Cell based therapy reduces secondary damage and increases extent of microglial activation following cortical injury

• Type of Material: Article
• Authors: Mary E. Orczykowski, Boston University; Samantha M. Calderazzo, Boston University; Eli Shobin, Boston University; Monica A. Pessina, Boston University; Adrian L. Oblak, Boston University; Seth P. Finklestein, Stemetix, Inc.; Brian C. Kramer, Janssen Scientific Affairs; Farzad Mortazavi, Boston University; Douglas Rosene, Emory University; Tara L. Moore, Boston University
• Language: English
• Date: 2020-08-15
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2019 Elsevier B.V. All rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.brainres.2019.04.015
• Title of Journal or Parent Work: Brain Research
• Volume: 1717
• Start Page: 147
• End Page: 159
• Grant/Funding Information: This study was supported by a contract from Advanced Technologies and Regenerative Medicine (ATRM), LLC. [RR# 101115-PR] who provided the cell therapy product and the vehicle control and by the National Institutes of Health [NIH-NINDS R21NS081261].
• Keywords: Cell Based Therapy; Secondary Damage; hUTC3; Cortical Damage; Microglia; Oxidative Stress
• Research Categories: Biology, Cell; Biology, Neuroscience; Biology, Anatomy; Health Sciences, Pathology

Abstract

Cortical injury elicits long-term cytotoxic and cytoprotective mechanisms within the brain and the balance of these pathways can determine the functional outcome for the individual. Cytotoxicity is exacerbated by production of reactive oxygen species, accumulation of iron, and peroxidation of cell membranes and myelin. There are currently no neurorestorative treatments to aid in balancing the cytotoxic and cytoprotective mechanisms following cortical injury. Cell based therapies are an emerging treatment that may function in immunomodul ation, reduction of secondary damage, and reorganization of surviving structures. We previously evaluated human umbilical tissue-derived cells (hUTC) in our non-human primate model of cortical injury restricted to the hand area of primary motor cortex. Systemic hUTC treatment resulted in significantly greater recovery of fine motor function compared to vehicle controls. Here we investigate the hypothesis that hUTC treatment reduces oxidative damage and iron accumulation and increases the extent of the microglial response to cortical injury. To test this, brain sections from these monkeys were processed using immunohistochemistry to quantify oxidative damage (4-HNE) and activated microglia (LN3), and Prussian Blue to quantify iron. hUTC treated subjects exhibited significantly reduced oxidative damage in the sublesional white matter and iron accumulation in the perilesional area as well as a significant increase in the extent of activated microglia along white matter pathways. Increased perilesional iron accumulation was associated with greater perilesional oxidative damage and larger reconstructed lesion volume. These findings support the hypothesis that systemic hUTC administered 24 hours after cortical damage decreases the cytotoxic response while increasing the extent of microglial activation.