The Role of Mesenchymal Stem Cells in Radiation-Induced Lung Fibrosis.
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ABSTRACT:
SUBMITTER: Zanoni M
PROVIDER: S-EPMC6719901 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Exposure to ionizing radiation (IR) can result in the development of cutaneous fibrosis, for which few therapeutic options exist. We tested the hypothesis that bone marrow-derived mesenchymal stem cells (BMSC) would favorably alter the progression of IR-induced fibrosis. We found that a systemic infusion of BMSC from syngeneic or allogeneic donors reduced skin contracture, thickening, and collagen deposition in a murine model. Transcriptional profiling with a fibrosis-targeted assay demonstrated increased expression of interleukin-10 (IL-10) and decreased expression of IL-1β in the irradiated skin of mice 14 days after receiving BMSC. Similarly, immunoassay studies demonstrated durable alteration of these and several additional inflammatory mediators. Immunohistochemical studies revealed a reduction in infiltration of proinflammatory classically activated CD80(+) macrophages and increased numbers of anti-inflammatory regulatory CD163(+) macrophages in irradiated skin of BMSC-treated mice. In vitro coculture experiments confirmed that BMSC induce expression of IL-10 by activated macrophages, suggesting polarization toward a regulatory phenotype. Furthermore, we demonstrated that tumor necrosis factor-receptor 2 (TNF-R2) mediates IL-10 production and transition toward a regulatory phenotype during coculture with BMSC. Taken together, these data demonstrate that systemic infusion of BMSC can durably alter the progression of radiation-induced fibrosis by altering macrophage phenotype and suppressing local inflammation in a TNF-R2-dependent fashion.
| S-EPMC7511998 | biostudies-literature
Project description:Radiation-induced lung injury (RILI) presents a common and major obstacle in the radiotherapy of thoracic cancers. The aim of this study was to examine whether RILI could be alleviated by mesenchymal stem cells (MSCs) expressing soluble transforming growth factor-? (TGF-?) type II receptor via an adenovirus (Ad-sT?R). Here, we systemically administered male MSCs into female mice challenged with thoracic irradiation. The data showed that either MSCs or Ad-sT?R transduced MSCs (Ad-sT?R-MSCs) specifically migrated into radiation-injured lung. Ad-sT?R-MSCs obviously alleviated lung injury, as reflected by survival and histopathology data, as well as the assays of malondialdehyde (MDA), hydroxyproline, plasma cytokines, and the expression of connective tissue growth factor (CTGF) and ?-smooth muscle actin (?-SMA). Furthermore, MSCs and Ad-sT?R-MSCs could adopt the characteristics of alveolar type II (ATII) cells. However, the MSCs levels in the lungs were relatively low to account for the noted therapeutic effects, suggesting the presence of other mechanisms. In vivo, MSCs-conditioned medium (MSCs CM) significantly attenuated RILI. In vitro, MSCs CM protected ATII cells against radiation-induced apoptosis and DNA damage, and modulated the inflammatory response, indicating the beneficial effects of MSCs are largely due to its paracrine activity. Our results provide a novel insight for RILI therapy that currently lack efficient treatments.
| S-EPMC3594026 | biostudies-literature
Project description:RationaleStem cells have been identified in the human lung; however, their role in lung disease is not clear. We aimed to isolate mesenchymal stem cells (MSC) from human lung tissue and to study their in vitro properties.MethodsMSC were cultured from lung tissue obtained from patients with fibrotic lung diseases (n = 17), from emphysema (n = 12), and normal lungs (n = 3). Immunofluorescence stainings were used to characterize MSC. The effect of MSC-conditioned media (MSC-CM) on fibroblast proliferation and on lung epithelial wound repair was studied.ResultsExpression of CD44, CD90, and CD105 characterized the cells as MSC. Moreover, the cells stained positive for the pluripotency markers Oct3/4 and Nanog. Positive co-stainings of chemokine receptor type 4 (CXCR4) with CD44, CD90 or CD105 indicated the cells are of bone marrow origin. MSC-CM significantly inhibited the proliferation of lung fibroblasts by 29% (p = 0.0001). Lung epithelial repair was markedly increased in the presence of MSC-CM (+ 32%). Significantly more MSC were obtained from fibrotic lungs than from emphysema or control lungs.ConclusionsOur study demonstrates enhanced numbers of MSC in fibrotic lung tissue as compared to emphysema and normal lung. The cells inhibit the proliferation of fibroblasts and enhance epithelial repair in vitro. Further in vivo studies are needed to elucidate their potential role in the treatment of lung fibrosis.
| S-EPMC5565112 | biostudies-literature
Project description:Radiation therapy is an important treatment modality for multiple thoracic malignancies. However, radiation-induced lung injury (RILI), which is the term generally used to describe damage to the lungs caused by exposure to ionizing radiation, remains a critical issue affecting both tumor control and patient quality of life. Despite tremendous effort, there is no current consensus regarding the optimal treatment approach for RILI. Because of a number of functional advantages, including self-proliferation, multi-differentiation, injury foci chemotaxis, anti-inflammation, and immunomodulation, mesenchymal stem cells (MSCs) have been a focus of research for many years. Accumulating evidence indicates the therapeutic potential of transplantation of MSCs derived from adipose tissue, umbilical cord blood, and bone marrow for inflammatory diseases, including RILI. However, reports have also shown that MSCs, including fibrocytes, lung hematopoietic progenitor cells, and ABCG2+ MSCs, actually enhance the progression of lung injuries. These contradictory results suggest that MSCs may have dual effects and that caution should be taken when using MSCs to treat RILI. In this review, we present and discuss recent evidence of the double-edged function of MSCs and provide comments on the prospects of these findings.
| S-EPMC5792737 | biostudies-literature
Project description:Less quantity of transplanted mesenchymal stem cells (MSCs) influences the therapeutic effects on radiation-induced lung injury (RILI). Previous studies have demonstrated that MSCs overexpressing Chemokine (C-X-C motif) receptor 4 (CXCR4) could increase the quantity of transplanted cells to local tissues. In the present study, we conducted overexpressing CXCR4 human umbilical cord mesenchymal stem cell (HUMSC) therapy for RILI. C57BL mice received single dose of thoracic irradiation with 13 Gy of X-rays and then were administered saline, control HUMSCs, or CXCR4-overexpressing HUMSCs via tail vein. Transfection with CXCR4 enhanced the quantity of transplanted HUMSCs in the radiation-induced injured lung tissues. CXCR4-overexpressing HUMSCs not only improved histopathological changes but also decreased the radiation-induced expression of SDF-1, TGF-β1, α-SMA, and collagen I and inhibited the radiation-induced decreased expression of E-cadherin. Transplanted CXCR4-overexpressing HUMSCs also could express pro-SP-C, indicated adopting the feature of ATII. These finding suggests that CXCR4-overexpressing HUMSCs enhance the protection against RILI and may be a promising strategy for RILI treatment.
| S-EPMC6379846 | biostudies-literature
Project description:Since radiotherapy is widely used in managing thoracic tumors, physicians have begun to realize that radiation-induced lung injury (RILI) seriously limits the effects of radiotherapy. Unfortunately, there are still no effective methods for controlling RILI. Over the last few decades numerous studies have reported the beneficial effects of mesenchymal stem cells (MSCs) on tissue repair and regeneration. MSCs can not only differentiate into lung alveolar epithelial cells and secrete anti-inflammatory factors, but they also deliver some vehicles for gene therapy in repairing the injured lung, which provides new ideas for managing RILI. Thus, many scientists have attempted to manage RILI using MSC-based therapy. However, as a novel therapy MSCs still face various limitations. Herein, we shed light on the current understanding of MSC-based therapy for RILI, including the feasibility, molecular mechanisms, animal studies, and clinical research of MSC-based therapy for RILI. We also present an overview of RILI and MSCs.
| S-EPMC5793340 | biostudies-literature
Project description: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-α (TNF-α). In particular, pro-fibrotic factors (TGF-β1 and α-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 + MSC2h+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 + MSC2h+7d group, as indicated by the reduced serum levels of pro-inflammatory cytokines (TNF-α, 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 + MSC2h+7d group) exhibited significantly reduced TGF-β1 and α-SMA levels, in contrast to rats in the R + MSC7d or R + MSC2h 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 (α-SMA) of rats in the R + MSC2h and R + MSC2h+7d groups. The present study concluded that two injections of Ad-MSCs (R + MSC2h+7d group) appear to be optimal for therapeutic efficacy and safety during RILF.
| S-EPMC6447528 | biostudies-literature
Project description:BackgroundRadiation is a commonly delivered therapeutic modality for cancer. The causes underlying the chronic, progressive nature of radiation injury in the lung are poorly understood.MethodsC57Bl/6NCr mice were exposed to thoracic irradiation (n = 3 per dose and time point for tissue collection). Microarray analysis of gene expression from irradiated murine lung was performed using one-way analysis of variance with post hoc Scheffe analysis. Senescence and type II airway epithelial cell (AECII) count were assayed in irradiated murine lung tissue (n = 3 per condition). Irradiated mice were treated with diphenyleneiodonium (DPI), an inhibitor of NADPH oxidase (NOX), and fibrosis was assessed by collagen assays. All statistical tests were two-tailed.ResultsGene expression in lung tissue from mice irradiated to 17.5 Gy clustered with that of aged unirradiated mice. Only fibrogenic exposures led to AECII senescence (0 Gy: 0.66% ± 0.67%; 5 Gy: 4.5% ± 1.19%; 17.5 Gy: 18.7% ± 3.05; P = .007) and depletion (0 Gy: 2.89 per alveolus ± 0.26; 5 Gy: 2.41 ± 0.19; 17.5 Gy: 1.6 ± 0.14; P < .001) at 30 weeks. Treatment of irradiated mice with DPI for 16 weeks markedly reduced collagen accumulation (5×6 Gy: 57.26 μg/lung ± 9.91; 5×6 Gy ± DPI: 36.54μg/lung ± 4.39; P = .03) and AECII senescence (5×6 Gy: 37.61% ± 4.82%; 5×6 Gy ± DPI: 12.38% ± 2.78; P < .001).ConclusionsThese studies identify senescence as an important process in AECII in vivo and indicate that NOX is a critical mediator of radiation-induced AECII senescence and pulmonary fibrosis.
| S-EPMC3787909 | biostudies-literature
Project description:NF-E2-related factor 2 (Nrf2) is a key transcription factor recently implicated in the control of radiation-induced lung fibrosis (RILF). However, the molecular mechanism of Nrf2 in the pathogenesis of RILF is still unclear. The purpose of this study was to evaluate the regulatory effect and mechanism of Nrf2 in the pathogenesis of RILF. The effects of different Nrf2 expression levels on RILF were explored in vitro and in vivo. The RILF model of Nrf2 knockout mice was established for in vivo study. In the study of the mechanism of action, ChIP-seq assay and metabolomics analysis were performed. The discovered mechanism of Nrf2-mediated RILF alleviation was further validated in vitro and in vivo. We found that overexpression of Nrf2 significantly alleviated the fibrosis caused by irradiation in vivo and in vitro. Conversely, Nrf2 silencing strongly aggravated the development of RILF. Mechanistically, Nrf2 signaling increased the expression of piwi-like RNA-mediated gene silencing 2 (PIWIL2), leading to the alteration of purine metabolism and contributing to the relief of RILF. These results suggest that Nrf2 promotes the attenuation of RILF in vivo and in vitro by directly targeting PIWIL2 and activating purine metabolism.
| S-EPMC7539767 | biostudies-literature
Project description:BackgroundInterstitial pneumonia in connective tissue diseases (CTD-IP) featuring inflammation and fibrosis is a leading cause of death in CTD-IP patients. The related autoimmune lung injury and disturbed self-healing process make conventional anti-inflammatory drugs ineffective. Equipped with unique immunoregulatory and regenerative properties, mesenchymal stem cells (MSCs) may represent a promising therapeutic agent in CTD-IP. In this study, we aim to define the immunopathology involved in pulmonary exacerbation during autoimmunity and to determine the potential of MSCs in correcting these disorders.MethodsLung and blood specimens, bronchoalveolar lavage fluid cells collected from CTD-IP patients, and human primary lung fibroblasts (HLFs) from patients pathologically diagnosed with usual interstitial pneumonia (UIP) and healthy controls were analyzed by histology, flow cytometry and molecular biology. T cell subsets involved in the process of CTD-IP were defined, while the regulatory functions of MSCs isolated from the bone marrow of normal individuals (HBMSCs) on cytotoxic T cells and CTD-UIP HLFs were investigated in vitro.ResultsHigher frequencies of cytotoxic T cells were observed in the lung and peripheral blood of CTD-IP patients, accompanied with a reduced regulatory T cell (Treg) level. CTD-UIP HLFs secreted proinflammatory cytokines in combination with upregulation of ?-smooth muscle actin (?-SMA). The addition of HBMSCs in vitro increased Tregs concomitant with reduced cytotoxic T cells in an experimental cell model with dominant cytotoxic T cells, and promoted Tregs expansion in T cell subsets from patients with idiopathic pulmonary fibrosis (IPF). HBMSCs also significantly decreased proinflammatory chemokine/cytokine expression, and blocked ?-SMA activation in CTD-UIP HLFs through a TGF-?1-mediated mechanism, which modulates excessive IL-6/STAT3 signaling leading to IP-10 expression. MSCs secreting a higher level of TGF-?1 appear to have an optimal anti-fibrotic efficacy in BLM-induced pulmonary fibrosis in mice.ConclusionsImpairment of TGF-? signal transduction relevant to a persistent IL-6/STAT3 transcriptional activation contributes to reduction of Treg differentiation in CTD-IP and to myofibroblast differentiation in CTD-UIP HLFs. HBMSCs can sensitize TGF-?1 downstream signal transduction that regulates IL-6/STAT3 activation, thereby stimulating Treg expansion and facilitating anti-fibrotic IP-10 production. This may in turn block progression of lung fibrosis in autoimmunity.
| S-EPMC4842299 | biostudies-literature