miR-27a-containing Exosomes Secreted by Irradiated Skin Keratinocytes Delayed the Migration of Unirradiated Skin Fibroblasts

Abstract

Radiation-induced bystander effect (RIBE), e.g. the biological response occurring in unirradiated cells when their neighboring cells are irradiated, is the consequence of intercellular communication between irradiated and unirradiated cells and intracellular signal transduction of these two cell populations. Although several miRNAs have been found to play an important role in RIBEs, the evidence for the regulatory effects of miRNAs on RIBEs is still limited. In this study, by using a two cell-line co-culture system, we first found that the migration of unirradiated bystander WS1 skin fibroblasts was inhibited after co-culture with irradiated HaCaT skin keratinocytes. Further study revealed that HaCaT cells exposed to α-particles and X-rays quickly showed an elevated miR-27a expression, which was essential for the induction of the bystander effect, resulting in the secretion of miR-27a-containing exosomes as a major RIBE signaling factor. Upon uptake of these exosomes, the recipient unirradiated WS1 cells displayed oxidative stress and increased miR-27a levels. Elevated levels of miR-27a that targets MMP2 in the recipient WS1 cells then led to slowed cell migration, which was dependent upon the redox status of WS1 cells. To summarize, the present study has revealed a critical role of miR-27a in every step of the induction of bystander migration inhibition of unirradiated WS1 fibroblasts co-cultured with irradiated HaCaT keratinocytes, confirming the important regulatory effects of miRNAs in RIBEs. Additionally, we provided direct evidence that RIBEs could affect wound healing.

Inhibition of Circulating Exosomal miRNA-20b-5p Accelerates Diabetic Wound Repair

“…20 As they can protect the encapsulated molecules from external factors, Exos are ideal nanovesicles for use when delivering miRNAs and other bioactive materials to target cells in an effort to modulate gene expression. 21 Fibroblasts are able to readily internalize serum-derived Exos 22 and are essential mediators of wound healing owing to their ability to promote collagen synthesis and localized remodeling of diverse tissue types. 6 As such, we explored the ability of diabetes patient-derived Exos to alter fibroblast functionality in vitro.…”

Deregulation of miR‐27a may contribute to canine fibroblast activation after coculture with a mast cell tumour cell line

“…Research into miR‐27a in fibroblasts has also yielded contradictory results. Experimental data demonstrated that exosome‐derived miR‐27a produced oxidative stress in human skin fibroblasts and inhibited their migration [23] and that miR‐27a overexpression hindered lung fibrosis [45]. In contrast, one report indicated that miR‐27a induced the reprogramming of fibroblasts into CAFs and also promoted proliferation, motility and metastasis of gastric cancer cells [21].…”

“…Some of this intercellular crosstalk occurring within the tumour microenvironment is also attributed to exosomes [21]. Exosomes are small membrane vesicles secreted by all types of cells capable of mediating cell‐to‐cell communication by means of exchanging DNA, proteins, mRNAs and miRNAs [22,23]. For instance, in vitro and in vivo models for the human disease have shown that exosome‐derived miR‐27a may regulate the transformation of normal fibroblasts into CAFs and also modulate the growth and metastasis of tumour cells [21].…”

Role of Mitochondria in Radiation Responses: Epigenetic, Metabolic, and Signaling Impacts

“…At present, there are not many reports on bystander effects and exosomes produced after high-LET irradiation [ 446 , 447 , 448 ]. Interestingly, Yu et al [ 449 ] and He et al [ 450 ] reported that in exosomes (nanovesicles) derived from the serum of prostate cancer patients after treatment with CIRT (C-ions LET: 33.7 keV/μm), 66 Gy equivalents in daily fractions of 2.75 Gy equivalents) nine specific miRNAs were identified among which expression levels of miR654-3p and miR-378-5p could be correlated with CIRT efficacy and thus could serve as biomarkers for antitumor treatment efficacy [ 449 , 450 ].…”