Peripheral Circulation and Astrocytes Contribute to the MSC-Mediated Increase in IGF-1 Levels in the Infarct Cortex in a dMCAO Rat Model.

Xiaobo Li,Wenxiu Yu,Zhiguo Chen,Min Huang,Renchao Zhao,Zhenhua Ren,Haiqiang Zou,Zhaohui Liang,Chunsong Zhao,Yunqian Guan

doi:10.1155/2020/8853444

Abstract

Materials and Methods Ischemic brain injury was induced by dMCAO in Sprague-Dawley rats. The transplantation group received MSC infusion 1 h after dMCAO. Expression of IGF-1 in GFAP+ astrocytes, Iba-1+ microglia/macrophages, CD3+ lymphocytes, Ly6C+ monocytes/macrophages, and neutrophil elastase (NE)+ neutrophils was examined to determine the contribution of these cells to the increase of IGF-1. ELISA was performed to examine IGF-1 levels in blood plasma at days 2, 4, and 7 after ischemia onset. Results In total, only 5-6% of Iba-1+ microglia were colabeled with IGF-1 in the infarct cortex, corpus callosum, and striatum at day 2 post-dMCAO. MSC transplantation did not lead to a higher proportion of Iba-1+ cells that coexpressed IGF-1. In the infarct cortex, all Iba-1+/IGF-1+ double-positive cells were also positive for CD68. In the infarct, corpus callosum, and striatum, the majority (50-80%) of GFAP+ cells were colabeled with ramified IGF-1 signals. The number of GFAP+/IGF-1+ cells was further increased following MSC treatment. In the infarct cortex, approximately 15% of IGF-1+ cells were double-positive for CD3. MSC treatment reduced the number of infiltrated CD3+/IGF-1+ cells by 70%. In the infarct, few Ly6C+ monocytes/macrophages or NE+ neutrophils expressed IGF-1, and MSC treatment did not induce a higher percentage of these cells that coexpressed IGF-1. The IGF-1 level in peripheral blood plasma was significantly higher in the MSC group than in the ischemia control group. Conclusion The MSC-mediated increase in IGF-1 levels in the infarct cortex mainly derives from two sources, astrocytes in brain and blood plasma in periphery. Manipulating the IGF-1 level in the peripheral circulation may lead to a higher level of IGF-1 in brain, which could be conducive to recovery at the early stage of dMCAO.

Highlights

Insulin-like growth factor-1 (IGF-1) is a member of the insulin gene family [1]
We reported that CD68+ microglia express insulin-like growth factor-1 (IGF-1) in the brain of a stroke model [15, 19]
GFAP+ astrocytes present in the striatum and corpus callosum might be the main sources of IGF-1 expression in that area, in that GFAP+/IGF-1+ double-positive cells constituted up to 72:66 ± 8:98% of IGF-1+ cells in the ischemia group, which was significantly increased to 81:22 ± 9:70% in the mesenchymal stem/stromal cells (MSCs) group (Figure 4(o))

Summary

Introduction

Insulin-like growth factor-1 (IGF-1) is a member of the insulin gene family [1]. In addition to regulating cerebral development, neurogenesis, cognition, and memory function [2], IGF-1 is an important player during the damage and recovery processes in ischemic stroke [3, 4]. The role of IGF-1 in the central nervous system (CNS) is, to a large extent, due to its ability to regulate immune cells in brain, such as microglia and infiltrated macrophages. By using ELISA in a previous study, we reported an increased level of IGF-1 in the ischemic core and periinfarct striatum in dMCAO rats at 48 h after intravenous (i.v.) infusion of rat bone marrow-derived MSCs [10]. We surveyed a wide spectrum of cell types that included Iba-1+ microglia, GFAP+ astrocytes, infiltrated immune cells such as CD3+ lymphocytes, neutrophil elastase (NE)+ neutrophils, and Ly6C+ monocytes/microphages, as well as the peripheral circulation, to determine their contribution to the increased IGF-1 level in the brain

Materials and Methods

Results

Discussion