Increase in the radioresistance of normal skin fibroblasts but not tumor cells by mechanical injury

Chen, Zelin; Wang, Xin; Jin, Taotao; Wang, Yu; Hong, Christopher S.; Tan, Li; Dai, Tingyu; Wu, Liao; Zhuang, Zhengping; Chen, Shi

doi:10.1038/cddis.2016.416

Cited by 12 publications

(12 citation statements)

References 48 publications

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“…The granulation tissues were harvested at 7 days after wounding. The isolation protocols of human fibroblasts, granulation tissue cells and neonatal ROSA26 mTmG mouse fibroblasts are described previously20. In Brief, skin tissues of 1-2 cm 2 pieces with subcutaneous tissue removal were digested over night at 4°C in a digestion medium containing 1mg/mL dispase (Roche).…”

Section: Methodsmentioning

confidence: 99%

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Fibrogenic fibroblast-selective near-infrared phototherapy to control scarring

et al. 2019

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Rationale: Fibroblasts, the predominant cell type responsible for tissue fibrosis, are heterogeneous, and the targeting of unique fibrogenic population of fibroblasts is highly expected. Very recently, elevated glycolysis is demonstrated to play a pivotal role in the determination of fibrogenic phenotype of fibroblasts. However, it is lack of specific strategies for targeting and elimination of such fibrogenic populations. In this study, a novel strategy to use the a near-infrared (NIR) dye IR-780 for the targeting and elimination of a fibrogenic population of glycolytic fibroblasts to control the cutaneous scarring is developed.Methods: The identification and cell properties test of fibrogenic fibroblasts with IR-780 were conducted by using fluorescence activated cell sorting, transplantation experiments, in vivo imaging, RNA sequencing in human cell experiments and mouse and rat wound models. The uptake of IR-780 in fibroblasts mediated by HIF-1α/SLCO2A1 and the metabolic properties of IR-780H fibroblasts were investigated using RNA interference or signaling inhibitors. The fibrogenic fibroblast-selective near-infrared phototherapy of IR-780 were evaluated in human cell experiments and mouse wound models.Results: IR-780 is demonstrated to recognize a unique glycolytic fibroblast lineage, which is responsible for the bulk of connective tissue deposition during cutaneous wound healing and cancer stroma formation. Further results identified that SLCO2A1 is involved in the preferential uptake of IR-780 in fibrogenic fibroblasts, which is regulated by HIF-1α. Moreover, with intrinsic dual phototherapeutic activities, IR-780 significantly diminishes cutaneous scarring through the targeted ablation of the fibrogenic population by photothermal and photodynamic effects.Conclusion: This work provides a unique strategy for the targeted control of tissue scarring by fibrogenic fibroblast-selective near-infrared phototherapy. It is proposed that IR-780 based theranostic methodology holds promise for translational medicine aimed at regulation of fibrogenic behavior.

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Section: Methodsmentioning

confidence: 99%

“…Colonies were fixed by 4% polyoxymethylene for 15 min at RT and stained with crystal violet for 10 min. After thrice washes with PBS, colonies and counted as previously described20.…”

Section: Methodsmentioning

confidence: 99%

Fibrogenic fibroblast-selective near-infrared phototherapy to control scarring

et al. 2019

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“…Human fibroblasts, CAL27 (CRL-2095), and MCF-7 cells (ATCC, HTB-22) were cultured in Dulbecco's minimum essential medium with high sugar (Invitrogen) supplemented with 10% fetal bovine serum (Gibco) and 1% streptomycin/penicillin. The isolation protocol for human fibroblasts was described previously (18).…”

Section: Cell Culturementioning

confidence: 99%

Senolytics (DQ) Mitigates Radiation Ulcers by Removing Senescent Cells

Wang

Huang

et al. 2020

Front. Oncol.

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Radiation ulcers are a prevalent toxic side effect in patients receiving radiation therapy. At present, there is still no effective treatment for the complication. Senescent cells accumulate after radiation exposure, which can induce cell and tissue dysfunction. Here we demonstrate increased expression of p16 (a senescence biomarker) in human radiation ulcers after radiotherapy and radiation-induced persistent cell senescence in animal ulcer models. Furthermore, senescent cells secreted the senescence-associated secretory phenotype (SASP) and induced cell senescence in adjacent cells, which was alleviated by JAK inhibition. In addition, the clearance of senescent cells following treatment with a senolytics cocktail, Dasatinib plus Quercetin (DQ), mitigated radiation ulcers. Finally, DQ induced tumor cell apoptosis and enhanced radiosensitivity in representative CAL-27 and MCF-7 cell lines. Our results demonstrate that cell senescence is involved in the development of radiation ulcers and that elimination of senescent cells might be a viable strategy for patients with this condition.

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“…TGF-β signaling has been suggested to have crucial roles in several features of CSCs, such as in tumor initiation, metastasis, and resistance to anticancer drugs [ 80 , 81 ]. As mentioned above, it has also an important role in the spontaneous formation of tumoral spheroids, and in promoting the malignant progression of these structures [ 81 , 82 ].…”

Section: Discovering Pharmacological Targets In Spheroid Model: Thmentioning

confidence: 99%

EMT/MET at the Crossroad of Stemness, Regeneration and Oncogenesis: The Ying-Yang Equilibrium Recapitulated in Cell Spheroids

Forte

Chimenti

Rosa

et al. 2017

Cancers

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The epithelial-to-mesenchymal transition (EMT) is an essential trans-differentiation process, which plays a critical role in embryonic development, wound healing, tissue regeneration, organ fibrosis, and cancer progression. It is the fundamental mechanism by which epithelial cells lose many of their characteristics while acquiring features typical of mesenchymal cells, such as migratory capacity and invasiveness. Depending on the contest, EMT is complemented and balanced by the reverse process, the mesenchymal-to-epithelial transition (MET). In the saving economy of the living organisms, the same (Ying-Yang) tool is integrated as a physiological strategy in embryonic development, as well as in the course of reparative or disease processes, prominently fibrosis, tumor invasion and metastasis. These mechanisms and their related signaling (e.g., TGF-β and BMPs) have been effectively studied in vitro by tissue-derived cell spheroids models. These three-dimensional (3D) cell culture systems, whose phenotype has been shown to be strongly dependent on TGF-β-regulated EMT/MET processes, present the advantage of recapitulating in vitro the hypoxic in vivo micro-environment of tissue stem cell niches and their formation. These spheroids, therefore, nicely reproduce the finely regulated Ying-Yang equilibrium, which, together with other mechanisms, can be determinant in cell fate decisions in many pathophysiological scenarios, such as differentiation, fibrosis, regeneration, and oncogenesis. In this review, current progress in the knowledge of signaling pathways affecting EMT/MET and stemness regulation will be outlined by comparing data obtained from cellular spheroids systems, as ex vivo niches of stem cells derived from normal and tumoral tissues. The mechanistic correspondence in vivo and the possible pharmacological perspective will be also explored, focusing especially on the TGF-β-related networks, as well as others, such as SNAI1, PTEN, and EGR1. This latter, in particular, for its ability to convey multiple types of stimuli into relevant changes of the cell transcriptional program, can be regarded as a heterogeneous "stress-sensor" for EMT-related inducers (growth factor, hypoxia, mechano-stress), and thus as a therapeutic target.

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Increase in the radioresistance of normal skin fibroblasts but not tumor cells by mechanical injury

Cited by 12 publications

References 48 publications

Fibrogenic fibroblast-selective near-infrared phototherapy to control scarring

Fibrogenic fibroblast-selective near-infrared phototherapy to control scarring

Senolytics (DQ) Mitigates Radiation Ulcers by Removing Senescent Cells

EMT/MET at the Crossroad of Stemness, Regeneration and Oncogenesis: The Ying-Yang Equilibrium Recapitulated in Cell Spheroids

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