Modulation of gene expression on a transcriptome-wide level following human neural stem cell transplantation in aged mouse stroke brains.

Publisher: Academic Press Country of Publication: United States NLM ID: 0370712 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1090-2430 (Electronic) Linking ISSN: 00144886 NLM ISO Abbreviation: Exp Neurol Subsets: MEDLINE

Publication: Orlando Fl : Academic Press
Original Publication: New York.

Aging/*genetics ; Neural Stem Cells/*physiology ; Stem Cell Transplantation/*methods ; Stroke/*genetics ; Stroke/*therapy ; Transcriptome/*physiology; Aging/drug effects ; Aging/metabolism ; Animals ; Cells, Cultured ; Cerebral Infarction/genetics ; Cerebral Infarction/metabolism ; Cerebral Infarction/therapy ; Fetus ; Gene Expression Regulation ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Neural Stem Cells/drug effects ; Neural Stem Cells/transplantation ; Oligopeptides/administration & dosage ; Stroke/metabolism ; Transcriptome/drug effects

Introduction: Neural stem cell (NSC) transplantation offers great potential for treating ischemic stroke. Clinically, ischemia followed by reperfusion results in robust cerebrovascular injury that upregulates proinflammatory factors, disrupts neurovascular units, and causes brain cell death. NSCs possess multiple actions that can be exploited for reducing the severity of neurovascular injury. Our previous studies in young adult mice showed that human NSC transplantation during the subacute stage diminishes stroke pathophysiology and improves behavioral outcome.
Methods: We employed a well-established and commonly used stroke model, middle cerebral artery occlusion with subsequent reperfusion (MCAO/R). Here, we assessed the outcomes of hNSC transplantation 48 h post-MCAO (24 h post-transplant) in aged mouse brains in response to stroke because aging is a crucial risk factor for cerebral ischemia. Next, we tested whether administration of the integrin α5β1 inhibitor, ATN-161, prior to hNSC transplantation further affects stoke outcome as compared with NSCs alone. RNA sequencing (RNA-seq) was used to assess the impact of hNSC transplantation on differentially expressed genes (DEGs) on a transcriptome-wide level.
Results: Here, we report that hNSC-engrafted brains with or without ATN-161 showed significantly reduced infarct size, and attenuated the induction of proinflammatory factors and matrix metalloproteases. RNA-seq analysis revealed DEGs and molecular pathways by which hNSCs induce a beneficial post-stroke outcome in aged stroke brains. 811 genes were differentially expressed (651 downregulated and 160 upregulated) in hNSC-engrafted stroke brains. Functional pathway analysis identified enriched and depleted pathways in hNSC-engrafted aged mouse stroke brains. Depletion of pathways following hNSC-engraftment included signaling involving neuroinflammation, acute phase response, leukocyte extravasation, and phagosome formation. On the other hand, enrichment of pathways in hNSC-engrafted brains was associated with PPAR signaling, LXR/RXR activation, and inhibition of matrix metalloproteases. Hierarchical cluster analysis of DEGs in hNSC-engrafted brains indicate decreased expression of genes encoding TNF receptors, proinflammatory factors, apoptosis factors, adhesion and leukocyte extravasation, and Toll-like receptors.
Conclusions: Our study is the first to show global transcripts differentially expressed following hNSC transplantation in the subacute phase of stroke in aged mice. The outcome of our transcriptome study would be useful to develop new therapies ameliorating early-stage stroke injury.
(Copyright © 2021 Elsevier Inc. All rights reserved.)

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P30 CA030199 United States CA NCI NIH HHS; R01 NS110370 United States NS NINDS NIH HHS

Keywords: Blood-brain barrier; Inflammation; Ingenuity pathway analysis; Neural stem cells; RNA sequencing; Stem cell transplantation; Stroke; Transcriptome

0 (Oligopeptides)
XW0H5LE42K (acetyl-prolyl-histidyl-seryl-cysteinyl-asparaginamide)

Date Created: 20211109 Date Completed: 20211228 Latest Revision: 20240404

20240404

PMC8647207

10.1016/j.expneurol.2021.113913

34752785