Stem cell transplantation reverses chemotherapy-induced cognitive dysfunction

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 determina...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2015-02, Vol.75 (4), p.676-686
Main Authors: Acharya, Munjal M, Martirosian, Vahan, Chmielewski, Nicole N, Hanna, Nevine, Tran, Katherine K, Liao, Alicia C, Christie, Lori-Ann, Parihar, Vipan K, Limoli, Charles L
Format: Article
Language:English
Subjects:
Animals
Behavior, Animal - drug effects
Cognition Disorders - chemically induced
Cognition Disorders - therapy
Cyclophosphamide - administration & dosage
Cyclophosphamide - adverse effects
Disease Models, Animal
Hippocampus - pathology
Hippocampus - transplantation
Humans
Mice
Neoplasms - drug therapy
Neoplasms - pathology
Neural Stem Cells - transplantation
Neurons - drug effects
Neurons - pathology
Quality of Life
Stem Cell Transplantation
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Summary: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.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-14-2237