Irradiated Mesenchymal Stromal Cells Remodel the Hematopoietic Niche Secretome and Modulate Leukemic Cell Behavior Via the Bystander Effect
Year: 2026
Type: article
Abstract: The interaction between mesenchymal stromal cells (MSCs) and hematopoietic cells is essential for maintaining bone marrow homeostasis and directly influences the progression of hematological malignancies. Radiation-induced alterations in the bone marrow microenvironment can trigger the Radiation-Induced Bystander Effect (RIBE), promoting biological responses in non-irradiated cells through soluble factors. However, the mechanisms by which the MSC secretome participates in this communication remain poorly understood. Thus, this study investigated the role of the secretome from irradiated MSCs in the functional and molecular modulation of leukemic cells. Murine C3H10T1/2 MSCs were irradiated and cultured to obtain conditioned medium, which was subsequently used to treat the murine leukemic cell line C1498. The secretome was characterized by quantifying soluble factors using ELISA. In the leukemic cells, we evaluated cell viability/metabolism, clonogenic capacity, and the expression of genes related to the cell cycle, differentiation, and tumor progression via RT-qPCR. To investigate the functional role of IL-6, neutralization assays using a specific antibody were performed. Irradiation remodeled the secretory profile of the MSCs, altering the production of various inflammatory mediators and significantly reducing IL-6 concentration. Conditioned medium from irradiated MSCs decreased the metabolic activity and colony-forming capacity of C1498 cells, demonstrating that alterations induced in the hematopoietic niche directly impact leukemic cell behavior. Concurrently, modulation of *Cdkn1a*, *Ccnd1*, *Gata3*, and *Notch1* expression was observed, indicating interference with pathways associated with cell cycle control, differentiation, and disease progression. Neutralization of IL-6 partially replicated the effects observed with irradiated conditioned medium, demonstrating that this cytokine is a key mediator of paracrine communication between MSCs and leukemic cells, although the observed response stems from the integrated action of multiple secretome components. The results demonstrate that the MSC response to radiation extends beyond direct cellular damage, promoting functional remodeling of the hematopoietic niche capable of reprogramming leukemic cell behavior. The identification of IL-6 as a key mediator, alongside changes induced in other factors secreted by MSCs, broadens the understanding of mechanisms involved in RIBE and reinforces the importance of the bone marrow microenvironment as a therapeutic target for strategies aimed at modulating the progression of hematological malignancies.
Institution: Universidade de São Paulo
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W7223129564