title: Stem cell transplantation reverses chemotherapy-induced cognitive dysfunction.
abstract: The frequent use of chemotherapy to combat a range of malignancies can elicit severe cognitive dysfunction often referred to as "chemobrain," a condition that can persist long after the cessation of treatment in as many as 75% of survivors. Although cognitive health is a critical determinant of therapeutic outcome, chemobrain remains an unmet medical need that adversely affects quality of life in pediatric and adult cancer survivors. Using a rodent model of chemobrain, we showed that chronic cyclophosphamide treatment induced significant performance-based decrements on behavioral tasks designed to interrogate hippocampal and cortical function. Intrahippocampal transplantation of human neural stem cells resolved all cognitive impairments when animals were tested 1 month after the cessation of chemotherapy. In transplanted animals, grafted cells survived (8%) and differentiated along neuronal and astroglial lineages, where improved cognition was associated with reduced neuroinflammation and enhanced host dendritic arborization. Stem cell transplantation significantly reduced the number of activated microglia after cyclophosphamide treatment in the brain. Granule and pyramidal cell neurons within the dentate gyrus and CA1 subfields of the hippocampus exhibited significant reductions in dendritic complexity, spine density, and immature and mature spine types following chemotherapy, adverse effects that were eradicated by stem cell transplantation. Our findings provide the first evidence that cranial transplantation of stem cells can reverse the deleterious effects of chemobrain, through a trophic support mechanism involving the attenuation of neuroinflammation and the preservation host neuronal architecture.
authors: Department of Radiation Oncology, University of California, Irvine, California.
authors: Munjal M
authors: MM
authors: Acharya
authors: Department of Radiation Oncology, University of California, Irvine, California.
authors: Vahan
authors: V
authors: Martirosian
authors: Department of Radiation Oncology, University of California, Irvine, California.
authors: Nicole N
authors: NN
authors: Chmielewski
authors: Department of Radiation Oncology, University of California, Irvine, California.
authors: Nevine
authors: N
authors: Hanna
authors: Department of Radiation Oncology, University of California, Irvine, California.
authors: Katherine K
authors: KK
authors: Tran
authors: Department of Radiation Oncology, University of California, Irvine, California.
authors: Alicia C
authors: AC
authors: Liao
authors: Department of Radiation Oncology, University of California, Irvine, California.
authors: Lori-Ann
authors: LA
authors: Christie
authors: Department of Radiation Oncology, University of California, Irvine, California.
authors: Vipan K
authors: VK
authors: Parihar
authors: Department of Radiation Oncology, University of California, Irvine, California. climoli@uci.edu.
authors: Charles L
authors: CL
authors: Limoli
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003072:Cognition Disorders / Q000139:chemically induced / Q000628:therapy*; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000473:pathology / Q000637:transplantation; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D058953:Neural Stem Cells / Q000637:transplantation*; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D011788:Quality of Life; D033581:Stem Cell Transplantation
chemical_list: D003520:Cyclophosphamide