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Optimization of the adipose-derived mesenchymal stem cell delivery time for radiation-induced lung fibrosis treatment in rats.

ABSTRACT: The present study attempts to identify the optimal time duration for the administration of Ad-MSCs, in order to maximize its therapeutic benefits, and compare the degree of fibrosis among three different administration time points using the RILF rat model system. Ad-MSCs were delivered to Sprague-Dawley rats through the tail vein at the following different time points after thorax irradiation: two hours, seven days, and two hours?+?seven days. Post Ad-MSCs transplantation and the histopathological analysis of the lungs were performed along with analysis of inflammatory cytokine levels, including interleukin (IL)-1, IL-2, IL-6, IL-10 and tumor necrosis factor-? (TNF-?). In particular, pro-fibrotic factors (TGF-?1 and ?-SMA) were also evaluated in serum and lung tissues. In addition, it was also determined whether Ad-MSCs had any role in inhibiting the transition of type II alveolar epithelial cells into fibroblasts in the lungs of injured rats. The present results demonstrated that the intravenous delivery of Ad-MSCs twice at the 2-hour and 7-day (R?+?MSC_2h+7d group) was effective in reducing lung fibrosis for long term durations, when compared with single delivery either at the two-hour or 7-day time points. In addition, a marked anti-inflammatory effect was also observed in RILF rats in the R?+?MSC_2h+7d group, as indicated by the reduced serum levels of pro-inflammatory cytokines (TNF-?, IL-1 and IL-6) and increased levels of anti-inflammatory cytokines IL-10 and IL-2. Rats that were delivered twice with Ad-MSCs (R?+?MSC_2h+7d group) exhibited significantly reduced TGF-?1 and ?-SMA levels, in contrast to rats in the R?+?MSC_7d or R?+?MSC_2h groups, after four weeks. Furthermore, it was also noted that after four weeks, Ad-MSCs increased the number of lung epithelial cells (SP-C) and inhibited the lung fibroblastic cells (?-SMA) of rats in the R?+?MSC_2h and R?+?MSC_2h+7d groups. The present study concluded that two injections of Ad-MSCs (R?+?MSC_2h+7d group) appear to be optimal for therapeutic efficacy and safety during RILF.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC6447528 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Optimization of the adipose-derived mesenchymal stem cell delivery time for radiation-induced lung fibrosis treatment in rats.

Zhang Yang Y Jiang Xinping X Ren Liqun L

Scientific reports 20190403 1

The present study attempts to identify the optimal time duration for the administration of Ad-MSCs, in order to maximize its therapeutic benefits, and compare the degree of fibrosis among three different administration time points using the RILF rat model system. Ad-MSCs were delivered to Sprague-Dawley rats through the tail vein at the following different time points after thorax irradiation: two hours, seven days, and two hours + seven days. Post Ad-MSCs transplantation and the histopathologic ...[more]

PMID: 30944348

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Project description:Peritoneal fibrosis (PF) represents a long-term complication of peritoneal dialysis (PD), affecting the peritoneal membrane (PM) function. Adipose tissue-derived mesenchymal stem cells (ASC) display immunomodulatory effects and may represent a strategy to block PF. The aim of this study was to analyze the effect of ASC in an experimental PF model developed in uremic rats. To mimic the clinical situation of patients on long-term PD, a combo model, characterized by the combination of PF and chronic kidney disease (CKD), was developed in Wistar rats. Rats were fed with a 0.75% adenine-containing diet, for 30 days, to induce CKD with uremia. PF was induced with intraperitoneal injections of chlorhexidine gluconate (CG) from day 15 to 30. 1 × 106 ASC were intravenously injected at days 15 and 21. Rats were divided into 5 groups: control, normal rats; CKD, rats receiving adenine diet; PF, rats receiving CG; CKD+PF, CKD rats with PF; CKD+PF+ASC, uremic rats with PF treated with ASC. PF was assessed by Masson trichrome staining. Inflammation- and fibrosis-associated factors were assessed by immunohistochemistry, multiplex analysis, and qPCR. When compared with the control and CKD groups, GC administration induced a striking increase in PM thickness and inflammation in the PF and CKD+PF groups. The development of PF was blocked by ASC treatment. Further, the upregulation of profibrotic factors (TGF-β, fibronectin, and collagen) and the increased myofibroblast expression observed in the CKD+PF group were significantly ameliorated by ASC. Beyond the antifibrotic effect, ASC showed an anti-inflammatory effect avoiding leucocyte infiltration and the overexpression of inflammatory cytokines (IL-1β, TNF-α, and IL-6) in the PM induced by GC. ASC were effective in preventing the development of PF in the experimental model of CKD+PF, probably due to their immunomodulatory properties. These results suggest that ASC may represent a potential strategy for treating long-term PD-associated fibrosis.

Project description:BackgroundKeloid is a fibroproliferative disease with unsatisfactory therapeutic effects and a high recurrence rate. exosomes produced by adipose-derived mesenchymal stem cells (ADSC-Exos) have attracted significant interest due to their ability to treat fibrosis. However, the molecular mechanisms of ADSC-Exos in keloids remain inconclusive.ObjectiveOur study revealed the relationship between ferroptosis and fibrosis in keloids. Subsequently, this study aimed to explore further the anti-fibrotic effect of ADSC-Exos on keloids through ferroptosis and the potential underlying mechanisms.MethodsTo investigate the impact of ferroptosis on keloid fibrosis, Erastin and ferrostatin-1 (fer-1) were utilized to treat keloid fibroblast. Keloid keloids treated with Erastin and fer-1 were cocultured with ADSC-Exos to validate the impact of ferroptosis on the effect of ADSC-Exos on keloid anti-ferrotic protein, peroxidase 4 (GPX4) and anti-fibrotic effects in vivo and in vitro by Western blot, as well as variations in iron metabolite expression, malondialdehyde (MDA), liposomal peroxidation (LPO) and glutathione (GSH) were analyzed. The effect of solute carrier family 7-member 11 (SLC7A11) silencing on ADSC-Exo-treated keloid fibroblast was investigated.ResultsIron metabolite dysregulation was validated in keloids. Fibrosis progression is enhanced by Erastin-induced ferroptosis. The anti-fibrotic effects of ADSC-Exos and fer-1 are related to their ability to prevent iron metabolism. ADSC-Exos effectively suppressed keloid fibrosis progression and increased GSH and GPX4 gene expression. Additionally, the use of Erastin limits the effect of ADSC-Exos in keloids. Furthermore, the effect of ADSC-Exos on keloids was associated with SLC7A11-GPX4 signaling pathway.ConclusionWe demonstrated a new potential mechanism by which anti-ferroptosis inhibits the progression of keloid fibrosis and identified an ADSC-Exo-based keloid therapeutic strategy. Resisting the occurrence of ferroptosis and the existence of the SLC7A11-GPX4 signaling pathway might serve as a target for ADSC-Exos.

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Project description:BackgroundThe therapeutic effect of mesenchymal stem cells (MSCs) from human adipose tissue on renal interstitial fibrosis has been demonstrated by several groups. However, the way to enhance the renoprotective effect of adipose-derived mesenchymal stem cells (AMSCs) and the possible mechanisms are still unclear. The present study aimed to determine whether glial cell line-derived neurotrophic factor (GDNF)-modified AMSCs hold an enhanced protective effect on renal fibrosis.MethodsAMSCs were isolated and purified for culture. The gene GDNF has been constructed to transfect into AMSCs. The ability of GFP-AMSCs and GDNF-AMSCs supernatants to promote tube formation of endothelial cells, repair damaged endothelial cell junctions, and improve endothelial cell function was compared by using tube formation assay, immunofluorescence techniques, and vascular ring assay, respectively. Furthermore, HE and Masson staining were used to observe the histological morphology of the kidney in vivo. Peritubular capillary changes were detected and analyzed by fluorescence microangiography (FMA). Meanwhile, the hypoxia, oxidative stress, fibrotic markers, and PI3K/Akt pathway proteins were measured by western blot or qRT-PCR technics.ResultsCompared with GFP-AMSCs only, GDNF-AMSCs could enhance the repair of injured endothelial cells and promote angiogenesis through secreting more growth factors in the supernatant of GDNF-AMSC culture media demonstrated in vitro studies. Studies in vivo, unilateral ureteral obstruction (UUO)-induced mice were injected with transfected AMSCs through their tail veins. We showed that enhanced homing of AMSCs was observed in the GDNF-AMSC group compared with the GFP-AMSC group. The animals treated with GDNF-AMSCs exhibited an improvement of capillary rarefaction and fibrosis induced by obstructed kidney compared with the GFP-AMSC group. Furthermore, we reported that GDNF-AMSCs protect renal tissues against microvascular injuries via activation of the PI3K/Akt signaling pathway. Therefore, GDNF-AMSCs further ameliorated the tissue hypoxia, suppressed oxidative stress, and finally inhibited endothelial to mesenchymal transition noting by decreased coexpression of endothelial cell (CD31) and myofibroblast (a-SMA) markers.ConclusionCollectively, our data indicated that the GDNF gene enhances the ability of AMSCs in improving renal microcirculation through PI3K/Akt/eNOS signaling pathway and afterward inhibit the EndMT process and kidney fibrogenesis, which should have a vast of implications in designing future remedies for chronic kidney disease (CKD) treatment.

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Optimization of the adipose-derived mesenchymal stem cell delivery time for radiation-induced lung fibrosis treatment in rats.

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Optimization of the adipose-derived mesenchymal stem cell delivery time for radiation-induced lung fibrosis treatment in rats.

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