Epidermal Physiology

Abstract

The epidermis, primarily made of keratinocytes, is continuously renewed by the proliferation of stem cells and the differentiation of their progeny, which undergo terminal differentiation as they leave the basal layer and move upward toward the surface, where they die and slough off. These cells are responsible for tissue homeostasis and regeneration of epidermis following injury. Basal keratinocytes append the dermal epidermal junction, a cell surface-associated extracellular matrix that provides structural support to keratinocytes and influences their behaviour. Similar to all basement membranes, the dermal epidermal junction primarily consists of laminins, type IV collagens, nidogens, and the heparan sulfate proteoglycan perlecan, all of which are necessary for tissue organization and structural integrity. Keratinocytes committed to the differentiation program downregulate integrins to become less adhesive, move to the suprabasal compartment and continue their upward movement until they are terminally differentiated and shed off. This produces several layers of keratinocytes, at different stages of differentiation that can be identified by the expression of keratins. Beside a function of protective barrier, epidermis has also an important secretory activity. The numerous and diverse factors produced by keratinocytes, that may act in an autocrine, paracrine or endocrine manner, are described in this chapter.

Full text

Epidermal Physiology
Patricia Rousselle, Edgar Gentilhomme, and Yves Neveux
Contents
1 Epidermal Proliferation and
Differentiation ................................... 3
2 Epidermal Secretions ........................... 4
2.1 Cytocrine Secretion ............................... 4
2.2 Endocrine Secretion .............................. 6
2.3 Other Roles . . ..................................... 6
Glossary ................................................ 7
References .............................................. 7
Abstract
The epidermis, primarily made of
keratinocytes, is continuously renewed by the
proliferation of stem cells and the differentia-
tion of their progeny, which undergo terminal
differentiation as they leave the basal layer and
move upward toward the surface, where they
die and slough off. These cells are responsible
for tissue homeostasis and regeneration of epi-
dermis following injury. Basal keratinocytes
append the dermal epidermal junction, a cell
surface-associated extracellular matrix that
provides structural support to keratinocytes
and influences their behaviour. Similar to all
basement membranes, the dermal epidermal
junction primarily consists of laminins, type
IV collagens, nidogens, and the heparan sulfate
proteoglycan perlecan, all of which are neces-
sary for tissue organization and structural
integrity. Keratinocytes committed to the dif-
ferentiation program downregulate integrins to
become less adhesive, move to the suprabasal
compartment and continue their upward move-
ment until they are terminally differentiated
and shed off. This produces several layers of
keratinocytes, at different stages of differenti-
ation that can be identified by the expression of
keratins. Beside a function of protective bar-
rier, epidermis has also an important secretory
activity. The numerous and diverse factors pro-
duced by keratinocytes, that may act in an
autocrine, paracrine or endocrine manner, are
described in this chapter.
P. Rousselle (*)
Tissue Biology and Therapeutic Engineering Unit, Institute
of Protein Biology and Chemistry, UMR 5305 –CNRS,
University of Lyon, Lyon, France
e-mail: patricia.rousselle@ibcp.fr
E. Gentilhomme
Lumbin, France
Y. Neveux
Livernon, France
e-mail: yves.neveux@free.fr
#Springer International Publishing Switzerland 2015
P. Humbert et al. (eds.), Measuring the Skin,
DOI 10.1007/978-3-319-26594-0_36-1
1

Keywords
Anti-bacterial peptide •Cytocrine secretion •
Endocrine secretion •Epidermis •Epidermal
barrier •Cytocrine secretion •Endocrine secre-
tion •Proliferation and differentiation •Growth
fraction, epidermis •hCAP-18 •Human
keratinocytes •Melanocytes •Papillas
This chapter describes the epidermis, formerly
called the Malpighi’s layer. As the skin’s outer
layer, the epidermis provides the barrier function
protecting mammals from environmental influ-
ences such as physical, chemical, or thermal stress
and also against dehydration. The epidermis is a
multilayered epithelium consisting of the
interfollicular epidermis and associated hair folli-
cles, sebaceous glands, and eccrine sweat glands.
Although keratinocytes are the main epidermal
cell type (95 % of the total cells), other cells are
found in mammalian epidermis, such as melano-
cytes and Merkel and Langerhans cells. Merkel
cells are neuroendocrine cells responsible for the
touch sensory function of the skin. Melanocytes
are specialized pigment cells producing melanin
granules, which are transferred to keratinocytes
for their protection against UV-induced DNA
damage. Langerhans cells are epidermal dendritic
cells involved in the adaptive immune response,
playing a critical role in the barrier function of the
skin. The epidermis itself is divided into five
layers which are, from the inner to the outer
most, the stratum germinativum (basal), stratum
spinosum (spinous), stratum granulosum (granu-
lar), stratum lucidum (only found in thickened
areas of the epidermis), and the stratum corneum
(cornified). The epidermis consists in approxi-
mately ten layers of keratinocytes piled up from
the basal layer to the cornified layer. In contrast
with the stratum corneum that features a horizontal
plane, the basal layer juxtaposes the dermis with
the dermal-epidermal junction in a corrugated out-
line manner, alternating in-depth epidermal cones
and dermal expansions named “papillas”(Fig. 1).
The thickness of the viable epidermis lies from
75 to 150 μm according to anatomical site to
reach 0.8 mm on the palms of the hands and
1.4 mm on the soles of the feet. Its metabolism
seems close to 0.4 ml min
1
/100 g tissue (Krueger
et al. 1994) (resting muscle, <0.2; muscle on exer-
cise, 13–15; brain, 3–4(Holtz1996)).
Its fundamental and first known function is to
generate the stratum corneum, the dead but vital
barrier that separates our body from the environ-
ment. It is accomplished through its perpetual
renewal from the division of basal cells and kera-
tinization of uppermost layers: the total turnover
takes about 15 days, the same as that of the stra-
tum corneum. Other fundamental functions are
extracellular matrix component production; hor-
mone secretion; cytokine production ruling angio-
genesis and vasomotricity in the papillary dermis;
homing and maturation of cells responsible for the
immune barrier (chapter “▶Skin Immune Sys-
tem”); protection against ultraviolet light and
homing of melanocytes (chapter “▶Skin
Photoprotection Function”); participation to the
skin neurosensorial function and homing of
Merkel cells (see dedicated chapters); participa-
tion in the skin mechanical protective function,
thanks to its cellular abundant keratin filaments
(see the dedicated chapter); and finally the
Fig. 1 Dermis and epidermis. Dermal papillae with a
basal layer and numerous suprabasal differentiated layers.
Resin semithin section. Toluidin blue staining. Objective
100
2 P. Rousselle et al.

capacity of self-repair (see the chapter “▶Wound
Healing”).
1 Epidermal Proliferation
and Differentiation
The epidermis is continuously renewed by the
proliferation of stem cells and the differentiation
of their progeny, which undergo terminal differen-
tiation as they leave the basal layer and move
upward toward the surface, where they die and
slough off. As for most epithelial tissues, prolifer-
ation and differentiation occur in two juxtaposed
compartments, represented by the basal layer and
the numerous suprabasal layers. The keratinocyte
population can be divided into at least three func-
tional types, keratinocyte stem cells, transit ampli-
fying cells, and postmitotic differentiating cells.
Stem cells, responsible for tissue renewal, have a
high mitotic potential but are rarely dividing. They
give birth to transit amplifying cells, which after a
finite number of division, are committed to differ-
entiate. By this way, a high output of differentiated
cells can be issued from a small number of infre-
quently solicited stem cells. The growth fraction
of human epidermis has been estimated to 10 % of
stem cells and 50 % of transit amplifying cells
versus 40 % of differentiated cells (Heenen and
Galand 1997). On the basis of their morphological
and functional characteristics, the proliferating
cells have also been described as clonogenic
keratinocytes: holoclones, meroclones, and
paraclones (Barrandon and Green 1987). Located
in the basal layer and in the bulge of hair follicles,
stem cells can be characterized by their size
(Barrandon and Green 1985), their high adhesive
properties (Kaur and Li 2000), their high level of
β1 integrin (Zhu et al. 1999), their expression of
keratin K19 (Michel et al. 1996), and their high
content in cytoplasmic β-catenin (Zhu and Watt
1999). Their spatial distribution in the basal layer
is not randomly disposed, showing clusters of
stem cells from which migrate transit amplifying
cells (Jensen et al. 1999). Generation of differen-
tiated progeny from stem cell is regulated by inter-
nal mechanisms such as transcription factors and
by external controls in the cellular
microenvironment such as secreted mediators, cel-
lular interactions, integrins, or other elements
(Watt and Hogan 2000). In this system, β1 integrin
is particularly involved and induce, depending on
the signaling pathway involved, either cellular
adhesion or differentiation (Levy et al. 2000).
Decrease of adhesion related to modifications of
integrins (Kaur and Li 2000) and reduction in
mitogen-activated protein (MAP) kinase activa-
tion (Zhu et al. 1999) induce this cellular exit
from the stem cell compartment. After a finite
number of divisions, the transit amplifying cells
undergo an irreversible multistage process of dif-
ferentiation. Keratinocytes committed to the dif-
ferentiation program downregulate integrins to
become less adhesive, move to the suprabasal
compartment, and continue their upward move-
ment until they are terminally differentiated and
shed off. This produces several layers of
keratinocytes, at different stages of differentiation
that can be identified by the expression of keratins.
Basal keratinocytes express keratins K5, K14, and
K15, whereas differentiating keratinocytes
express keratins K1 and K10. Integrins β1 and
hemidesmosomal components (integrin α6β4 and
BP180) decrease by transcriptional decrease of
mRNA and by a posttranslational mechanism of
ineffective subunits. Some intracellular organelles
disappear (mitochondria, nucleus, etc.) when
other elements (keratohyalin granules, filaggrin,
etc.) appear, leading to the future horny layer
cells. During this cellular differentiation, modifi-
cations of receptors’expression are observed,
either decreasing (receptors for TGFβ1, PDGF A,
etc.) or increasing (receptors for acid FGF, basic
FGF, PDGFβr, IL-1ra, etc.). Modulation of trans-
membrane ion transport is also noted with
upregulation of sodium channels (Brouard
et al. 1999; Deliconstantinos et al. 1995; Eming
et al. 1998; Fenjves et al. 1989; Heenen and
Galand 1997; Holick 1988; Insogna et al. 1988;
Jensen et al. 1999; Kaplan et al. 1988; Katz and
Taichman 1994,1999; Kaur and Li 2000; Krueger
et al. 1994; Kupper 1990; Levy et al. 2000;
Malaviya et al. 1996; Martinez et al. 1997;
Maruyama et al. 1995; Mazereeuw Hautier
et al. 2000; Michel et al. 1996; Nathan and Sporn
1991; Oda et al. 1999).
Epidermal Physiology 3

2 Epidermal Secretions
Beside a function of protective barrier, epidermis
has also a secretory activity (Boyce 1994), esti-
mated in vitro to a rate of 0,67 μg protein/h/10
6
cells (Katz and Taichman 1994).
2.1 Cytocrine Secretion
Non-lesional epidermis is in a low steady state of
secretion and keratinocytes seem quiescent. After
endogenous or exogenous (physical, chemical,
biological, or immunological) stimulation, the
Fig. 2 Stratum basale
protrusions into the dermis.
Thick keratin filaments
bundles separate into small
bundles which attach to
hemidesmosomes at cell
periphery (Small arrow
head). Large arrowheads
point at dermis reticulum
fibers that are attached to
the basement membrane
perpendicularly. Fixation
by glutaraldehyde and
osmic acid. Uranyl acetate
and lead citrate staining. 
29,000
Fig. 3 Stratum spinosum.
Section though the
periphery of a keratinocyte.
Fixation by glutaraldehyde
and osmic acid. Uranyl
acetate and lead citrate
staining. 25,000
4 P. Rousselle et al.

keratinocyte is “activated”and secretes various
peptides. These peptides are represented by cyto-
kines (IL-1α, IL-1β, IL-6), tumor necrosis factor
(TNFα), growth factors (GMCSF, GCSF, MCSF,
TGFα, acid and basic FGF, KGF, PDGF A,
PDGF B, NGF), chemokines (IL-8, IFNγ-IL10,
huGRO of G-X-C family, or MCAF of G-C fam-
ily), or suppressor factors/anticytokines (TGFβ,K
LIF, Contra IL-1) (Stoof et al. 1994). Cytokines
are small protein hormones primarily secreted by
immune cells and are important mediators of host
defense, post-injury repair, cell growth, and mat-
uration. This secretion shows particular character-
istics (Kupper 1990), such as the release of
secondary cytokines after stimulation by primary
cytokines. The activated keratinocyte is modu-
lated through the action of specific receptors pre-
sent on the cell membrane (IL-1 receptors, IFNγ
receptors,etc.) and induced by stimulation. Species
of activated keratinocytes and secretion types
would differ depending on the nature of the signal.
All these pleiotropic or specificpeptidesactby
autocrine or paracrine mechanisms (Schröder
1995). Their action must be evaluated, considering
numerous mechanisms of amplifying or inhibitory
regulation (Nathan and Sporn 1991)suchasaction
of anticytokines, direct antagonism between sev-
eral cytokines (Reinartz et al. 1996), or specific
Fig. 4 Stratum
granulosum: section
through the boundary
between two keratinocytes.
Kkeratinosomes (Odland’s
bodies). KH keratohyalin.
Mmitochondria, thick
arrow tonofilaments
bundle, thin arrow single
tonofilament. As in the
whole epidermis,
desmosomes bind cells at
their tonofilaments bundles.
Phosphate buffered
glutaraldehyde and osmium
after fixation. Uranyl
acetate and lead citrate
staining. 30,000
Epidermal Physiology 5

action of the cytokine on the same keratinocyte
(Maruyama et al. 1995). Structural proteins (hepa-
rin, decorin, etc.) or cellular environment such as
interaction with fibroblastic cells (Boxman
et al. 1996) or with a structure like the skin immune
system (Bos and Kapsenberg 1993) modulates the
effect of these factors (Figs. 2,3,and4).
Other proteins secreted by the epidermis are
regularly identified. Katz and Taichman (Katz and
Taichman 1999) listed a catalogue of twenty pro-
teins released by keratinocytes in culture,
suggesting new physiological functions to be
identified. These proteins may induce various cel-
lular responses. Among these, the phospholipase
A2 was suggested to play a role in the mainte-
nance of tissue integrity (Mazereeuw Hautier
et al. 2000) and regeneration (Rys-Sikora
et al. 2000). The multifunctional peptide
adrenomedullin is involved in epithelial homeo-
stasis or even in epidermal protection (Martinez
et al. 1997). Many proteins, such as proteases
(Katz and Taichman 1999) or antileukopro-
teinases (Wiedow et al. 1998), have been shown
to be involved in matrix remodeling.
Keratinocytes produce the basement membrane
laminin 332 and modulate fibroblast behavior
through the secretion of β1G-H3 (Katz and
Taichman 1999).
2.2 Endocrine Secretion
In normal conditions, epidermis can also be a
source of circulating compounds that have effects
at distant sites in the body. The role of epidermis
in vitamin D synthesis has been early shown
(Holick 1988). Keratinocytes also release
chemicals like triiodothyronine (Kaplan
et al. 1988) or parathyroid hormone-related pro-
teins (Insogna et al. 1988; Jensen et al. 1999;
Kaplan et al. 1988; Katz and Taichman 1994,
1999; Kaur and Li 2000; Krueger et al. 1994;
Kupper 1990; Levy et al. 2000; Malaviya
et al. 1996; Martinez et al. 1997; Maruyama
et al. 1995; Mazereeuw Hautier et al. 2000;
Michel et al. 1996; Nathan and Sporn 1991; Oda
et al. 1999; Reinartz et al. 1996; Rys-Sikora
et al. 2000; Schauer et al. 1994; Shimizu
et al. 1997; Schröder 1995; Stoof et al. 1994;
Watt and Hogan 2000; Wiedow et al. 1998;
Wysolmerski and Stewart 1998), endothelin, and
the C3 complement component. Neuropeptides
such as substance P (Bae et al. 1999) and neuro-
hormones such as proopiomelanocortin and
derived peptides αMSH and ACTH (Schauer
et al. 1994) are produced by epidermal cells. The
generation of nitric oxide (Deliconstantinos
et al. 1995; Eming et al. 1998; Fenjves
et al. 1989; Heenen and Galand 1997; Holick
1988; Insogna et al. 1988; Jensen et al. 1999;
Kaplan et al. 1988; Katz and Taichman 1994,
1999; Kaur and Li 2000; Krueger et al. 1994;
Kupper 1990; Levy et al. 2000; Malaviya
et al. 1996; Martinez et al. 1997; Maruyama
et al. 1995; Mazereeuw Hautier et al. 2000;
Michel et al. 1996; Nathan and Sporn 1991; Oda
et al. 1999; Reinartz et al. 1996; Rys-Sikora
et al. 2000; Schauer et al. 1994; Shimizu
et al. 1997) or histamine (Malaviya et al. 1996)
has been also confirmed, showing the role of
stimulated epidermis in inflammatory reactions.
The systemic distribution of naturally produced
protein has been found even after epidermal trans-
plantation, as proved for apolipoprotein E
(Fenjves et al. 1989). These results may permit
the use of keratinocytes for gene therapy (Eming
et al. 1998; Fenjves et al. 1989; Heenen and
Galand 1997; Holick 1988; Insogna et al. 1988;
Jensen et al. 1999; Kaplan et al. 1988; Katz and
Taichman 1994; Katz and Taichman 1999; Kaur
and Li 2000; Krueger et al. 1994).
Keratinocytes can synthesize acetylcholine
and its receptors and thereby generate an auto-
crine system, which has been shown to regulate
cell motility. Besides, the epidermis has the ability
to generate catecholamine mediators including
epinephrine. These catecholamines can activate
adrenergic receptors present on keratinocytes to
modulate their migratory behavior.
2.3 Other Roles
Afine balance between cell proliferation
and differentiation maintains the barrier
function of the epidermis. In quiescent tissue,
6 P. Rousselle et al.

homeostasis is regulated by both autocrine and
paracrine secretions. After stimulation, these
secretions are amplified, and the epidermis acts
as a transducer, transforming exogenous stimu-
lations into specific immune or inflammatory
responses.
Human keratinocytes play an important role
in the innate immune response and produce sev-
eral antibacterial peptides that are important for
both homeostatic and wound healing purposes.
Human keratinocytes are known to produce four
such peptides: human beta defensin 1 (hBD-1),
hBD-2, hBD-3, and hCAP-18 (as well as its
biologic active proteolytic product LL-37)
(Harder et al. 1997; Nizet et al. 2001). hCAP-
18 is a member of the cathelicidin family of
antimicrobials. Both hCAP-18 and LL-37 are
expressed and released in response to an inflam-
matory stimulus (Ong et al. 2002). The
cathelicidin hCAP-18 is normally processed
and stored in the lamellar bodies of the
keratinocytes and may be released as a result of
injury or exposure to microbial components.
After secretion, hCAP-18 is processed into
LL-37 and various other peptides, which are
important in killing the skin pathogens
S. aureus and C. albicans. They might have a
major role in epithelium protection during
wound healing (Dorschner et al. 2001) and pso-
riasis (Ong et al. 2002). In atopic dermatitis, the
heavy carriage of S. aureus and the increased
sensitivity to herpes and M. contagiosum infec-
tion may be related to a lower expression of both
peptides, due to the production of IL-4 and IL-13
cytokines by Th2-T4 lymphocytes (Ong
et al. 2002).Epidermisisalsoactivebyaninten-
sive release of other peptides during wound
healing. Beta-defensin-2 and LL-37 are
upregulated in the epidermis of wounded
human skin within 24 h of wounding, reaching
highest levels at 48 h post-wounding and
returning to basal levels when the wound is
re-epithelialized.
Glossary
ACTH Adrenocorticotrophic hormone
Autocrine Peptides (cytokine, extracellular
matrix components, epidermal proteins etc.)
are released but bind immediately to receptors
and act on the cell that produced them.
Contra IL-1 Contra interleukin 1
Endocrine Peptides, synthesized by the
keratinocytes, enter the circulation and induce
specific biologic responses in distant target
tissues.
Exocrine Release of secretion toward the exter-
nal part of the body. Glandular epithelia (seba-
ceous and sweat) of the skin are specialized for
this function.
FGF Fibroblast growth factor. Either acid FGF
or basic FGF
GCSF Granulocyte colony-stimulating factor
GMCSF Granulocyte-/macrophage-stimulating
factor
Homeostasis Maintenance of the organism’s
physiological parameters at their normal value
huGRO Human growth factor
IL Interleukin: IL-1α, interleukin 1α;IL-1β,
interleukin 1 β; IL-1ra, interleukin 1 receptor
antagonist; IL-6, interleukin 6
IFNγ-IP10 Interferon gamma-induced protein
Juxtacrine Peptides are released and will act on
cells in contact with the producing cell.
KGF Keratinocyte growth factor
K LIF Keratinocyte-derived lymphocyte inhibi-
tory factor
MCAF Monocyte chemotactic and activating
factor
MCSF Macrophage colony-stimulating factor
MSH Melanocyte-stimulating hormone
NGF Nerve growth factor
Paracrine Peptides are released by a cell and
will act on cells immediately surrounding the
producing cell.
PDGF Platelet-derived growth factor
TGFαTransforming growth factor alpha
TGFβ1Transforming growth factor beta1
TNFαTumor necrosis factor alpha
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