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On the one hand, radiosensitivity/radioresistance of cancer stem cells affects the radiocurability of tumors, on the other hand, radiosensitivity is responsible for the stem cell depletion of organs at risk exposed to irradiation. The article of Park and colleagues demonstrated that SOX2 contributed to the induction of colorectal cancer cells and is regulated by radio-induced activation of the PI3K/AKT pathway [2]. Nrf2-Keap1 signaling controls mesenchymal–epithelial plasticity and regulates tumor-initiating ability and promotes the radioresistance of breast cancer stem cells [3].

Fibrosis is a leading cause of death in occidental states. The increasing number of patients with fibrosis requires innovative approaches. Despite the proven beneficial effects of mesenchymal stem cell (MSC) therapy on fibrosis, there is little evidence of their anti-fibrotic effects in colorectal fibrosis. The ability of MSCs to reduce radiation-induced colorectal fibrosis has been studied in vivo in Sprague–Dawley rats. After local radiation exposure, rats were injected with MSCs before an initiation of fibrosis. MSCs mediated a downregulation of fibrogenesis by a control of extra cellular matrix (ECM) turnover. For a better understanding of the mechanisms, we used an in vitro model of irradiated cocultured colorectal fibrosis in the presence of human MSCs. Pro-fibrotic cells in the colon are mainly intestinal fibroblasts and smooth muscle cells. Intestinal fibroblasts and smooth muscle cells were irradiated and cocultured in the presence of unirradiated MSCs. MSCs mediated a decrease in profibrotic gene expression and proteins secretion. Silencing hepatocyte growth factor (HGF) and tumor necrosis factor-stimulated gene 6 (TSG-6) in MSCs confirmed the complementary effects of these two genes. HGF and TSG-6 limited the progression of fibrosis by reducing activation of the smooth muscle cells and myofibroblast. To settle in vivo the contribution of HGF and TSG-6 in MSC-antifibrotic effects, rats were treated with MSCs silenced for HGF or TSG-6. HGF and TSG-6 silencing in transplanted MSCs resulted in a significant increase in ECM deposition in colon. These results emphasize the potential of MSCs to influence the pathophysiology of fibrosis-related diseases, which represent a challenging area for innovative treatments.

Fibrosis is the endpoint of many chronic inflammatory diseases and is defined by an abnormal accumulation of extracellular matrix components. Despite its slow progression, it leads to organ malfunction. Fibrosis can affect almost any tissue. Due to its high frequency, in particular in the heart, lungs, liver, and kidneys, many studies have been conducted to find satisfactory treatments. Despite these efforts, current fibrosis management therapies either are insufficiently effective or induce severe adverse effects. In the light of these facts, innovative experimental therapies are being investigated. Among these, cell therapy is regarded as one of the best candidates. In particular, mesenchymal stromal cells (MSCs) have great potential in the treatment of inflammatory diseases. The value of their immunomodulatory effects and their ability to act on profibrotic factors such as oxidative stress, hypoxia, and the transforming growth factor-β1 pathway has already been highlighted in preclinical and clinical studies. Furthermore, their propensity to act depending on the microenvironment surrounding them enhances their curative properties. In this paper, we review a large range of studies addressing the use of MSCs in the treatment of fibrotic diseases. The results reported here suggest that MSCs have antifibrotic potential for several organs.

We here determine the influence of mesenchymal stem cell (MSC) therapy on the progression of solid tumors. The influence of MSCs was investigated in human colorectal cancer cells as well as in an immunocompetent rat model of colorectal carcinogenesis representative of the human pathology. Treatment with bone marrow (BM)‐derived MSCs significantly reduced both cancer initiation and cancer progression by increasing the number of tumor‐free animals as well as decreasing the number and the size of the tumors by half, thereby extending their lifespan. The attenuation of cancer progression was mediated by the capacity of the MSCs to modulate the immune component. Specifically, in the adenocarcinomas (ADKs) of MSC‐treated rats, the infiltration of CD68+ monocytes/macrophages was 50% less while the presence of CD3+ lymphocytes increased almost twofold. The MSCs reprogrammed the macrophages to become regulatory cells involved in phagocytosis thereby inhibiting the production of proinflammatory cytokines. Furthermore, the MSCs decreased NK (Natural Killer) and rTh17 cell activities, Treg recruitment, the presence of CD8+ lymphocytes and endothelial cells while restoring Th17 cell activity. The expression of miR‐150 and miR‐7 increased up to fivefold indicating a likely role for these miRNAs in the modulation of tumor growth. Importantly, MSC administration limited the damage of healthy tissues and attenuated tumor growth following radiotherapy. Taken together, we here show that that MSCs have durable action on colon cancer development by modulating the immune component of the tumor microenvironment. In addition, we identify two miRNAs associated with the capacity of MSCs to attenuate cancer growth. Stem Cells Translational Medicine 2019;8:285&300 After fractionated irradiation, mesenchymal stem cell administration inhibited residual tumor growth, protected healthy tissue. Mesenchymal stem cells modified the immune profile in tumor microenvironment and in irradiated healthy tissue by reprogramming resident cells. These findings support the use of mesenchymal stem cell administration for treatment of severe radiation damage in patients.

Chronic skin ulcers and burns require advanced treatments. Mesenchymal Stromal Cells (MSCs) are effective in treating these pathologies. Bone Morphogenic Protein-2 (BMP-2) is known to enhance angiogenesis. We investigated whether recombinant human hBMP-2 potentiates the effect of MSCs on wound healing. Severe ulceration was induced in rats by irradiation and treated by co-infusion of MSCs with hBMP-2 into the ulcerated area which accelerated wound healing. Potentiation of the effect of MSCs by hBMP-2 on endothelial repair improved skin healing. HBMP-2 and MSCs synergistically, in a supra additive or enhanced manner, renewed tissue structures, resulting in normalization of the epidermis, hair follicles, sebaceous glands, collagen fibre density, and blood vessels. Co-localization of MSCs with CD31 + cells suggests recruitment of endothelial cells at the site of injection. HBMP-2 and MSCs enhanced angiogenesis and induced micro-vessel formation in the dermis where hair follicles were regenerated. HBMP-2 acts by causing hypoxia-inducible factor-1 α (HIF-1α) expression which impacts endothelial tube formation and skin repair. This effect is abolished by siRNA. These results propose that new strategies adding cytokines to MSCs should be evaluated for treating radiation-induced dermatitis, burns, and chronic ulcers in humans.

Mesenchymal stem cells (MSC), multipotent adult stem cells, feature the potential to regenerate tissue damage and, in parallel, inhibit inflammation and fibrosis. MSC can be safely transplanted in autologous and allogeneic ways as they are non-immunogenic, and consequently represent a therapeutic option for refractory connective tissue diseases, fibrosing diseases like scleroderma and fistulizing colitis like in Crohn’s disease. Actually, there are more than 200 registered clinical trial sites for evaluating MSC therapy, and 22 are on autoimmune diseases. In irradiation-induced colitis, MSC accelerate functional recovery of the intestine and dampen the systemic inflammatory response. In order to provide rescue therapy for accidentally over-irradiated prostate cancer patients who underwent radiotherapy, allogeneic bone marrow-derived MSC from family donors were intravenously infused to three patients with refractory and fistulizing colitis resembling fistulizing Crohn’s disease. Systemic MSC therapy of refractory irradiation-induced colitis was safe and effective on pain, diarrhoea, hemorrhage, inflammation and fistulization accompanied by modulation of the lymphocyte subsets towards an increase of T regulatory cells and a decrease of activated effector T cells. The current data indicate that MSC represent a promising alternative strategy in the treatment of various immune-mediated diseases. Encouraging results have already been obtained from clinical trials in Crohn’s disease and SLE as well as from case series in systemic sclerosis. MSC represent a safe therapeutic measure for patients who suffer from chronic and fistulizing colitis. These findings are instructional for the management of refractory inflammatory bowel diseases that are characterized by similar clinical and immunopathological features.

Background Cellular therapy seems to be an innovative therapeutic alternative for which mesenchymal stem cells (MSCs) have been shown to be effective for interstitial and hemorrhagic cystitis. However, the action of MSCs on chronic radiation cystitis (CRC) remains to be demonstrated. The aim of this study was to set up a rat model of CRC and to evaluate the efficacy of MSCs and their mode of action. Methods CRC was induced by single-dose localized irradiation of the whole bladder using two beams guided by tomography in female Sprague–Dawley rat. A dose range of 20–80 Gy with follow-up 3–12 months after irradiation was used to characterize the dose effect and the kinetics of radiation cystitis in rats. For the treatment, the dose of 40 Gy was retained, and in order to potentiate the effect of the MSCs, MSCs were isolated from adipose tissue. After expansion, they were injected intravenously during the pre-chronic phase. Three injections of 5 million MSCs were administered every fortnight. Follow-up was performed for 12 months after irradiation. Results We observed that the intensity and frequency of hematuria are proportional to the irradiation dose, with a threshold at 40 Gy and the appearance of bleeding from 100 days post-irradiation. The MSCs reduced vascular damage as well as damage to the bladder epithelium. Conclusions These results are in favor of MSCs acting to limit progression of the chronic phase of radiation cystitis. MSC treatment may afford real hope for all patients suffering from chronic radiation cystitis resistant to conventional treatments.

To evaluate the potential therapeutic effect of the infusion of hMSCs for the correction of liver injuries, we performed total body radiation exposure of NOD/SCID mice. After irradiation, mir-27b level decreases in liver, increasing the directional migration of hMSCs by upregulating SDF1α. A significant increase in plasmatic transaminases levels, apoptosis process in the liver vascular system, and in oxidative stress were observed. hMSC injection induced a decrease in transaminases levels and oxidative stress, a disappearance of apoptotic cells, and an increase in Nrf2, SOD gene expression, which might reduce ROS production in the injured liver. Engrafted hMSCs expressed cytokeratin CK18 and CK19 and AFP genes indicating possible hepatocyte differentiation. The presence of hMSCs expressing VEGF and Ang-1 in the perivascular region, associated with an increased expression of VEGFr1, r2 in the liver, can confer a role of secreting cells to hMSCs in order to maintain the endothelial function. To explain the benefits to the liver of hMSC engraftment, we find that hMSCs secreted NGF, HGF, and anti-inflammatory molecules IL-10, IL1-RA contributing to prevention of apoptosis, increasing cell proliferation in the liver which might correct liver dysfunction. MSCs are potent candidates to repair and protect healthy tissues against radiation damages.

Cystitis is a bladder disease with a high rate of prevalence in the world population. This report focuses on Interstitial Cystitis (IC), Hemorrhagic Cystitis (HC) and Chronic Radiation Cystitis. These pathologies have different etiologies, but they share common symptoms, for instance, pain, bleeding, and a contracted bladder. Overall, treatments are quite similar for abacterial cystitis, and include bladder epithelium protective or anti-inflammatory agents, alleviating pain and reducing bleeding. This review summarizes the mechanisms that the pathologies have in common, for instance, bladder dysfunction and inflammation. Conversely, some mechanisms have been described as present in only one pathology, such as neural regulation. Based on these specificities, we propose identifying a mechanism that could be common to all the above-mentioned pathologies.

The main difficulty of radiotherapy is to destroy cancer cells without depletion of healthy tissue [...]