bims-stacyt 2019-07-07 papers

Int J Biochem Cell Biol. 2019 Jul 02. pii: S1357-2725(19)30135-9. [Epub ahead of print] 105564

Exosomes from adipose-derived mesenchymal stem cells ameliorate cardiac damage after myocardial infarction by activating S1P/SK1/S1PR1 signaling and promoting macrophage M2 polarization.

Shengqiong Deng, Xianjin Zhou, Zhiru Ge, Yuting Song, Hairong Wang, Xinghui Liu, Denghai Zhang.

Exosomes derived from mesenchymal stem cells (MSCs) are known to participate in myocardial repair after myocardial infarction (MI), but the mechanism remains unclear. Here, we isolated exosomes from adipose-derived MSCs (ADSCs) and examined their effect on MI-induced cardiac damage. To examine the underlying mechanism, H9c2 cells, cardiac fibroblasts, and HAPI cells were used to study the effect of ADSC-exosomes on hypoxia-induced H9c2 apoptosis, TGF-β1-induced fibrosis of cardiac fibroblasts, and hypoxia-induced macrophage M1 polarization using qRT-PCR, western blot, ELISA, immunohistochemistry, immunofluorescence and flow cytometry. ADSC-exosome treatment mitigated MI-induced cardiac damage by suppressing cardiac dysfunction, cardiac apoptosis, cardiac fibrosis, and inflammatory responses in vitro and in vivo. In addition, ADSC-exosome treatment promoted macrophage M2 polarization. Further experiments found that S1P/SK1/S1PR1 signaling was involved in the ADSC-exosome-mediated myocardial repair. Silencing of S1PR1 reversed the inhibitory effect of ADSC-exosomes on MI-induced cardiac apoptosis and fibrosis in vitro. ADSC-exosome-induced macrophage M2 polarization was also reversed after downregulation of S1PR1 under hypoxia conditions, which promoted NFκB and TGF-β1 expression, and suppressed the MI-induced cardiac fibrosis and inflammatory response. In sum, these results indicate that ADSC-derived exosomes ameliorate cardiac damage after MI by activating S1P/SK1/S1PR1 signaling and promoting macrophage M2 polarization.

Keywords: ADSCs; exosome; macrophage; myocardial infarction; sphingosine 1-phosphate

DOI: https://doi.org/10.1016/j.biocel.2019.105564

Clin Exp Ophthalmol. 2019 Jul 02.

Effects of VEGF inhibitors on human retinal pigment epithelium under high glucose and hypoxia.

Bobak Bahrami, Weiyong Shen, Ling Zhu, Ting Zhang, Andrew Chang, Mark Gillies.

BACKGROUND: Retinal pigment epithelium (RPE) is known to secrete factors important for retinal homeostasis. How this secretome changes in diabetic eyes treated with anti-vascular endothelial growth factor (VEGF) inhibitors is unclear.
METHODS: Diabetic conditions were simulated in vitro using ARPE-19 cell-line culture, with high glucose (25mM) culture media and hypoxia was chemically induced using cobalt chloride. Stress was assessed using cell viability assays as well as Western blots and enzyme-linked immunosorbent assay (ELISA) for production of HIF-1a and VEGF-A. Production of neurotrophic factors was quantified once conditions were established using ELISA under stress with and without the addition of VEGF inhibitors. Changes were analysed with one-way ANOVA.
RESULTS: Hypoxia downregulated pigment epithelium derived factor (PEDF) expression. The addition of bevacizumab, ranibizumab and aflibercept in normoxic conditions all led to a significant downregulation of PEDF. Glucose concentration had no effect on secretion of PEDF. Brain derived neurotrophic factor (BDNF) secretion was downregulated in high glucose and was upregulated in hypoxia. Placental growth factor (PlGF) secretion by ARPE-19 was undetectable by ELISA.
CONCLUSIONS: We found that hypoxia, high glucose or VEGF inhibitors affected secretion of neurotrophic factors. This variation under different conditions may influence neuron and photoreceptor survival in the diabetic state and VEGF inhibitor treated eyes. This article is protected by copyright. All rights reserved.

Keywords: anti-VEGF drugs; diabetic retinopathy; neurotrophic factors; retinal pigment epithelium

DOI: https://doi.org/10.1111/ceo.13579

Int J Mol Sci. 2019 Jun 29. pii: E3212. [Epub ahead of print]20(13):

Tumor Microenvironment as A "Game Changer" in Cancer Radiotherapy.

Magdalena Jarosz-Biej, Ryszard Smolarczyk, Tomasz Cichoń, Natalia Kułach.

Radiotherapy (RT), besides cancer cells, also affects the tumor microenvironment (TME): tumor blood vessels and cells of the immune system. It damages endothelial cells and causes radiation-induced inflammation. Damaged vessels inhibit the infiltration of CD8+ T lymphocytes into tumors, and immunosuppressive pathways are activated. They lead to the accumulation of radioresistant suppressor cells, including tumor-associated macrophages (TAMs) with the M2 phenotype, myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs). The area of tumor hypoxia increases. Hypoxia reduces oxygen-dependent DNA damage and weakens the anti-cancer RT effect. It activates the formation of new blood vessels and leads to cancer relapse after irradiation. Irradiation may also activate the immune response through immunogenic cell death induction. This leads to the "in situ" vaccination effect. In this article, we review how changes in the TME affect radiation-induced anticancer efficacy. There is a very delicate balance between the activation of the immune system and the immunosuppression induced by RT. The effects of RT doses on immune system reactions and also on tumor vascularization remain unclear. A better understanding of these interactions will contribute to the optimization of RT treatment, which may prevent the recurrence of cancer.

Keywords: hypoxia; immunosuppression; radioresistance; radiotherapy; tumor microenvironment; tumor vasculature; “in situ” vaccination

DOI: https://doi.org/10.3390/ijms20133212

Dev Cell. 2019 Jun 26. pii: S1534-5807(19)30485-X. [Epub ahead of print]

EGFR-Pak Signaling Selectively Regulates Glutamine Deprivation-Induced Macropinocytosis.

Szu-Wei Lee, Yijuan Zhang, Michael Jung, Nathalia Cruz, Basheer Alas, Cosimo Commisso.

Macropinocytosis has emerged as an important nutrient-scavenging pathway that supports tumor cell fitness. By internalizing extracellular protein and targeting it for lysosomal degradation, this endocytic pathway functions as an amino acid supply route, permitting tumor cell growth and survival despite the nutrient-poor conditions of the tumor microenvironment. Here, we provide evidence that a subset of pancreatic ductal adenocarcinoma (PDAC) tumors are wired to integrate contextual metabolic inputs to regulate macropinocytosis, dialing up or down this uptake pathway depending on nutrient availability. We find that regional depletion of amino acids coincides with increased levels of macropinocytosis and that the scarcity of glutamine uniquely drives this process. Mechanistically, this stimulation of macropinocytosis depends on the nutrient stress-induced potentiation of epidermal growth factor receptor signaling that, through the activation of Pak, controls the extent of macropinocytosis in these cells. These results provide a mechanistic understanding of how nutritional cues can control protein scavenging in PDAC tumors.

Keywords: EGFR; Pak; Ras; cancer metabolism; macropinocytosis; pancreatic cancer; protein scavenging

DOI: https://doi.org/10.1016/j.devcel.2019.05.043