Soluble intracellular adhesion molecule-1 secreted by human umbilical cord blood-derived mesenchymal stem cell reduces amyloid-beta plaques

Abstract

Presently, co-culture of human umbilical cord blood mesenchymal stem cells (hUCB-MSCs) with BV2 microglia under amyloid-beta 42 (A beta 42) exposure induced a reduction of A beta 42 in the medium as well as an overexpression of the A beta-degrading enzyme neprilysin (NEP) in microglia. Cytokine array examinations of co-cultured media revealed elevated release of soluble intracellular adhesion molecule-1 (sICAM-1) from hUCB-MSCs. Administration of human recombinant ICAM-1 in BV2 cells and wild-type mice brains induced NEP expression in time-and dose-dependent manners. In co-culturing with BV2 cells under A beta 42 exposure, knockdown of ICAM-1 expression on hUCB-MSCs by small interfering RNA (siRNA) abolished the induction of NEP in BV2 cells as well as reduction of added A beta 42 in the co-cultured media. By contrast, siRNA-mediated inhibition of the sICAM-1 receptor, lymphocyte function-associated antigen-1 (LFA-1), on BV2 cells reduced NEP expression by ICAM-1 exposure. When hUCB-MSCs were transplanted into the hippocampus of a 10-month-old transgenic mouse model of Alzheimer's disease for 10, 20, or 40 days, NEP expression was increased in the mice brains. Moreover, A beta 42 plaques in the hippocampus and other regions were decreased by active migration of hUCB-MSCs toward A beta deposits. These data suggest that hUCB-MSC-derived sICAM-1 decreases A beta plaques by inducing NEP expression in microglia through the sICAM-1/LFA-1 signaling pathway. Cell Death and Differentiation (2012) 19, 680-691; doi:10.1038/cdd.2011.140; published online 21 October 2011