Therapeutic effects of extracellular vesicles for the treatment of radiation-induced musculo-cutaneous injury
Thesis: Exposure to high dose ionizing radiation (IR), consecutive to accidents of industrial or medical origin, results in acute syndromes or lesions, potentially leading to late chronic complications, appearing up to several years following IR exposure. Therefore searching for biomarkers of IR exposure represents a major public health challenge, in order to improve the medical management of exposed individuals. In addition, the prediction of the severity of complications developed following exposure still remains difficult and unreliable. In the context of the localized cutaneous radiation syndrome, the medical management of the victims involves cell therapy by injection of autologous mesenchymal stromal cells (MSCs), combined with surgery (exeresis and autograft). Recent research on animal models has shown that MSCs contribute to the control of inflammation, and promote tissue regeneration essentially owing to their paracrine activity. In particular, this activity leads to the production of extracellular vesicles (EVs), including microvesicles (MVs) and exosomes. EVs are carriers of biological information participating in intercellular communication, and involved in numerous physiological and pathological processes. A number of studies have demonstrated the therapeutic efficacy of EVs (exosomes) in different preclinical models of kidney and heart ischemia, or cutaneous wound healing. Moreover, several studies suggested that EVs could be used as biomarkers, in particular in the context of cardiovascular diseases and cancer. The objectives of this thesis project aim at demonstrating the therapeutic potential of EVs for the treatment of radiological burns, and evaluating the use of EVs as prognostic biomarkers of radiation-induced toxicity following radiotherapy. Owing to a preclinical model of radiological burn, we demonstrated the therapeutic potential of exosomes derived from human MSCs. Specifically, our results show that: 1- exosomes exert a beneficial effect on tissue repair of the radiation-induced cutaneous injury; 2- exosomes stimulate angiogenesis, in particular by restoring the cutaneous perfusion and the vascular density of the irradiated limb, and by increasing the tissue and systemic concentrations of pro-angiogenic factors; 3- exosomes promote the mobilization of monocytes toward the injury site, where they participate to rebuild the vascular network. Furthermore, the use of EVs as biomarkers was evaluated through a clinical study on a cohort of patients treated by radiotherapy against prostate cancer. We showed that circulating MVs, but not exosomes, could be used as biomarkers of late high grade toxicity. We indeed show that: 1- the number of MVs produced by platelets, monocytes and endothelial cells, is correlated with the risk of developing severe toxicity following RI exposure; 2- the protein content of MVs allows to discriminate patients with highest toxicity grade; 3- the amount of platelet- and monocyte-derived MVs correlates with IR doses received by the organs at risk (bladder, rectum, anterior prostate). In conclusion, this work brings new insights regarding the prognostic and diagnostic of individuals exposed to ionizing radiations. The use of EVs could allow a faster and more effective medical management of these patients, while offering a therapeutic solution applicable to a large panel of victims. In addition, this study allows to consider the possibility of a clinical transfer for the treatment of radiation-induced cutaneous burn.
Author(s)
Alexandre Ribault
Date of publication
- 2018
Keywords
- Exosomes
- Microvesicles
- Radiation
- Radiotherapy
- Extracellular vesicles
- Biomarker
Issuing body(s)
- Sorbonne Université
Date of defense
- 13/12/2018
Thesis director(s)
- Marc Benderitter
- Radia Tamarat
URL of the HAL notice
Version
- 1