Cell Science at a Glance

391

The hair cycle

phase, follicles produce an entire hair

shaft from tip to root; during catagen
and telogen, follicles reset and prepare
their stem cells so that they can receive
the signal to start the next growth phase
and make the new hair shaft. The hair
cycle represents a remarkable model for
studies of the regulation of stem cell
quiescence and activation, as well as
transit-amplifying cell proliferation,
cell-fate choice, differentiation and
apoptosis in a regenerative adult
epithelial tissue. Here we summarize the
major events of the hair cycle, and touch
on known regulators of the transitions.
Detailed reviews of the hair cycle and its
regulation can be found elsewhere
(Lavker et al., 2003; Millar, 2002;
Muller-Rover et al., 2001).

Laura Alonso and

Elaine Fuchs2,*
1

Department of Medicine, Division of

Endocrinology, University of Pittsburgh, 200 Lothrop
Street, Pittsburgh, PA 15261, USA
2
Howard Hughes Medical Institute, Laboratory of
Mammalian Cell Biology and Development, The
Rockefeller University, 1230 York Avenue, New
York, NY 10021, USA
*Author for correspondence
(e-mail: fuchslb@rockefeller.edu)
Journal of Cell Science 119, 391-393
Published by The Company of Biologists 2006
doi:10.1242/jcs02793

Journal of Cell Science

The hair coat, which keeps most

mammals warm, dry and protected from
harmful elements, requires a constant
supply of new hairs throughout the
lifetime of the animal. To produce new
hairs, existing follicles undergo cycles
of growth (anagen), regression (catagen)
and rest (telogen). During each anagen

single layer of epidermal stem cells.

Soon after, as mesenchymal cells
populate the skin to form the
underlying
collagenous
dermis,
morphogenesis of the hair follicle
begins (Schmidt-Ullrich and Paus,
2005). Specialized dermal cells
organize in small clusters directly
beneath
the
epidermal
layer,
stimulating the overlying epithelial
stem cells to grow downward and
produce a hair follicle. The follicle is
contiguous with the epithelium; both
are separated from the dermis by
a basement membrane rich in
extracellular matrix and growth factors
synthesized and deposited largely but
not solely by epithelial cells. As the
follicle grows down, it assumes the
shape of a rod several cell diameters
wide. The inner layers begin to
differentiate into concentric cylinders
to form the central hair shaft (HS)

Morphogenesis
In the embryo, the skin begins as a

Abbreviations

Catagen

Anagen-to-catagen
transition

Regression phase
Extensive apoptosis
Differentiation ceases
Hair club formed
DP remains in contact
with epithelium

Proliferation ceases
Apoptosis begins in bulb/ORS
Differentiation slows

jcs.biologists.org

Bulge stem cell niche

Anagen

Forming
HS club

HS growth phase
Rapid proliferation in bulb
HS/IRS differentiation
IRS degrades in infundibulum
Duration of anagen
determines length of HS
Sensitive to chemotherapy

Apoptosis
Epithelial strand
DP

SGK3
p53

Catagen-to-telogen
transition
Club hair anchored
Apoptosis ceases
DP reaches stem cell niche
Follicle becomes quiescent

TGF
EGF
FGF5

Telogen

Interfollicular
epidermis

Sebaceous
gland

Epithelial lineages
ORS
CCL

IRS

Henley
Huxley
Cuticle

Bulge
stem cell
niche

HS

Cuticle
Cortex
Medulla

DP
Dividing cells
Matrix

ene

BMP

DP

TGF

Exogen

IRS

Differentiating
cells

M orp h o g

Bulge stem
cell niche

Club hair loss

(may not occur each
hair cycle)

HS

Bulb

Resting phase
No significant proliferation,
apoptosis or differentiation
DP near stem cells

HS club

Infundibulum

Telogen-to-anagen transition
Stem cells activated
Cells near DP proliferate
Formation of new hair bulb
IRS/HS differentiation begins after bulb formed

sis

The Hair Cycle

Laura Alonso and Elaine Fuchs

Journal of Cell Science 2006 (119, pp. 391-393)

(See poster insert)

392

Journal of Cell Science 119 (3)

Journal of Cell Science

and the surrounding channel, the inner

root sheath (IRS). An inductive
mesenchymal cluster called the dermal
papilla (DP) becomes a permanent part
of the follicle base (Jahoda et al., 1984;
Kishimoto et al., 2000). It travels
with the epithelial downgrowth and
becomes enveloped by the hair bulb.
The follicle becomes fully mature as its
bulb nears the bottom of the dermis. At
this point (in mouse back skin around
postnatal day 6 or P6), the proliferative
cells (matrix) at the follicle base
continue to divide, producing progeny
cells that terminally differentiate to
form the growing hair that exits the skin
surface.
Anagen
Histologically, anagen follicles are long
and very straight, but the follicles are
angled to permit the hair coat to lie
flat along the body surface. The
proliferating matrix cells have a cellcycle length of approximately 18 hours
(Lavker et al., 2003). Daughter cells
move upwards, adopting one of six
lineages of the IRS and HS; from
outermost to innermost, the layers
include Henley, Huxley and cuticle
layers of the IRS, and the cuticle, cortex
and medulla layers of the HS. As HS
cells terminally differentiate, they
extrude their organelles and become
tightly packed with bundles of 10-nm
filaments assembled from cysteine-rich
hair keratins, which become physically
cross-linked to give the hair shaft high
tensile strength and flexibility. The IRS
also keratinizes so that it can rigidly
support and guide the hair shaft during
its differentiation process, but its dead
cells degenerate as they reach the upper
follicle, thereby releasing the HS that
continues through the skin surface. The
duration of anagen determines the
length of the hair and is dependent
upon continued proliferation and
differentiation of matrix cells at the
follicle base.
Anagen-to-catagen transition
The matrix cells are referred to as
transit-amplifying cells because they
undergo a limited number of cell
divisions before differentiating. As the
supply of matrix cells declines, HS and
IRS differentiation slow and the follicle
enters a destructive phase called

catagen. The timing of the first catagen

onset varies slightly between strains of
mice and varies significantly from one
skin region to another. In pigmented
mice, the progression of catagen is
evident from the color of the skin, which
changes from the dark gray to black of
anagen to pale pink by telogen. As with
morphogenesis, the first catagen begins
in a wave, spreading from the top of the
head caudally towards the tail and
laterally down the sides of the animal. In
back skin taken from the midline, the
onset of the first catagen ranges from
P14 at the upper back near the head to
P18 in the lower back near the tail.
Catagen lasts 3-4 days in mice.
Some molecular regulators of the
anagen-catagen transition have been
identified, although how they work
together to promote catagen or terminate
anagen is not yet understood. Molecules
that promote the transition to catagen
include the growth factors FGF5 and
EGF, neurotrophins such as BDNF and
possibly the p75-neurotrophin receptor,
p53 and TGF-family pathway
members such as TGF1 and the
BMPRIa (Andl et al., 2004; Foitzik et
al., 2000; Hansen et al., 1997; Hebert et
al., 1994; Schmidt-Ullrich and Paus,
2005). Factors known to maintain
anagen include SGK3 and Msx2
(Alonso et al., 2005; Ma et al., 2003).
Catagen
Catagen is the dynamic transition
between anagen and telogen (MullerRover et al., 2001). During catagen, the
lower cycling portion of each hair
follicle regresses entirely in a process
that includes apoptosis of epithelial cells
in the bulb and outer root sheath (ORS),
the outermost epithelial layer (Lindner
et al., 1997). HS differentiation ceases,
and the bottom of the HS seals off into
a rounded structure called a club, which
moves upward until it reaches the
permanent, non-cycling upper follicle,
where it remains anchored during
telogen. As the lower follicle recedes,
a temporary structure forms the
epithelial strand which is unique to
catagen. This connects the DP to the
upper part of the hair follicle, contains
many apoptotic cells and is completely
eliminated by the time the DP reaches
the cells that surround the remnant club
hair.

Telogen
Following catagen, follicles lie dormant
in a resting phase (telogen). In mice, the
first telogen is short, lasting only 1 or 2
days, from approximately P19 to P21 in
the mid back. The second telogen,
however, lasts more than 2 weeks,
beginning around P42.
The follicle stem cell
compartment
Although no new hair follicles are made
postnatally, the lower portion of the hair
follicle regenerates in order to produce
a new hair. For this purpose, and for
the maintenance of the epidermis
and sebaceous gland, reservoirs of
multipotent epithelial stem cells are set
aside during development. These
precious cells are found in the lowest
permanent portion of the hair follicle
the bulge (Oshima et al., 2001; Taylor
et al., 2000). Follicle stem cells are
activated at the telogen-to-anagen
transition, to initiate a new round of hair
growth.
Telogen-to-anagen transition
The transition from telogen to anagen
occurs when one or two quiescent stem
cells at the base of the telogen follicle,
near the DP, are activated to produce a
new hair shaft (Blanpain et al., 2004;
Tumbar et al., 2004). These cells now
begin to proliferate rapidly, and become
the transit-amplifying daughter cells that
are fated to form the new hair follicle.
The new follicle forms adjacent to the
old pocket that harbors the club hair,
which will eventually be shed (exogen).
This creates the bulge and adds a layer
to the stem cell reservoir. The new hair
emerges from the same upper orifice as
the old hair. In many ways, the telogento-anagen transition resembles the
activation of embryonic skin stem cells
that are stimulated to make the follicle de
novo. Signaling by Wnts (Gat et al.,
1998; Huelsken et al., 2001; Lo Celso et
al., 2004; Lowry et al., 2005; Van Mater
et al., 2003) and Shh (Callahan et al.,
2004; Mill et al., 2003; St-Jacques et al.,
1998) is indispensable for new anagen,
whereas Bmps (Botchkarev et al., 1999;
Kulessa et al., 2000) have been
implicated in follicle differentiation. The
molecular steps involved are likely to
hold clues to understanding the
activation and specification of stem cells.

Cell Science at a Glance

Journal of Cell Science

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