ARTICLE
Auteur(s) : Hervé
Pageon1, Hilaire Bakala2, Vincent M
Monnier3, Daniel Asselineau1
1L’Oréal, Life Sciences, Centre Charles Zviak, 90 rue
du Général Roguet, 92583 Clichy Cédex France
2Laboratoire de Biologie et Biochimie Cellulaire,
Université Paris VII, 2 place Jussieu, 75251 Paris Cédex 05
3Case Western Reserve University, Departments of
Pathology and Biochemistry, 2085 Adelbert Road, Cleveland, Ohio
44106-2622 USA
accepté le 20 Août 2006
Aging has recently gained considerable interest because of the
astonishing fact that life expectancy has considerably increased in
the last decades [1]. Aging is a complex process in which several
mechanisms operate simultaneously. These include accumulation of
mutations in the genome, accumulation of toxic metabolites,
hormonal deprivation, increased formation of free radicals
(oxidative damage), and cross-linking of macromolecules by
glycation [2].Skin is an important model for aging studies since it
is submitted to both extrinsic influences from the environment
(mostly exposure to sunlight but also chemicals and allergens) and
intrinsic factors that are presumed to be mostly of genetic origin
[3]. Intrinsic aging of skin is characterised by changes in the
dermal matrix which becomes less elastic [4] and thinner with age
[5] so that the dermis is the main cause for the appearance of
“old” skin [6].A very attractive characteristic of skin and skin
cells is that it is possible to reproduce in vitro the three
dimensional architecture of skin by reconstructing serially the
dermal and epidermal compartments. Many different ways to do this
have been proposed [7].For instance it is possible to produce a
dermal equivalent by mixing collagen and fibroblasts in certain
conditions to form a dermal tissue in culture and then to obtain a
reconstructed skin model by growing epidermal keratinocytes on this
substrate provided the culture has been raised at the liquid air
interphase and air-exposed. We have extensively used this approach
in our laboratory to investigate several aspects of skin physiology
including detailed studies of the effects of UV light [8, 9]. The
purpose of the present study was to modify the dermal matrix
(namely collagen) in a way which mimics the effect of chronologic
aging in vivo in order to produce aged skin in vitro. Glycation
seemed to us the way to achieve this goal.Glycation is a
non-enzymatically driven reaction between free amine groups like
those of amino acids in proteins and reducing sugars like glucose.
This reaction, also called the Maillard reaction [10], eventually
leads to the formation Advanced Glycation End products (AGEs) such
as carboxymethyl lysine (CML), pentosidine and others, which can be
responsible for the formation of cross-links between macromolecules
by covalent bonding. This reaction therefore preferentially affects
tissues in which macromolecular structures have a slow turnover
rate, and is therefore thought to play an important role in aging
[11]. For instance glycation has been shown to affect skin, hair,
lens, basement membrane (kidney), vessel walls, circulating albumin
and hemoglobin [12]. Moreover, accelerated accumulation of AGE
products has been clearly shown in diabetes mellitus and premature
aging of tissues such as in end stage renal disease [12]. Recently,
it has been proposed that pentosidine accumulation serves as a
marker for aging since it significantly increases with age in
healthy individuals [13]. Moreover a correlation between life span
of several species and pentosidine accumulation rate was observed
[14]. In skin it is thought that accumulation of cross-links
between macromolecules of the dermal extracellular matrix is in
part responsible for the alterations of the mechanical properties
of skin (stiffness) that take place as a function of age. Finally,
AGE product formation and accumulation in skin [15] as well as
collagen crosslinking were correlated with the severity of diabetes
mellitus.This study was undertaken to investigate the effects of
glycation in the reconstructed skin model by pre-glycation of the
collagen. Several skin markers of interest were modified in a way
mimicking in vivo aging and in addition these modifications were
prevented by aminoguanidine, a well-known inhibitor of glycation.
We propose that this modified reconstructed skin therefore
represents a novel promising model of skin aging. This also
suggests that in vivo glycation of dermal extracellular matrix
molecules like collagen may actually participate to the biological
mechanisms of skin aging.
Materials and methods
Skin samples, keratinocyte and fibroblast cultures
Normal human skin was obtained from mammary plastic surgery. Human
epidermal keratinocytes were obtained and cultured as described by
Rheinwald and Green [16] on a feeder layer of Swiss 3T3
fibroblasts. Human adult dermal fibroblasts were isolated after
spreading from skin explants made in the pieces used for isolation
of epidermal keratinocytes. The reference strain of our laboratory
[8, 9] was used throughout this study. Human skin samples from
donors of various ages (young age 20-30, 5 samples vs old age
55-70, 8 samples) were also used for comparison with reconstructed
skin (normal vs young skin and glycated vs old skin respectively).
Preglycation of the collagen
Bovine skin collagen (mostly collagen I) from Gattefossé SA or
Coletica SA or Symatèse SA (all unpepsinized collagens and all from
Lyon, France) at approx. 4-5 mg/mL in 0.5 N acetic acid
solution was incubated in the presence of 10 mM ribose at room
temperature during three weeks before extensive dialysis against
acetic acid 0.5 N (twice instead of once usually) and three
times for 24 hours against acetic acid 0.017 N (or 1:
1000 v/v acetic acid/water) as usually performed for standard
collagen preparations. The glycation of collagen in solution was
monitored as follows: an aliquot of the type I bovine collagen was
solubilized by pepsin digestion (Sigma, 100 μg pepsin in
0.5 ml 0.5 M acetic acid) at 37 °C for
14 hours. At the end of the incubation, the pH of the digested
material was adjusted to 7.0 with 0.5 N NaOH. After
centrifugation for 5 minutes at 10,000 g, the supernatant
containing digested collagen was used for fluorescence measurement.
Fluorescence was measured at λem 440 nm (λex 370 nm) for
total AGE and at λem 378 nm (λex 328 nm) for pentosidine.
HPLC analysis was also performed to demonstrate the presence of AGE
products at the biochemical level like CML, a very representative
AGE product in skin. This control was also performed at the end of
the cultures after enzymatic digestion of reconstructed skin
control samples.
Reconstructed skin in vitro
Dermal equivalents (fibroblasts contracted collagen gels) and
reconstructed skins were prepared as described in detail previously
[17]. Briefly after contraction of the lattice, adult human
keratinocytes were seeded on the lattice and kept submerged for 7
days allowing the cells to form a monolayer. The culture was then
raised at the air liquid interface and kept 1 week to allow the
keratinocytes to stratify and differentiate completely. Collagen
lattices modified by glycation of the collagen (and consequently
reconstructed skins made with glycated collagen) were prepared by
using a 1: 1 untreated collagen and glycated collagen
solutions mixed prior to use to obtain a homogeneous solution,
instead of using normal untreated collagen. Nine independent series
of both normal and glycated reconstructed skins were made and
studied without observing significant variations in the results. In
some experiments it was necessary to have normal unglycated
collagen and glycated collagen in two separate dermal compartments.
This could be obtained by making two successive half gels, one
above the other, provided the first gel was allowed to take before
the second one was made. In other experiments the fibroblasts
embedded in the collagen gels were lysed by an osmotic shock after
stabilization of the gel contraction. This could be obtained
without altering the dermal structure by replacing the culture
medium of the dermal equivalent by distilled water during 24 hours,
with several changes before being left overnight as previously
described and successfully used by others [18]. Aminoguanidine
(hemisulfate salt, from Sigma), 10 mM in water, was eventually
added during preincubation of the collagen.
Histology
Samples were fixed in neutral formalin and treated for histology.
Paraffin sections were stained with hematoxylin, eosin, saffron
(HES) or Van Gieson stain.
Immunohistochemistry
Immunolabelling was performed on air-dried vertical 5 μm
cryosections as described [10] mostly using immunofluorescence
techniques except for AGE products in human skin where
immunoperoxidase staining was preferred because of autofluorescence
[19].
We used essentially mouse monoclonal antibodies against CML
(clone 6D12 from Wako, Richmond, VA, USA) but also, polyclonal
rabbit antibodies against pentosidine [20], and rabbit polyclonal
antibodies against AGE products [21]. Monoclonal antibodies against
vimentin (clone 9) were from Monosan, Uden, The Netherlands.
Monoclonal antibodies against and procollagen III were both from
Chemicon, Temecula, CA, USA. Rabbit polyclonal antibodies against
collagen IV were from Novotec, Lyon, France and Chemicon
respectively. Monoclonal antibodies against α6 (clone GOH3), β1
(clone K20) were all from Immunotech, Marseille, France.
FITC-conjugate rabbit anti-mouse immunoglobulins or FITC-conjugate
swine anti-rabbit immunoglobins (Dako, Denmark) were used as second
antibodies.
Enzyme – Linked Immuno Assays (ELISA)
The matrix metalloproteinases MMP1 (or institutial collagenase 1)
and MMP2 and MMP9 (respectively 72 kD and 92 kD) content of the
tissue culture medium was determined using ELISA essays (Biotrak
kit from Amersham Pharmacia, Orsay, France) according to the
manufactor’s instructions.
Zymography
Precast zymogram gels from NOVEX (Prolabo, France) were used to
study metalloproteinases through the detection of proteolytic
activity. Culture medium (20 μL) was used without heating or
reduction for SDS-PAGE containing blue casein or gelatin. After
electrophoresis, gels were washed twice in zymogram renaturing
buffer (Biorad, Ivry sur Seine, France). Gels were incubated for
72 h at 37 °C in a zymogram developing buffer (Biorad),
then fixed and stained in gel code blue (Pierce, Bezons, France).
Results
Morphogenesis of skin in vitro using preglycated collagen and
related modifications of skin markers
Histology mostly revealed that the dermis appeared slightly
different when preglycated collagen was used and was characterized
by more apparent collagen fibres (( figure 1 )). It was
possible to relate these dermal modifications to actual glycation
of the collagen used as matrix, in particular CML was clearly
identified using specific antibodies ( (figure 1) ). The staining
obtained also confirmed the modification of the extracellular
matrix organisation, especially the presence of unusual thick
collagen bundles likely to correspond to the presence of glycated
collagen fibers. Epidermis however in the context of glycation of
the dermis was histologically normal looking ( (figure 1) ) and comparable
to control epidermis with all stages of differentiation including
granular and horny layers, although slightly thicker suggesting
increased keratinocyte proliferation. This could be confirmed by
Ki67 labelling (data not shown).
Immunochemistry, in general, provides the means to look more in
detail at markers of the different compartments of reconstructed
skin and additional changes were revealed.
In keeping with histological findings, immunostaining of human
type III collagen suggested an increase in the production of dermal
collagen by fibroblasts ( (figure 2) ) as well as an
increase of the staining of basement membrane components like
collagen IV ( (figure
2) ) or laminin (data not shown). Vimentin labelling (
(figure 2) )
also revealed that fibroblasts appeared more spindle-shaped looking
and they were more frequently close to the epidermis as well as
increased in number, an observation likely to be relevant
especially because glycated dermal equivalents were slightly larger
(slightly less contracted). In addition, an increase of Matrix
Metallo Proteinases or MMPs (mostly MMP1 or collagenase 1 and MMP2
or 72 kD gelatinase in its processed form) detected in the tissue
culture medium was observed ( (figure 3) ), indicating
activation of the fibroblasts and degradation of the dermal matrix.
Therefore, it was tempting to relate this increase in MMPs to a
decreased thickness of the dermal compartment as seen by means of
histology ( (figure
1D) ). Interestingly β1 integrin, a broad integrin able to
bind not only collagens but also laminin and tenascin, as well as
α6 which also binds laminin were seen in most suprabasal epidermal
layers or at least in the epidermal basal layer, respectively (
(figure 4) ).
This labeling pattern was different from that observed in controls
where β1 staining appeared restricted to the epidermal basal layer
and α6 to the basement membrane ( (figure 4) ), as described
[22]. Taken together, these observations suggest that not only the
collagen of the extracellular matrix and dermal fibroblasts but
also epidermal keratinocytes were affected by glycation of the
collagen. Interestingly, similar modifications were seen in
epidermis in vivo as a function of age when the distribution of β1
and α6 integrin was studied in samples from young and old skin (
(figure 4) ).
Moreover it was possible to relate the “aged skin” phenotype to the
presence of glycation products in the dermis ( (figure 4) ). The
immunoreactivity of these AGEs can be related to numerous studies
based on chromatographic techniques which have documented their
three- to five-fold elevation in old vs. young skin [33, 34].
Diffusible factor(s) are likely to be responsible for the “aged
skin” phenotype obtained with preglycated collagen in reconstructed
skin
The findings above indicate that among the integrin family members,
β1 and α6 which are normally restrictively expressed in basal
keratinocytes, were affected and enhanced by glycation. Since they
also bind collagens or laminin present at the dermal epidermal
junction or in the dermis of reconstructed skin, it was therefore
tempting to attribute these results to direct contact between
epidermal keratinocytes and glycated collagen molecules of the
dermis. To test this hypothesis reconstructed skins were modified
by introducing an upper normal dermal layer made of untreated
collagen in order to separate epidermis from the glycated dermal
substrate (see materials and methods). Surprisingly, this
modification did not suppress the previously observed increase of
β1 and α6 integrin labelling in epidermis ( (figure 5) ), suggesting
that one or more diffusible factors most likely stemming from the
fibroblast layer were involved, rather than direct contact between
keratinocytes and the glycated matrix. This hypothesis was
confirmed by making reconstructed skins in which fibroblasts were
lysed (see material and methods). β1 integrin labelling in
epidermis was expanded in the presence of glycated collagen only
when living fibroblasts were there ( (figure 6) ).
Anti-glycation effect of aminoguanidine in reconstructed
skin
In order to confirm the relationship between the altered patterns
observed in reconstructed skin made with preglycated collagen to
glycation of the collagen, we examined in this system the effect of
aminoguanidine, a well-known inhibitor of glycation [23], both on
the presence of AGE products like CML and the distribution of β1
integrin as a skin marker reflecting the effect of glycation. (
Figure 7 ) shows
that the amount of detectable glycation products was decreased and
that the distribution of β1 integrin tended to normalize when the
incubation of collagen was performed in the presence of
aminoguanidine. These findings suggested that not only specific
chemical inhibition of glycation itself was obtained but also
prevention of at least some of the biological effects of glycation
observed in the skin model.
Discussion
The reconstructed skin as a model of aging
This study demonstrates for the first time that some of the
phenotypic changes that were observed in aging skin can be
reproduced in skin reconstructed in vitro using collagen modified
by glycation. Histology revealed that the dermal structure itself
was only slightly modified in its fibrous appearance while a
normal-looking epidermis was formed. The changes in the dermal
matrix were related to the presence of advanced glycation products
revealed by immunolabeling and the fact that glycation is known to
alter collagen fibril organisation [24], expand molecular packing
of collagen [25] and may inhibit collagen lattice contraction [26,
27]. All these phenomena are likely to be related.
This modified phenotype was also associated with an increase in
fibroblast number suggesting “activation” of these cells by
glycation. Glycation, for example, is known to abolish the growth
inhibitory effect of native collagen onto cells [28]. In our
experiments, we also noted a change of fibroblast morphology
characterized by a much more elongated shape of the cells, as shown
by vimentin labeling. This is a phenomenon previously observed in
reconstructed skin made with fibroblasts from patients affected by
xeroderma pigmentosum (XP), a genetic disease known to be related
not only to hypersensitivity to UV light but also to premature skin
aging [29]. There also was an increase in collagen III and I (not
shown) as well as in MMP1, or collagenase 1, and other MMPs like
MMP2 and MMP9. Such features are reminiscent of the properties of
“activated fibroblasts” in dermal equivalents after UVA exposure
also accompanied by reduction in dermal thickness [9]. An apparent
increase in the rate of collagen III and collagenase production are
associated with skin aging [30, 31]. Both aging and diabetes
mellitus are characterized by the accumulation of AGE products and
collagen cross-links [32-34], some of which are biologically
active, such as carboxymethyl-lysine [35]. On the other hand, UVA
is thought to play an important role in skin aging and is
accompanied by an increase in several MMPs including MMP1 [9].
In contrast to our findings, others have reported a decrease in
MMP1 when cultivating fibroblasts on glycated collagen lattice
while noticing decreased contraction of the gel [36]. This may be
due to lack of 3-dimensional environment for the fibroblasts in
their culture system. Thus our observation of an increase in MMP1
is likely the direct result of a biological response mediated by
AGE products. Assuming the age-related decrease in skin thickness
is in part due to collagen digestion, our data suggest that such
processes might be mediated by glycation. Paradoxically, however,
we have also observed increased labelling of basement membrane zone
or BMZ molecules like collagen IV or collagen VII (not shown) at
the dermal epidermal junction (DEJ), suggesting possible
accumulation of these basement membrane components as a consequence
of glycation. The increase in laminin and collagen IV [56], or
alteration only [37] or increase in collagen IV only [38] in
basement membranes of diabetic rats has been shown in several
reports [37-39] and related to glycation using cultured cells [40]
or even correlated with elevated glucose in humans [41]. An
increase in the thickness of the basement membrane in human skin as
a function of age has also been reported [42]. A less effective
interaction between basement membrane components in aging skin [43]
or diabetes mellitus [44] has been proposed to explain these
findings and may be related to our observations.
An interesting result of this study is that not only dermal but
also epidermal markers were affected by glycation [34]. Among all
classical epidermal markers investigated, especially those related
to epidermal stratification and differentiation such as desmosomes,
filaggrin, and loricrin and others, only integrins, i.e. β1 and α6,
specifically and clearly showed altered patterns after glycation of
the collagen. The fact that these two integrins rather than others
(not shown), were affected by glycation is not surprising. Because
of its numerous ligands depending on its alpha partner, β1 integrin
is involved in a wide variety of important biological functions
such as epithelial cytoskeletal organization, basement membrane
biosynthesis, adhesion and migration of fibroblasts and
keratinocytes, and collagen synthesis. It is in association with α2
the major collagen receptor on epithelial cells [45] and similar
results were obtained for α2β1 (not shown). It is therefore a broad
integrin whose substrates include collagen I, collagen IV, laminin
and fibronectin which were directly (collagen I and III) or
indirectly (collagen IV) affected by glycation. α6 is another
integrin which can combine with β1 to bind laminin as a
preferential substrate whose production was also increased by
glycation in this system (data not shown). In this system,
glycation also resulted in increased expression of α6, another
integrin which can combine with β1 to bind laminin as a
preferential substrate.
Cell adhesion and migration have been shown to be altered by
glycation, and even mechanical properties like tension [46] and are
likely to be modified by the presence of glycation products. Of
great interest is the fact that the integrins were more expressed
in epidermal layers of glycated reconstructed skins than in the
control, especially in the case of β1 integrin that was observed in
most suprabasal layers. β1 and α6 have both been previously
proposed to be epidermal stem cell markers [47, 48], but the
increased expression of β1 integrin observed here seems unlikely
related to a stem cell property in the context of aging. In fact,
β1 has been shown to be expressed in most suprabasal layers of
epidermis in numerous situations such as following retinoic acid
treatment in vivo [49] or in vitro [50], suggesting that some kind
of de-differentiation has occurred as also seen in normal in vivo
situations like wound healing [51].
Similar changes have been noticed when re-programming of
epidermal cells occurs [52] or during alteration of the
differentiation program as in psoriasis [53]. Induction of β1
expression in suprabasal epidermal layers has then been associated
with enhanced migratory activity of human fibroblasts [54], which
is in agreement with the activation of these cells in response to
glycation of the collagen. In addition, β1 seems to be involved in
the control of collagen synthesis as suggested by wound studies
[55]. This is also supported by the fact that differentiation may
be affected by glycation in other tissues as well. For instance,
collagen glycation seems to reduce the differentiation of certain
cells like osteoblasts [56], while glycation products would
accelerate differentiation of pericytes [57]. Finally, in the
context of these studies it is also of interest to recall that β1
knockout mice have increased epidermal thickness [58], suggesting
that β1 may play a general role in the control of epidermal
morphogenesis and homeostasis rather than differentiation per se
[59]. This observation is relevant since i) we also found that β1
was increased in aged skin in vivo and ii) in vivo skin aging is
known to be accompanied by reduction of epidermal thickness.
Role of diffusible factors
Numerous reports suggest that dermal-epidermal interactions are
important in skin physiology either in vivo or in vitro [18, 60,
61] in reconstructed skin. These interactions work both ways and
diffusible factors can be produced by mutual induction [60, 61],
i.e. by fibroblasts which influence keratinocytes [59], and
vice-versa by keratinocytes which influence fibroblasts [62]. It
was interesting and unexpected, however, that modification of the
dermal extracellular matrix (i.e. glycation of the collagen) was
only indirectly responsible for the effects observed at the level
of the epidermis especially since integrins were affected. On the
other hand, our findings do not exclude that the triggering
mechanism takes place through cell (fibroblast) matrix
interactions, since AGE receptors have been described on the
surface of certain cell types [63]. These integrins can be
influenced by diffusible factors [64], in particular when the
basement membrane is missing or not yet mature like in wound
healing [65]. This is an important observation because it suggests
that an actual increase of integrins β1 and α6 does occur (rather
than a lack of degradation of β1 and α6 integrins by keratinocytes
migrating upwards in the epidermis). It also suggests that, through
diffusion, a broader biological effect of glycation is produced in
the skin model rather than a localized effect restricted to cells
in contact with glycated molecules of collagen.
Inhibition of glycation by aminoguanidine in reconstructed
skin
The fact that aminoguanidine, although known to inhibit enzymatic
activities not related to glycation, was able to prevent some of
the most striking biochemical and biological alterations produced
in reconstructed skin by glycation of the collagen like the
modification of β1 integrin pattern as well as others like collagen
or basement membrane molecules, (data not shown) strongly argues in
favor of the idea that the modifications seen are specific for
glycation. Such functional inhibition of the effect of glycation
has been seen in other systems [38]. The functional effect of
aminoguanidine on integrin pattern in the epidermis of
reconstructed skin made with glycated collagen strengthens the
potential importance of glycation in skin aging and hence its
prevention.
Organotypic approach of skin aging in vitro
To our knowledge only a few approaches using 3D systems of
reconstructed skin have been proposed so far with a view either to
looking at the effect of glycation or to reproducing in vitro some
aspect of aging in vivo. For instance Jeanmaire et al. have
proposed incubating dead de-epidermized human dermis with glucose
in vitro to reproduce age induced glycation [66], while Rittié et
al. have cultivated fibroblasts in the presence of collagen gels
containing glycated collagen, but in their system fibroblasts were
grown at the surface of the glycated collagen gel and epidermis was
missing [36]. In previous studies, as mentioned above, we looked at
the effect of UVA on reconstructed skin. We also made a modified
model of reconstructed skin using cells of XP patients [29], XP
being a disease known to be responsible not only for UV light
hypersensitivity but also for premature skin aging. A striking
result was that in reconstructed skin made with XP cells as well as
in reconstructed skin prepared with glycated collagen, both β1 and
α6 integrin patterns were modified in the same way. This data again
is in favour of the fact that glycation effects in reconstructed
skin are actually representative of some effects of aging in vivo.
Finally it is of interest to mention that others have prepared
reconstructed skin containing fibroblasts isolated either from
young or old donors but did not see significant differences [67].
In conclusion the data presented above demonstrate that the in
vitro model of reconstructed skin can mimic several features of
skin aging when cells were grown onto a glycated matrix. The
ability of aminoguanidine to prevent these changes not only
supports a role for glycation products in skin aging, but also
provides a pharmacological paradigm for the development of drugs
with anti-skin aging properties.
Acknowledgements
Financial support: None. Conflict of interest: None.
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