Articles |
From the Department of Anatomy and Embryology (M.C.D., R.E.P., J.C.V., A.C.G.-de G.), Leiden University, Leiden, the Netherlands, and the Department of Cell Biology (V.M., R.R.M.), Medical University of South Carolina, Charleston.
Correspondence to M.C. DeRuiter, PhD, Department of Anatomy and Embryology, Leiden University, Wassenaarseweg 62, PO Box 9602, 2300 RC Leiden, the Netherlands. E-mail RUITER{at}RULLF2.leidenuniv.nl
| Abstract |
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-smooth muscle actin, were present. In such
cells, QH1 expression was reduced to a cell membrane localization. A
similar antigen switch was also observed during endocardial-mesenchymal
transformation in vitro. Our results are the first direct in vivo
evidence that embryonic endothelial cells may transdifferentiate into
candidate vascular smooth muscle cells. These data arouse new
interpretations of the origin and differentiation of the cells of the
vascular wall in normal and diseased vessels.
Key Words:
-smooth muscle actin endothelial cell embryo smooth muscle cell vessel wall
| Introduction |
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A first indication of media formation is observed as mesenchymal
condensations spreading around an endothelial tube.11 This
process proceeds from caudal to cranial areas and is initially
patchy.12 During thickening of the aortic media, the
premature SMCs can be distinguished from neighboring non-SMCs by the
expression of muscle-specific actins. During subsequent
maturation,13 14 15 16 17 18 SMCs start to express contractile
proteins, such as
-SM actin, SM myosin light and heavy chains, and
cytoskeletal proteins, such as desmin, filamin, and
SM-phosphoglucomutaserelated protein, whereafter the regulatory
proteins associated with the myosin and actin complex, such as myosin
light chain kinase, tropomyosin, SM-22, h-caldesmon, and calponin, are
expressed to complete the SMC phenotype.
To study the complete SMC lineage in the embryo, a marker is necessary that is present during all stages of differentiation and maturation of SMCs. Until now, none of the known "SMC-specific" proteins is restricted to SMCs and is present during the entire lifetime.15 Except for the late differentiation markers, such as myosin light chain kinase and calponin,13 the earlier SMC proteins are also (transiently) expressed by other muscle and nonmuscle cell types.14 19 20 21 Recent data on SM22 expression indicate that it is an early marker in the chick13 and mouse,17 18 but not solely SMC specific. Therefore, to study the SMC lineage, it is important to use differentiation-independent markers, such as heterospecific cells, retroviral reporter gene transfer, or wheat germ agglutinincolloidal gold incorporation.
Arciniegas et al22 reported that adult bovine ECs can
transdifferentiate into SM-like cells in vitro. They showed
TGF-ß1induced
-SM actin expression in aortic ECs, whereas
expression of factor VIIIrelated antigen was lost. Moreover, several
experiments show that embryonic endocardial (=endothelial) cells can
transdifferentiate into mesenchymal cells during cushion
formation.23 24 25 If already specialized ECs can
interconvert into a phenotype that is more typical of SMCs in vitro,
the following old question can be addressed: Do ECs and SMCs in vivo
belong to distinct cell lineages, or do they convert their phenotype
during developmental or pathological processes? In contrast to SMCs,
the characteristic epithelial phenotype of ECs in vivo appears to be
quite immutable. Several authors,26 27 28 however, have
speculated that ECs can give rise to a population of subendothelial
cells during atherosclerotic intimal thickening.
To study a possible endothelial origin for embryonic aortic SMCs in vivo, quail ECs were labeled with WGA-Au by injection into the lumen of the vascular system of quail embryos at stage HH14-15. At this stage, the dorsal aortas between the pharyngeal arch area and the more caudal fusion site do not as yet have cells that express SM actin. WGA-Au has been used before as a cell-lineage marker, eg, for neural crest and primitive streak.29 30 Wheat germ agglutinin binds with high affinity to N-acetylglucosamine oligomers31 that are present on the cell membrane of ECs. After endocytosis of WGA-Au, the fate of individual labeled ECs can be traced even after delamination from the endothelial monolayer. In addition, immunohistochemistry was performed to study the change in antigen expression of delaminated cells.
| Materials and Methods |
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Colloidal Gold Injections
The colloidal gold solution (average particle size, 12 nm) was
prepared according to Smits-van Prooije et al.29 The
colloidal gold solution precipitates easily in
15 minutes into large
aggregates, which can no longer be endocytosed by the cells. Therefore,
the colloidal gold solution needs to be freshly prepared and stored in
the dark at 4°C. A small amount (
10 µL) of the solution was
injected into the left or right anterior vitelline vein by a glass
needle (tip diameter, 10 to 15 µm) that was connected by a
pressure-insensitive oil-filled tube to a Hamilton syringe, as was
described previously.33 After injection, the eggs were
sealed with tape and reincubated for 5 minutes, 10 minutes, 30 minutes,
5 hours, or 19 hours. Subsequently, the embryos were removed from the
yolk, rinsed several times in PBS, pH 7.2, and fixed for 24 hours in
half-strength Karnovsky fixative34 for TEM. For
immunohistochemical analysis, the embryos were fixed for 48 hours in
2% acetic acid in absolute ethanol or for 4 hours in
periodate-lysine-paraformaldehyde35 for immuno-TEM.
TEM
The embryos were rinsed in 0.1 mol/L cacodylate buffer, pH 7.2,
postfixed in 1% OsO4 for 2 hours at 4°C in the same
buffer. The embryos were rinsed again, dehydrated in graded ethanol,
and transferred via propylene oxide (twice for 15 minutes each) and
propylene oxide/Epon 812 (Merck) (1:1, twice for 30 minutes each; 1:2,
twice for 30 minutes each) to Epon 812 (2 hours at room temperature and
18 hours at 60°C). Ultrathin sections were contrasted with uranyl
acetate and lead citrate.36 To obtain both low-power light
microscopic and electron microscopic pictures of the same colloidal
goldlabeled cells, semithin sections (2 µm) were produced and
stained with toluidine blue for 5 seconds at 40°C, rinsed with
distilled water, and air-dried. After photography, these sections were
reembedded by placing Beem capsules (Balzers, Liechtenstein) filled
with Epon 812 upside down on top of the sections. After
polymerization, the capsules were removed from the glass in liquid
nitrogen for 10 seconds. Ultrathin sections prepared from this
same region were then studied electron-microscopically.
Immuno-TEM
Quail endothelial and hematopoietic cells are recognized by the
monoclonal antibody QH137 (IgG1, Hybridoma Bank). Cellular
and possible extracellular antigen location in the vessel wall was
determined by immunoelectron microscopy. After they were rinsed in 0.1
mol/L phosphate buffer (pH 7.3), the embryos were dehydrated in graded
ethanol. They were then placed for 1 hour in ethanol/Lowicryl K4M
(1:1), 1 hour in ethanol/Lowicryl K4M (1:2), and overnight in Lowicryl
K4M (Bio-Rad). Polymerization was performed for 24 hours at -20°C
under 254-nm UV light. The blocks were then hardened for 48 hours at
room temperature. Ultrathin sections, mounted on nickel grids, were
rinsed in PBS. Overnight incubation was at 4°C with QH1, 1:500
diluted in PBS containing 1% ovalbumin. After thorough washing in PBS
(three times for 5 minutes each), the sections were incubated with a
second antibody, rabbit anti-mouse (Dako), in the same buffer for 2
hours at room temperature. Redundant antibodies were washed away in
PBS. Protein A conjugated to 10 nm gold (Dr G. Posthuma, Laboratory for
Cell Biology, Utrecht, the Netherlands; 1:50 diluted in PBS with 1%
ovalbumin) was added to visualize the complexes of antibodies. The
sections were washed again in PBS (three times for 5 minutes) and once
in 0.1 mol/L cacodylate buffer, pH 7.2. After short postfixation in 1%
glutaraldehyde in 0.1 mol/L cacodylate buffer and subsequent washing in
distilled water, the sections were contrasted for 5 minutes with
uranyl acetate.
Immunohistochemistry on Paraffin Sections
After dehydration in graded ethanol and 100% xylene, injected
and noninjected embryos were embedded in paraffin and serially
sectioned transversely at 5 µm. Deparaffination, rehydration,
and washing two times in PBS and once in PBS with 0.05% Tween 20 was
followed by overnight incubation at room temperature with QH1 diluted
in PBS (1:500) with 0.05% Tween 20 and 1% ovalbumin. After they were
washed repeatedly, sections were then incubated with the second primary
mouse antibody 1A4,
-SM actin specific (IgG2a, Dako; M851), in the
dilution buffer (1:100) for 3 hours. The sections were incubated
sequentially with secondary antibodies, goat anti-mouse IgG1-FITC
(Boehringer-Mannheim; 100823) and goat-anti-mouse IgG2a-TRITC (Southern
Biotechnology Associates; 1080-03), in the dilution buffer (1:100),
each for 1 hour at room temperature in a dark chamber, with repeated
washings in between. Negative controls were performed by omitting a
primary or secondary antibody from a selected section. The muscle
actinspecific antibody HHF35 (IgG1, Dako M635) was used to confirm
the SMC characteristics in separate incubations at a dilution of
1:1000. Subsequently, the sections were washed again and mounted in 2%
triethylenediamine (D522, Sigma Chemical Co) in 90% glycerol with 10%
Tris-NaCl buffer, pH 8.0. The sections were evaluated with CLSM
(MRC600, Bio-Rad) in combination with reflection contrast microscopy.
The optical section thickness was 1.2 µm. FITC excitation was
studied with standard K1 filters and TRITC excitation with K2 filters.
To visualize the colloidal goldpositive vesicles, standard Biorad
REFL and AREF filters were used. To merge the files, the various
primary pictures were recorded at the same optical level.
Cell Culture
Heart tubes of quail embryos, stages HH14, 15, and 18,
containing both atrioventricular and ventricular endocardium were
longitudinally opened. The hearts, with the endocardium facing the
bottom, were placed on 35-mm plastic dishes (Nunc well). The heart
tubes were allowed to adhere to the plastic for 3 to 4 hours with a
minimal of culture medium 199 (GIBCO), containing 1% chick serum
(Spafas), 5 µg/mL insulin, 5 µg/mL transferrin, 5 µg/mL selenium
ITS (Collaborative Research), and streptomycin/penicillin (GIBCO).
After that time had elapsed, complete medium was carefully added to
prevent detachment from the plastic. After it was cultured overnight,
the myocardium was removed by microdissection using a 10-gauge needle.
Endocardial cells formed monolayers that survived 2 or more days,
depending on the developmental stage of the explanted tissue. The
explants were fixed in 70% ethanol, and after rehydration, they were
incubated overnight in PBS containing 1% bovine serum albumin. The
cell cultures were incubated for 1 hour with both QH1 and 1A4 and
subsequent incubation with secondary fluorescently labeled antibodies
as essentially described above. After they were washed, the cultures
were mounted in glycerol.
| Results |
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At stage HH20, 19 hours after injection, both gold-labeled endothelial
and subendothelial cells were detected light microscopically. After
they were prepared by reembedding and ultrathin sectioning, the same
subendothelial cells could be studied by electron microscopy. The
WGA-Au in the subendothelial cells was present in large endosomes (Fig 1C
and 1D
). The first cells were detected at the ventral and dorsal
sides of the aorta. Some of these cells still resembled ECs, containing
many mitochondria and a large amount of rough endoplasmic reticulum,
whereas others already had a contractile apparatus with fewer
mitochondria and less rough endoplasmic reticulum (Fig 1D
). Thirty
minutes after injection, virtually all ECs were labeled. Thereafter,
the combined effects of cell division and asymmetric distribution of
the gold label precluded further attempts to clearly determine the
incidence of labeled ECs versus mesenchymal cells.
Differentiation Markers
The ultrastructural and WGA-Au data were confirmed by an
immunohistochemical approach using differentiation markers. ECs of the
quail dorsal aorta were characterized by the endothelium-specific
monoclonal antibody QH1. The QH1 antigen is detected in the TEM on both
the luminal and abluminal membranes of ECs (Fig 2A
).
Moreover, all ECs contain cytoplasmic aggregations of the antigen. Most
likely, this cytoplasmic expression of the protein is restricted to the
Golgi apparatus or vesicles. Prospective SMCs were defined by the
presence of actin filaments, recognized by HHF35 monoclonal antibody
(specific for muscle actins in general) and 1A4 (specific for
-SM
actin). These actin stainings can be considered to represent the first
differentiation markers of prospective SMCs.
|
Fig 3
shows representative CLSM fluorescence micrographs
in combination with CLSMreflection contrast microscopy to detect the
fluorescence at the same optical level as the vesicles containing
WGA-Au. At stage HH18, some of the subendothelial cells contained gold
particles, which were incorporated at stage HH15, when they lined the
lumen of the descending aorta as ECs. Because they are characterized by
the presence of actin filaments, they are regarded as candidate SMCs.
ECs lining the lumen do not express
-SM actin at any stage.
|
As shown with TEM, the QH1 antibody recognizes both cytoplasmic and
cell membranebound epitopes. Until stage HH13, the QH1 staining was
confined to ECs lining the lumen. Subsequently, at stage HH16, just
before actin expression, in the mesenchyme surround-ing the aorta,
the QH1 antigen is also expressed and visualized as thin lines in the
CLSM (Fig 4A
). The extraendothelial QH1 expression is
mainly localized to the cell surface membranes of the stained
mesenchymal cells (Fig 2B
), but expression is not as abundant as in the
ECs; expression in the cytosol was not detected. At stage HH18, many of
these subendothelial mesenchymal cells, showing extensive actin
filament bundles (Fig 2B
and 4B
), still express QH1 in their cell
membrane (Fig 4B
). In later stages, all cells in the condensed layer
around the aorta are actin positive but QH1 negative.
|
Endothelial-Mesenchymal Transformation In Vitro
The shift in antigen expression was also studied in vitro, using
stage HH15-18 heart explants of ventricular and atrioventricular
endocardial cells. During the culture period, endocardial cells from
the ventricular region did not transform into mesenchyme and did not
lose QH1 expression or acquire
-SM actin. In contrast, the
atrioventricular endocardial cells demonstrated within 2 days of
culture a gradual loss of their epithelium-like morphology as they
migrated peripherally and acquired mesenchymal characteristics (Fig 5
). The abundant cell-cell contacts and QH1 expression
observed in cells remaining in the center of the explant (Fig 5A
)
progressively disappeared in cells located at the periphery. Cells at
the periphery were more separated and spread out. This change in
morphology was accompanied by a transition in protein expression. The
initial endothelium-specific QH1 expression decreased, whereas
-SM
actin expression increased. The presence of transitional cells,
expressing both QH1 and
-SM actin, indicates that we are dealing
with a gradual transformation process.
|
| Discussion |
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-SM actin. Significantly, a similar mechanism of loss of
the QH1 expression pattern and subsequent appearance of
-SM actin
were also shown with the endocardial explant technique, which is an
appropriate model for the endocardial-mesenchymal transformation during
cushion formation in the heart.39 40 The WGA-Aulabeling technique has been described as a reliable method for cell-lineage studies of the neural crest and primitive streak.29 30 In the present study, the injection of WGA-Au into the vascular system similarly indicates a lineage for candidate SMC precursor cells from the endothelium of the dorsal aorta at the lower thoracic level. Leakage of WGA-Au through fenestrae was not detected, nor was phagocytosis of labeled ECs by neighboring mesenchymal cells observed. Therefore, the WGA-labeling technique was also considered to be a reliable method to study the cell lineage of the EC. Because no differences in antigen expression (QH1 and 1A4) between labeled and nonlabeled embryos were found, there is no indication that the transformation of ECs into mesenchymal cells was induced by the lectin.
QH137 as a marker for ECs has been accepted for many
studies on vasculogenesis. It has a disadvantage, however, because it
is also known to label hematopoietic precursors in the para-aortic
mesenchyme surrounding the dorsal aorta.37 We have also
observed this phenomenon in our material, but limited to the
lateroventral aortic wall containing large globular
cells.41 The difference with our cells is that they are
double labeled with QH1 and
-SM actin and are clearly circularly
positioned around the vessel.
A likely candidate to regulate EC-SMC transformation is the ES130
protein, which plays an essential role in endocardial-mesenchymal
transformation during cushion formation in the heart.24
Preliminary data of ES130 protein expression in the descending aorta
(HH16) show that aortic ECs also express the ES130 protein in the area
in which we observe transformation into mesenchymal cells. The presence
of ES130 in vascular endothelium is consistent with its proposed role
as an inducer of cushion mesenchyme formation. Likewise, TGF-ß1 is a
candidate for regulation or initiation of transformation, because it
has been shown to promote differentiation of ECs into SM-like cells in
vitro.22 To be clear, we propose ECs as but one potential
source of mesenchymal cells, particularly those that would lie closest
to the endothelium and, by dint of their position, could reasonably be
expected to become part of the intima. If this potential subpopulation
of mesenchyme is formed in a manner analogous to cushion mesenchyme,
these potential vascularly derived ECs might be anticipated to also
express markers similar to atrioventricularly derived mesenchyme
besides
-SM actin. Studies are in progress to determine if such
markers, eg, JB3,25 fibulin,42 and
ES130,24 are correlatively expressed.
Thus, we believe our data are the first direct in vivo evidence that
embryonic endothelium may give origin to mesenchymal cells that express
-SM actin. The capacity for ECs to be able to start expressing
-SM actin is supported by the in vitro endothelial-mesenchymal
transformation data of adult aortic ECs.21
Because a high rate of cell division occurs during the embryonic
stages, studied application of the colloidal gold technique was limited
to
24 hours or less after administration of the label. When the
embryos survive until stage HH18,
-SM actin expression in the
mesenchyme is one of the first indications of vessel wall
differentiation. However,
-SM actin expression is not restricted to
medial SMCs, is reported in a number of adult cell types, such as
myofibroblasts,43 tumors,44 and
ECs,22 and is transiently expressed in various embryonic
tissues, such as the myotomes of the somites and
myocardium.45 During endocardial-mesenchymal
transformation in the atrioventricular cushions,
-SM actin is also
transiently expressed in vivo.46 Actin is necessary for
cell motility and migration. Recent theories of cell locomotion are
based on cycles of attachment, proteolysis, contraction, and
detachment, which are critical steps for an invasive behavior of
cells.47 Thus, it is likely that the expression of
-SM
actin is functionally related to the invasive behavior of
endothelium-derived mesenchymal cells, as can be observed in the
endocardial cushions. From the literature,12 48 49
however, it is evident that the expression of
-SM actin in the
mesenchymal cells around the aorta is not transient and will gradually
be strengthened with other (SMC-specific) proteins, such as myosin
light chain kinase, calponin,13 1E12,50 and
SM-22.17 18 Expression patterns of 1E1250 and
SM-2213 in the descending aorta recapitulate the pattern
of our
-SM actin, showing that we are dealing with differentiating
SMCs. This indicates that although
-SM actin expression is not
limited to SMCs in general, it is a valuable marker to study the
earliest vessel wall formation.
The present study was performed at a level of the dorsal aorta just below the pharyngeal arch area, where we know that neural crest cells do not contribute to the SMC population of the vessel wall.51 We performed the study above the site of fusion of the dorsal aortas because the fusion site is complicated and mechanistically not well understood. Additional experiments will be needed to substantiate whether the EC-mesenchymal transformation is a generalized process that occurs at every site of vessel formation in the embryo or whether it occurs only at certain sites. The presence of von Willebrand factor, which is an EC-specific protein, in subendothelial cells of the intimal cushion of a normal closing ductus arteriosus52 suggests that the capacity of ECs to transform is not restricted to embryonic development. This idea is additionally supported by the observation of QH1-positive subendothelial intimal cells in atherosclerotic plaques of the quail.53
Literature data refer to endothelium-derived cells containing SM actin in various pathological processes, such as restenosis,26 inflammation, and hypertension,27 and to their induction in in vitro experiments.22 The impact of our findings for both development and disease of the vessel wall needs further study. SMC heterogeneity54 55 56 is already a well-described phenomenon in fetal, neonatal, and adult vessel wall, and its impact for disease processes forms the basis of many studies. If, however, in fully differentiated stages in the adult the EC can participate in the formation of intimal thickening, this might open new ways of thinking in controlling this process in the setting of endothelium-mediated gene therapy.
| Selected Abbreviations and Acronyms |
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| Acknowledgments |
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Received September 6, 1996; accepted December 19, 1996.
| References |
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-smooth muscle
actin. Development. 1992;115:1165-1173. [Abstract]
, a
marker of adult smooth muscle, is expressed in multiple myogenic
lineages during embryogenesis. Circ Res. 1996;78:188-195.
promoter in transgenic mice provides evidence for
distinct transcriptional regulatory programs in vascular and visceral
smooth muscle cells. J Cell Biol. 1996;132:849-859.
-actin genes during avian cardiogenesis: vascular smooth muscle
-actin gene transcripts mark the onset of cardiomyocyte
differentiation. J Cell Biol. 1988;107:2575-2586.
-smooth muscle actin expression in
cultured fibroblasts and in granulation tissue myofibroblasts.
Lab Invest. 1992;67:716-726. [Medline]
[Order article via Infotrieve]
-Smooth
muscle actin is transiently expressed in embryonic rat cardiac and
skeletal muscles. Differentiation. 1988;39:161-166. [Medline]
[Order article via Infotrieve]
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