Children suffering from neurologic cancers undergoing chemotherapy and radiotherapy are at high risk of reduced neurocognitive abilities likely via damage to proliferating neural stem cells (NSC). Therefore, strategies to protect NSCs are needed. We argue that induced cell-cycle arrest/quiescence in NSCs during cancer treatment can represent such a strategy. Here, we show that hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels are dynamically expressed over the cell cycle in NSCs, depolarize the membrane potential, underlie spontaneous calcium oscillations and are required to maintain NSCs in the actively proliferating pool. Hyperpolarizing pharmacologic inhibition of HCN channels during exposure to ionizing radiation protects NSCs cells in neurogenic brain regions of young mice. In contrast, brain tumor-initiating cells, which also express HCN channels, remain proliferative during HCN inhibition. IMPLICATIONS: Our finding that NSCs can be selectively rescued while cancer cells remain sensitive to the treatment, provide a foundation for reduction of cognitive impairment in children with neurologic cancers.

Central European Institute of Technology Masaryk University Brno Czech Republic

College of Veterinary Medicine Jilin University Changchun Jilin China

Department of Immunology Genetics and Pathology Uppsala University Rudbeck Laboratory Uppsala Sweden

Department of Medicine Karolinska Institutet Huddinge Sweden

Department of Microbiology New York University School of Medicine New York New York

Department of Molecular Neurosciences Center for Brain Research Medical University of Vienna Vienna Austria

Department of Neuroscience Karolinska Institutet Solna Sweden

Department of Physiology and Pharmacology Karolinska Institutet Stockholm Sweden

Department of Women's and Children's Health Karolinska Institutet Stockholm Sweden

Gladstone Institute of Neurological Disease San Francisco California

Pediatric Oncology Karolinska University Hospital Stockholm Sweden

Citace poskytuje Crossref.org