What interaction with the outside world. Below is

 

 

What is known about the
sensory innervation of the epidermis and the molecular factors that influence
it?

 

 

2088364

Supervised by
Professor Quondamatteo

BSc
Anatomy   BIOL4247P

 

 

 

Table of Contents

Abstract. 1
Abbreviations. 1
Introduction. 1
Structure and Function of the
Epidermis. 1
Molecular Factors Influencing
Innervation of the Epidermis. 4
Receptors. 4
Neurotrophic Factors. 4
Negative Guidance Cues. 4
Other Factors. 4
Discussion. 4
 

Abstract

Abbreviations

Introduction

Structure and Function of the Epidermis

 

The epidermis is a multi-layered
epithelium that covers the entire outer body. One of its main functions is to
protect the body from outside influences, and generate information about the
surrounding environment. This makes it one of the principal facilitators of
interaction with the outside world. Below is a summary of the structural and
functional aspects of the epidermis to provide context for the review of the
molecular factors that influence its growth, mapping, and density of its
innervation

 

Structure
of Epidermis

The epidermis is the most superficial layer of skin. It sits on
the basement membrane above the dermis. The epidermis has
no blood supply of its own and therefore relies on the dermis to exchange
nutrients and waste, which diffuse across the dermoepidermal junction. They both
rest on a fatty layer, the panniculus adiposus. The
epidermis is comprised of 4 or 5 strata (layers), each with its own functions
and distinctive structure (Akinduro O, 2016), from the most
superficial to deepest: stratum cornea, lucid, granulosum, spinosum, and
basale; as shown in figure 1 . Each layer is mainly made of keratinocytes, at
different stages of maturity.  The layers
of the epidermis are very much connected and work together as the cells from
the lower layers are pushed up until they reach the external layer, after which
they are shed, and are replaced by new keratinocytes. The deepest layers
called the Stratum Basale, sits on the basement membrane which is onto of the
dermis. The keratinocytes here are stem cells that will go on to pass through
each layer of the epidermis as they mature. The next layer is the stratum
spinosum. The stratum spinosum has a distinct “spiny” appearance. It is also
where keratinisation of the cells begins. Keratinocytes then migrate further
towards the surface of the skin, to the stratum granulosum. The outermost
layer, the Stratum Corneum, is a tough layer of dead fully differentiated
keratinocytes. It provides a relatively impermeable barrier to foreign
bacteria, mechanical insults and a barrier to water diffusion. These cells are
set in an intercellular lipid “mortar”, which is thought to be another contributor
to the waterproof property of the epidermis. 
This layer sheds regularly allowing damage to these dead cells, and
preventing damage to underlying tissues.

Functions of Epidermis

 

The epidermis facilitates sensory
perception and acts as a protective barrier from trauma, uv, and bacteria (Sung-Tsang Hsieh, 1997). It acts as
both an outside-in barrier, and an inside-out barrier. As an inside-out barrier
its waterproof properties prevent the dehydration of underlying tissues. The
outside-in barrier protects underlying tissues, with the continuous renewal of keratinocytes
allowing minor damage to the exterior body at very little biological cost. It
also provides other functions, facilitated by the different cell types found in
the epidermis: melanocytes, Langerhans cells, and merkel cells. Melanocytes aid
in protection from UV radiation by the production melanin, which absorbs the UV
preventing damage to the tissues. Langerhans cells are used to protect against
foreign antigens (Chu Cheng, 2010), and Merkel cells aid in sensory
perception.

Sensory
Function of Epidermis

Being the most superficial layer of
the skin means that the epidermis is often the bodies’ first point of contact
with external environment. Sensory perception is carried out by the
sensory nerve fibres that innervate the epidermis. The epidermis
contains receptors
that can detect stimuli such as pain, heat, and pressure; this provides
protective information generated by external stimuli to protect the body from
harm (David M Owens, 2014). When a stimulus
reaches its threshold, a point where tissue damage is possible, the receptors
fire, sending information on the sensation to the CNS. This helps to
make sense of the surrounding world, by giving the brain information on size,
texture, and shape of objects.

 

Innervation
of Epidermis

It was once believed that the
epidermis did not contain any nerve fibres (Kennedy, 1992). In a review of cutaneous innervation
from 1976 it was stated that nerve fibres that penetrate the epidermis are very
rarely, if ever, present (Bourlond, 1976). For most of the 20th
century, imaging techniques were not able to photograph the nerves of the
epidermis as they are unmyelinated. Advances in immunohistochemical techniques,
especially the discovery of an antibody that made it possible to stain
unmyelinated nerve fibres (Sung-Tsang Hsieh, 1997) ,made it possible to
view previously invisible nerve fibres of the epidermis, although their
existence had been theorised by some (Kennedy, 1992). New imaging techniques showed that
these fibres, known as intraepidermal nerve fibres (IENFs) terminate in free
nerve endings, or at specialised keratinocytes, called Merkel cells, in the
stratum basale.

Merkel cells are specialised
keratinocytes of the stratum basale that detect light touch. Their fibres
extend into the dermis where the join together to travel to the CNS. They
detect light touch, and when stimulated internal vesicles excrete neuropeptides,
which over time will attach to a neuropeptide receptor within the cell and
cause ion channels to open. The opening of the ion channels allows Na+ to enter
the Merkel cell, then the afferent nerve fibre, which creates the action
potential to communicate with the CNS.

Neurophysiologically, the epidermal
nerve fibres are either A? or C fibres (Sung-Tsang Hsieh, 1997). The first
difference between these two fibres is myelination. Myelination is the
phospholipid wrapping around axons by schwann cells, which provides insulation
and a guide for regrowth. A? fibres are myelinated whereas C fibres are not,
however any myelination is lost at the dermoepidermal junction, passing through
the basement membrane (A Oakland, 2005) (Andrea Truini, 2015). The
biochemical mechanism that results in this is not well known. This insulation
means the A? fibres have higher velocity conductivity than C fibres, which
attributes to their distinct functions. A? fibres sense sharp pain associated
with the reflex arch (i.e. pulling hand away from source of pain), and C fibres
react to slower, deeper pain.

C fibres lack the myelination of the
A? fibres, but still have Schwann cells, which hold the fibres in bundles while
prevent them from touching each other (Murinson BB1, 2004).

Both A delta and C fibres follow the spinothalamic
tract. This pathway is the principal pathway for pain and temperature
perception. The
specific chain of action potentials produced convey extra information about the
stimulus.

Recently, it has been demonstrated that the nerves of
the epidermis do not only convey information about stimuli, but are much more
interactive with the keratinocytes and other cells of the epidermis. It has
been found that the stimulation of keratinocytes can impact activation of the
surrounding nerve fibres (Lumpkin EA, 2007). Even though no synaptic contact has
been found, there appears to be a mechanism signally intercellularly in the
epidermis. They have also been found to be direct and indirect targets for
neurotropins and are thought to aid in the homeostatic control of the
epidermis. If keratinocytes play a part in transmission of sensations, such as
pain and temperature, this could contribute to seemingly unexplained
transmission of pain, such as in sensory neuropathy.  

Sensory neuropathy is when the
activation of nociceptors is distorted from normal, for example feeling intense
pain at the lightest touch, or pain being sensed with no distinct cause. Sensory
neuropathy can be idiopathic, or caused by diseases such as diabetes mellitus,
but also caused by lesions and peripheral nerve injury. It is thought that the
activation threshold of the receptors may be lowered, causing hyperactivity.
The nerve endings of the epidermis can be damaged, causing other dysfunction
such as excess itching and a lack of sensation, but remarkable regeneration
abilities appear to be present. (Jeffrey P. Rasmussen, 2015). If this ability to
repair and regenerate can be manipulated, it may lead to treatments of sensory
neuropathy, as well as understand better how to prevent it.

However, much of this knowledge is
gained from animal studies presumed to apply in the same way to humans (Kennedy, 1992).  For ethical reasons, it has been difficult to
perform studies in humans. There is an inherent difficulty in studying this
topic as only in the last 20 years or so with new imaging techniques have
allowed the demonstration of unmyelinated neurons, which were often over looked
in old staining techniques (Sung-Tsang Hsieh, 1997). 

Molecular Factors Influencing Innervation of
the Epidermis

During development, the mapping of nerve terminals in the epidermis is
dictated by molecular factors. These factors dictate the growth of the fibre
and the degree of axon branching. Growth and branching varies across the body,
creating areas of different densities, which accounts for the variation in skin
sensitivity. The density of the different types of nerve endings varies across
different areas of the body according to the function of the epidermis in that
area.  It is not well understood how the
nerves of the epidermis are “mapped” and how they achieve differentiation (Shan
Lou, 2015). Less still is known about the mechanisms behind these effects
(Laura Mòdol, 2015). There are several known choice points for somatosensory
axon growth, these are known as growth cones (Fang Wang, 2013)

Factors that enhance growth and survival of the sensory nerve endings
are called neurotrophic factors.  They
are not only present during development, but maintain sensory neurons
throughout life. An imbalance in these factors may contribute to sensory
neuropathy as damaged nerve may not be able to repair, and receptor threshold
levels may change because of this.

Finally, variation in epidermal sensitivity is the result of the varied
innervation of the epidermis. This would seem to be the result of interactions
between the molecular factors and the area specific secretion patterns of these
factors. In order to design therapies for neuropathic conditions, the
mechanisms that control the growth and pattern of innervation must be fully
understood. This review aims to examine knowledge of the sensory innervation of
the epidermis, its influencing factors, and highlight the questions that remain
to be answered.?

In healthy development, neurotrophic factors ensure that the right number
of neurones survive for the target end organ. They control patterns of
innervation, dendrite pruning, and axon growth. Neurotrophic factors also
regulate the expression of vital proteins, like neurotransmitters and ion
channels. They continue to play a crucial role in the mature organism,
supporting neuronal survival and controlling synaptic function and plasticity
(Huang EJ, 2001).

Neurotrophic factors bind to one of two receptors: tyrosine kinase
A(TrkA) receptors and p75 neurotrophic receptors (p75NTR).  They are structurally different receptors;
trkA is a high affinity

The neurotrophic factor hypothesis suggests that there is a limited
quantity of neurotrophic factors, and nerve terminals compete for these. Cells
in the intended area produce these factors in accordance with the required
innervation. The factors are essential for survival; this mechanism of
competition may be there to limit nerve fibre density.  

?

 

Receptors

Neurotrophic Factors

Nerve
Growth Factor

Brain
Derived Neurotrophic Factor

Neurotrophin
– 3

Negative Guidance Cues

Semaphorin
3A

 

Other Factors

 

Discussion

To allow nerve fibres to travel the long distances from the
dorsal root ganglion to their target end organ, growth cones are navigated by
guidance cues. These guidance cues ensure the appropriate density of nerve
endings for an area, differentiation, as well as preventing self-crossing or
other malformations.

The role that these molecular
factors play in the mapping, differentiation of nerve fibres gives great
insight into the growth and maintenance of the nervous system. With knowledge
of the pathways and molecular factors, therapies for those with hyper or hypo
innervation may be found. It has been shown with neurotrophic factors that
therapies involving them can induce sensitisation of epidermal innervation.
Target organ tissues secrete neurotrophic factors to guide the nerve fibres to
their required area. They also control the degree of branching and
differentiation at the end organs. Other factors guide the dendrite on their
way through repulsion, either away from other dendrite to prevent self
crossing, or to prevent them from entering undesirable areas.

 

 

 

 

Acknowledgements