© 1998 American Heart Association, Inc.
Original Contributions |
In Vitro–Differentiated Embryonic Stem Cell Macrophages
A Model System for Studying Atherosclerosis-Associated Macrophage Functions
From the Lipid Metabolism Unit, Massachusetts General Hospital, Boston, Mass.
Correspondence to Mason W. Freeman, MD, Chief, Lipid Metabolism Unit, Massachusetts General Hospital, GRJ 1328, 55 Fruit St, Boston, MA 02114. E mail freeman@frodo.mgh.harvard.edu
Abstract—Monocytes/macrophages
(Mø) appear to play a critical role in the initiation and progression
of atherosclerotic lesions. In this study, we characterized in
vitro–differentiated embryonic stem (ES) cell macrophages as a
model system for studying atherosclerosis-associated
Mø functions. Using immunofluorescence staining
and Western analysis, we demonstrate that ES Mø express
typical macrophage cell surface markers, as well as the known
receptors for modified forms of low density lipoprotein (LDL),
including the Mø scavenger receptors (SR-A type I and type II), CD36,
and CD68. Differentiated ES Mø specifically bind and degrade
125I-labeled acetylated LDL with high affinity, and
their incubation with acetylated LDL (15 µg/mL) for 48 hours
produces characteristic "foamy" Mø, as visualized by oil red O
staining. ES Mø also express matrix-degrading metalloproteinases
(MMP-3, MMP-9), which have been implicated in collagen breakdown in the
fibrous cap of atherosclerotic plaques, and secrete cytokines
(tumor necrosis factor-
, interleukin-6) in response to inflammatory
stimuli. Transfection experiments, using a green fluorescent
protein reporter gene, driven by the myeloid-specific promoter, CD11b,
demonstrated that ES Mø can also be used to study
macrophage-restricted gene expression in vitro. Taken together,
these data demonstrate that ES Mø exhibit many properties typical of
arterial lesion macrophages. Its ease of genetic
manipulation makes it an attractive system for investigations of
macrophage functions in vitro.
Key Words: atherosclerosis • macrophage • scavenger receptor • foam cell
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