Nasal administration of mesenchymal stem cells restores cisplatin-induced cognitive impairment and brain damage in mice
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Gabriel S. Chiu1, Nabila Boukelmoune1, Angie C.A. Chiang1, Bo Peng2, Vikram Rao3, Charles Kingsley4, Ho-Ling Liu4, Annemieke Kavelaars1, Shelli R. Kesler3 and Cobi J. Heijnen1
1Neuroimmunology Laboratory, Department of Symptom Research, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
2Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
3Section of Neuropsychology, Department of Neuro-Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
4Department of Imaging Physics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Cobi J. Heijnen, email: [email protected]
Keywords: chemobrain; mesenchymal stem cells; nasal administration; mitochondrial function; cisplatin
Received: April 28, 2018 Accepted: October 06, 2018 Published: October 30, 2018
Cognitive impairments are a common side effect of chemotherapy that often persists long after treatment completion. There are no FDA-approved interventions to treat these cognitive deficits also called ‘chemobrain’. We hypothesized that nasal administration of mesenchymal stem cells (MSC) reverses chemobrain. To test this hypothesis, we used a mouse model of cognitive deficits induced by cisplatin that we recently developed. Mice were treated with two cycles of cisplatin followed by nasal administration of MSC. Cisplatin treatment induced deficits in the puzzle box, novel object/place recognition and Y-maze tests, indicating cognitive impairment. Nasal MSC treatment fully reversed these cognitive deficits in males and females. MSC also reversed the cisplatin-induced damage to cortical myelin. Resting state functional MRI and connectome analysis revealed a decrease in characteristic path length after cisplatin, while MSC treatment increased path length in cisplatin-treated mice. MSCs enter the brain but did not survive longer than 12-72 hrs, indicating that they do not replace damaged tissue. RNA-sequencing analysis identified mitochondrial oxidative phosphorylation as a top pathway activated by MSC administration to cisplatin-treated mice. Consistently, MSC treatment restored the cisplatin-induced mitochondrial dysfunction and structural abnormalities in brain synaptosomes. Nasal administration of MSC did not interfere with the peripheral anti-tumor effect of cisplatin. In conclusion, nasal administration of MSC may represent a powerful, non-invasive, and safe regenerative treatment for resolution of chemobrain.
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