Biodistribution of Mesenchymal Stromal Cells Labeled with [89Zr]Zr-Oxine in Local Radiation Injuries in Laboratory Animals.

BACKGROUND: Tracking the migration pathways of living cells after their introduction into a patient's body is a topical issue in the field of cell therapy. Questions related to studying the possibility of long-term intravital biodistribution of mesenchymal stromal cells in the body currently remain open. METHODS: Forty-nine laboratory animals were used in the study. Modeling of local radiation injuries was carried out, and the dynamics of the distribution of mesenchymal stromal cells labeled with [89Zr]Zr-oxine in the rat body were studied. RESULTS: the obtained results of the labelled cell distribution allow us to assume that this procedure could be useful for visualization of local radiation injury using positron emission tomography. However, further research is needed to confirm this assumption. CONCLUSIONS: intravenous injection leads to the initial accumulation of cells in the lungs and their subsequent redistribution to the liver, spleen, and kidneys. When locally injected into tissues, mesenchymal stromal cells are not distributed systemically in significant quantities.

Effect of Radiation Therapy on Composition of Lymphocyte Populations in Patients with Primary Breast Cancer.

BACKGROUND: Radiation therapy (RT) is an important step in the treatment of primary breast cancer as it is one of the leading contributors to cancer incidence among women. Most patients with this disease acquire radiation-induced lymphopenia in the early post-radiation period; however, little is known about the effect of RT on the composition of lymphocyte populations in such patients. This study was aimed at investigating the effect of adjuvant remote RT-performed in the classical mode for patients with primary breast cancer-on the main components of cell-mediated immunity (major lymphocyte populations), including those in patients receiving chemotherapy. METHODS: Between 2020 and 2022, 96 patients with stage I-III breast cancer were included in this study. All patients in the final stage of complex treatment received RT via a 3D conformal technique (3DCRT). The clinical target volume of this RT included the breast or chest wall and locoregional lymphatics. Flow cytometry was used to assess the levels and phenotypes of circulating lymphocytes before and after RT (no more than 7 days before and after RT). The evaluation of the impact of polychemotherapy (PCT) was conducted to determine whether it was a risk factor for the onset of radio-induced lymphopenia (RIL) in the context of RT. RESULTS: When assessing the immune status in the general group of patients (n = 96), before the start of adjuvant external beam radiotherapy (EBRT), the average number of lymphocytes was 1.68 ± 0.064 × 109/L; after the course of adjuvant EBRT, it decreased to 1.01 ± 0.044 × 109/L (p < 0.001). When assessing the absolute indicators of cellular immunity in the general group of patients with BC after a course of adjuvant EBRT, significant dynamics were revealed by the changes in all cell populations of lymphocytes (paired t-test, p < 0.05). CONCLUSION: The adaptive immune system in breast cancer patients changed in the early post-radiation period. The absolute levels of B-, T- and natural killer cells significantly reduced after RT regardless of whether the patients previously underwent chemotherapy courses. RT for patients with primary breast cancer should be considered in clinical management because it significantly alters lymphocyte levels and should be considered when assessing antitumor immunity, as significant changes in T-cell immunity have been observed. In addition, the identified changes are critical if specific targeted therapy or immunotherapy is needed.

Evaluation of Changes in Some Functional Properties of Human Mesenchymal Stromal Cells Induced by Low Doses of Ionizing Radiation.

Each person is inevitably exposed to low doses of ionizing radiation (LDIR) throughout their life. The research results of LDIR effects are ambiguous and an accurate assessment of the risks associated with the influence of LDIR is an important task. Mesenchymal stromal cells (MSCs) are the regenerative reserve of an adult organism; because of this, they are a promising model for studying the effects of LDIR. The qualitative and quantitative changes in their characteristics can also be considered promising criteria for assessing the risks of LDIR exposure. The MSCs from human connective gingiva tissue (hG-MSCs) were irradiated at doses of 50, 100, 250, and 1000 mGy by the X-ray unit RUST-M1 (Russia). The cells were cultured continuously for 64 days after irradiation. During the study, we evaluated the secretory profile of hG-MSCs (IL-10, IDO, IL-6, IL-8, VEGF-A) using an ELISA test, the immunophenotype (CD45, CD34, CD90, CD105, CD73, HLA-DR, CD44) using flow cytometry, and the proliferative activity using the xCelligence RTCA cell analyzer at the chosen time points. The results of study have indicated the development of stimulating effects in the early stages of cultivation after irradiation using low doses of X-ray radiation. On the contrary, the effects of the low doses were comparable with the effects of medium doses of X-ray radiation in the long-term periods of cultivation after irradiation and have indicated the inhibition of the functional activity of MSCs.

Evaluation of the Effectiveness of Mesenchymal Stem Cells of the Placenta and Their Conditioned Medium in Local Radiation Injuries.

BACKGROUND: The search for an effective therapy for local radiation injuries (LRI) is urgent; one option is mesenchymal stem cells (MSC) derived from the placenta and their conditioned medium for the regenerative processes of the skin. METHODS: We used 80 animals, randomly assigned to four groups: control (C) animals that did not receive therapy; control with the introduction of culture medium concentrate (CM); introduction of MSCs (PL); introduction of CMPL. LRI modeling was performed on an X-ray machine at a dose of 110 Gy. Histological and immunohistochemical tests were performed. RESULTS: On the 112th day, the area of the open wound surface in the CMPL group was 6.7 times less than in the control group. Complete healing of the open wound surface of the skin in the CM group was observed in 40%, in CMPL 60%, in the PL group 20%, and in the C group there were no animals with a prolonged wound defect. A decrease in inflammatory processes was observed in the CMPL group. CONCLUSIONS: the use of a concentrate of conditioned MSCs (CMPL group) in severe LRI in laboratory animals accelerates the transition of the wound process to the stage of regeneration and epithelization.

Residual γH2AX foci induced by low dose x-ray radiation in bone marrow mesenchymal stem cells do not cause accelerated senescence in the progeny of irradiated cells.

Mechanisms underlying the effects of low-dose ionizing radiation (IR) exposure (10-100 mGy) remain unknown. Here we present a comparative study of early (less than 24h) and delayed (up to 11 post-irradiation passages) radiation effects caused by low (80 mGy) vs intermediate (1000 mGy) dose X-ray exposure in cultured human bone marrow mesenchymal stem cells (MSCs). We show that γН2АХ foci induced by an intermediate dose returned back to the control value by 24 h post-irradiation. In contrast, low-dose irradiation resulted in residual γН2АХ foci still present at 24 h. Notably, these low dose induced residual γН2АХ foci were not co-localized with рАТМ foci and were observed predominantly in the proliferating Кi67 positive (Кi67+) cells. The number of γН2АХ foci and the fraction of nonproliferating (Кi67-) and senescent (SA-ß-gal+) cells measured at passage 11 were increased in cultures exposed to an intermediate dose compared to unirradiated controls. These delayed effects were not seen in the progeny of cells that were irradiated with low-dose X-rays, although such exposure resulted in residual γН2АХ foci in directly irradiated cells. Taken together, our results support the hypothesis that the low-dose IR induced residual γH2AÐ¥ foci do not play a role in delayed irradiation consequences, associated with cellular senescence in cultured MSCs.