Leukemic Cells Manipulate MSCs Bioelectrical Signals to Reshape the Bone Marrow Niche

ABSTRACT Mesenchymal stromal cells (MSCs) are key components of the tumor microenvironment (TME), influencing leukemia progression through poorly understood mechanisms. We investigated the bioelectrical properties of MSCs derived from pediatric AML patients (AML-MSCs) and identified a significant depolarization of their resting membrane potential (V mem , −14.7mV) compared to healthy MSCs (h-MSCs, −28.5mV), accompanied by downregulation of CaV1.2 L-type calcium channel expression. AML-MSCs displayed increased spontaneous calcium oscillations, suggesting altered ion homeostasis. Notably, h-MSCs exposed to AML blasts underwent a similar V mem depolarization (−11.8mV) and CaV1.2 downregulation, indicating that leukemic cells actively reprogram MSCs. Functionally, V mem depolarization in h-MSCs promoted a pro-leukemic phenotype, whereas hyperpolarization of AML-MSCs restored a normal behavior. CaV1.2 over-expression by lentiviral vectors in AML-MSCs shifted V mem toward hyperpolarization and partially reversed their leukemia-supportive properties, in part through CaV1.2 transfer via tunneling nanotubes. These findings reveal that AML blasts impose a bioelectrical signature on MSCs, modulating ion channel activity to sustain a leukemic niche. Targeting this electrical reprogramming through CaV1.2 restoration represents a potential strategy to re-establish homeostasis in the bone marrow microenvironment.