the impact of CSF1-Fc on resolution of advanced fibrosis and liver regeneration, utilizing a non-resolving toxin-induced model of chronic liver injury and fibrosis in C57BL/6J mice. Co-administration of CSF1-Fc with exposure to thioacetamide (TAA) exacerbated inflammation consistent with monocyte contributions to initiation of pathology. After removal of TAA, either acute or chronic CSF1-Fc treatment promoted liver growth, prevented progression and promoted resolution of fibrosis. Acute CSF1-Fc treatment was also anti-fibrotic and pro-regenerative in a model of partial hepatectomy in mice with established fibrosis. The beneficial impacts of CSF1-Fc treatment were associated with monocyte-macrophage recruitment and increased expression of remodeling enzymes and growth factors. These studies indicate that CSF1-dependent macrophages contribute to both initiation and resolution of fibrotic injury and that CSF1-Fc has therapeutic potential in human liver disease.Summary statementMacrophages contribute to both progression and resolution of chronic tissue injury and fibrogenesis. Administration of a macrophage growth factor promoted liver regeneration and resolution of advanced liver fibrosis in mice.

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“…Gene therapy consists in the delivery of therapeutic genes to a target organ through different type of vectors, where viral vectors are mostly used. Our research group has demonstrated the therapeutic effect of different human proteins like urokinase Plasminogen Activator (uPA) [ 11 , 12 ], ΔTGFbRII [ 13 ] (TGFβ1 truncated receptor) and MMP8 [ 10 , 14 , 15 ] coded by cognate cDNAs resulting in significantly reduced fibrotic tissue in experimental cirrhosis models. Thus, the aim of this study was to expand our knowledge in other fibrotic organs, and evaluate the therapeutic effect on kidney fibrotic tissue via administration of a recombinant human MMP8 cDNA cloned in an adenoviral vector in an adenine-induced CKD experimental model.…”

Section: Introductionmentioning

confidence: 99%

Fibrosis regression is induced by AdhMMP8 in a murine model of chronic kidney injury

et al. 2020

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Adenoviral vector AdhMMP8 (human Metalloproteinase-8 cDNA) administration has been proven beneficial in various experimental models of liver injury improving liver function and decreasing fibrosis. In this study, we evaluated the potential therapeutic AdhMMP8 effect in a chronic kidney damage experimental model. Chronic injury was induced by orogastric adenine administration (100mg/kg/day) to Wistar rats for 4 weeks. AdhMMP8 (3x1011vp/kg) was administrated in renal vein during an induced-ligation-ischemic period to facilitate kidney transduction causing no-additional kidney injury as determined by histology and serum creatinine. Animals were sacrificed at 7- and 14-days post-Ad injection. Fibrosis, histopathological features, serum creatinine (sCr), BUN, and renal mRNA expression of αSMA, Col-1α, TGF-β1, CTGF, BMP7, IL-1, TNFα, VEGF and PAX2 were analyzed. Interestingly, AdhMMP8 administration resulted in cognate human MMP8 protein detection in both kidneys, whereas hMMP8 mRNA was detected only in the left kidney. AdhMMP8 significantly reduced kidney tubule-interstitial fibrosis and glomerulosclerosis. Also, tubular atrophy and interstitial inflammation were clearly decreased rendering improved histopathology, and down regulation of profibrogenic genes expression. Functionally, sCr and BUN were positively modified. The results showed that AdhMMP8 decreased renal fibrosis, suggesting that MMP8 could be a possible therapeutic candidate for kidney fibrosis treatment.

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Simultaneous Administration of ADSCs-Based Therapy and Gene Therapy Using Ad-huPA Reduces Experimental Liver Fibrosis

Cited by 7 publications

References 27 publications

Stem cell enriched lipotransfer reverses the effects of fibrosis in systemic sclerosis

Stem cell enriched lipotransfer reverses the effects of fibrosis in systemic sclerosis

Therapeutic potential of macrophage colony-stimulating factor (CSF1) in chronic liver disease

Fibrosis regression is induced by AdhMMP8 in a murine model of chronic kidney injury

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