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

Abstract

Background and Purpose. Previously, we found that insulin-like growth factor-1 (IGF-1) levels in the infarct cortex in the acute phase of distal middle cerebral artery occlusion (dMCAO) rats are increased by intravenous infusion of allogeneic mesenchymal stem/stromal cells (MSCs). CD68+ microglia and NeuN+ neurons are part, but not all, of the sources of IGF-1. The present study is aimed at exploring the respective contributions of brain endogenous Iba-1+ microglia, GFAP+ astrocytes, infiltrated neutrophils, lymphocytes and monocytes/macrophages, and peripheral circulation, to the increased IGF-1 level in the infarct cortex after MSC infusion. 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.

Oral administration of ellagic acid mitigates perioperative neurocognitive disorders, hippocampal oxidative stress, and neuroinflammation in aged mice by restoring IGF-1 signaling

“…We observed that EA's reduction of microglial proliferation and its enhancement of M2 markers were impeded by co-administration of the IGF1R inhibitor PPP. IGF-1 and its receptor IGF1R are found in a wide array of cell types in the central nervous system, including neurons 59 , 60 , astrocytes 60 , 61 , and macrophage/microglia 60 , 62 . IGF-1 is recognized for its anti-inflammatory role in the brain, which it accomplishes by managing microglial inflammation 63 , the reduction of pro-inflammatory factors 24 , 64 , and modulation of astrocytic phagocytosis 65 .…”

Preclinical and clinical evidence of IGF-1 as a prognostic marker and acute intervention with ischemic stroke

“…Importantly, this increase in IGF-1 expression and secretion with MSC transplant is accompanied by significant improvements in behavioral function. 144,145 The causal role of MSCderived IGF-1 as a neuroprotector is supported by recent findings that overexpression of IGF-1 in MSCs transplanted into a rodent model of spinal cord injury showed a significant reduction in inflammation, oxidative stress, and neurological deficits. 144,145 There are limited studies on IGF-1 as a modulator of stem cell therapies in humans, however, a recent study in a small cohort of chronic stroke patients disclosed that exogenous IGF-1 was used to prep neural stem cells for effective transplant.…”

“…144,145 The causal role of MSCderived IGF-1 as a neuroprotector is supported by recent findings that overexpression of IGF-1 in MSCs transplanted into a rodent model of spinal cord injury showed a significant reduction in inflammation, oxidative stress, and neurological deficits. 144,145 There are limited studies on IGF-1 as a modulator of stem cell therapies in humans, however, a recent study in a small cohort of chronic stroke patients disclosed that exogenous IGF-1 was used to prep neural stem cells for effective transplant. 146 Additional work in this area is needed to understand whether supplemental IGF-1 can support effective stem cell therapies for individuals in recovery from stroke.…”

New insights on the cardiovascular effects of IGF-1

“…New findings suggest that matrix metalloproteinases receptor cleavage has a notable role in the ineffective IGF-1 signaling in hypertension and might be significant for peripheral vascular resistance ( 19 ). Interestingly, manipulation of IGF-1 levels in the peripheral circulation and its increased levels in the brain could be used to recover early manifestations of cerebral artery occlusion ( 78 ). Regarding human studies, IGF-1 infusion reduced peripheral resistance in patients with chronic heart failure, suggesting its acute impact on the CV system ( 79 ).…”