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

Abstract EN

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.