J Ayub Med Coll Abbottabad 2002; 14(1) pp 30-33
CELLS: LEADER OF NERVENKITT
Muhammad Mirajullah and Shen Xinya*
of Anatomy, Ayub Medical College, Abbottabad, Pakistan & *Shanghai Medical
University, P.R. China
cells (SC) are the major & only glial cell element of peripheral nervous
system (PNS) which by virtue of their unique biological activities give the
distinction of regeneration not only to the peripheral nervous system (PNS)
but also induce regeneration in the central nervous system (CNS) by changing
the hostile & inhospitable environments around its neurons to neurite
promoting favourable conditions. These multifunctional cells synthesize,
secrete & express many neurotrophic, neurotropic, neurite promoting &
growth factors, major myelin glycoproteins, cell adhesive molecules (CAMs),
basement membrane components as well as a cornucopia of receptors at various
stages of life. Their important role in neural tissue development,
organization & maintenance cannot overshadow their emerging vital
contributions to the ongoing studies on demyelinating diseases (e.g. multiple
sclerosis) & other debilitating and disfiguring neurological defects
(e.g. neurofibromatosis). Underlying SC defects may be responsible for
abnormalities in peripheral neuropathies. SC are the primary cells in the
disfiguring disease of neurofibromatosis as well as shoulder the
responsibility for Schwannoma & Neurilemoma tumours. Their versatility is
evidenced by their phagocytic nature during Wallerian & traumatic
degeneration. They are indispensable to the normal functioning of axons.
Inhibiting their proliferation at the stage of regeneration not only retards
axonal growth but profoundly impairs myelination. Their proliferation &
physical presence is a prerequisite for the reparative process providing a
proper terrain or scaffolding essential for the regeneration & survival of
the last more than one and a half century, since the recognition of SC in 1839
through the monumental work of the great German anatomist Theodor Schwann1,
tremendous work has been done to reveal the potential biological functions of
the SC, but perhaps much more is left for the bicentennial celebrations of the
cell. The story dates back to Theodor Schwann's attempts to study the cellular
nature of living organisms & his claim that the fatty sheath of the
peripheral nerve had a cellular nature & was not an amorphous entity.
Although invention of the Electron Microscope settled the controversy in
favour of SC but it opened a new era of conflicting findings, which will
continue to keep the 21st century investigators sweating well into the near
the pioneering work of in vitro nervous tissue culture by Harrison (1906) and others, many
investigators cultured a variety of tissues & cells2.
It was in the middle of this century, among attempts by various laboratories
to study the morphological & intracellular aspects, based on the ingenious
work of Murray & Stout3
who cultured the non-neuronal cells of adult & embryonic human peripheral
nerves, that the miraculous nature of the Schwann cells came into the
Owing to the development of these cell culture techniques, SC have been isolated from many sources: human, rodent, reptile and avian; adult, young, neonate, fetus and embryo; fresh, cryopreserved and autopsy material. Despite distinct morphological features, SC have a long list of immunocytochemical markers to their credit as well.
great versatility of SC reaction to nerve injuries4
is suggestive of the fact that these cells make significant, vital, decisive
& multifaceted contributions to the recovery & restoration of
functions of injured axons. Although the question whether the SC are the
leaders or the followers during nerve regeneration is still un-resolved5-7
but looking at the evidences provided by many excellent studies, the balance
seems to be tilting in favour of the former role 8. Viable SC are
now proved to be a prerequisite for successful regeneration to occur in the
nervous system by providing the trophic support for regrowing axons &
establishing a regenerative milieu9-11.
It has been reported that freeze dried acellular nerve grafts do not engender
& inhibiting SC co-migration with regenerating peripheral nerve axons into
an acellular graft significantly impedes neurite out-growth12.
Peripheral nerves & Retinal Ganglion Cells do extend neurites for some
distance into peripheral nerve grafts devoid of SC but far less than in the
presence of SC10,12.
It has also been reported that preventing SC proliferation during regeneration
retards the nerve regenerative capacity. The large number of SC (transplanted
or proliferated by trauma) & their advantageous position, as well as their
ability to present their own surfaces, basal lamina & multiple secretory
activity count for their extraordinary ability to foster axonal resurgence in
an effective manner9.
addition to its regenerative potential for PNS, SC when transplanted into CNS
in the form of isolated cultured cells or as
peripheral nerve grafts, induce the potentially capable CNS axons to
regenerate by converting the unfriendly & iniquitous cellular milieu13,14
of CNS (presence of oilgodendrocytes, astrocytes, CNS myelin, TN, lack of
basal lamina components & other neurotrophic & neurotropic factors)
into a regenerative favouring microenvironment4,
have the remarkable capacity to induce regeneration in the PNS as well as in
the CNS when they are transplanted as isolated purified cells suspension, as a
spreadsheet on collagen rolls, as a heterogenous cell population, in the form
of a nerve segment, or even SC conditioned medium. SC influence the
regenerating neurites in more than one way.
They have been reported to function as the presidential motorcade for
the resurging neurites to make the pathway by their proteolytic &
susbstratum carpeting actions. Many of the neurotrophic substances have been
reported to direct the axonal regrowth by targetting receptor sites on neurite
of the close relationship between functional status or type & their
the SC in whatever form they are presented, induce pronounced neurite
outgrowth. The Wallerian degeneration within hours reprograms the traumatic
site for axonal regeneration by stimulation of rapid proliferation of SC21
(probably macrophage mediated); migration of SC from both stumps
(predominantly proximal); preferential axonal growth along interfaces of basal
lamina (BL) & SC surfaces; and reexpression of CAMs8,22,23
(L1, N-CAM) & Extracellular Matrix Molecules [Laminin
(LMN) & Tennacin (TN) accumulated at axon SC contact surfaces] by
upregulating their mRNA. Antibodies against L1significantly inhibits this
growth. Re-expression of CAMs has
been indicated as the primary factor behind the significant post-transection
regeneration. These events are further added to by increases in production of
NGF & other NTFs24.
BL tubes, in absence of SC, can support nerve regeneration25
but not as effectively as in the presence of SC. SC also respond to trauma by
changing their phenotype26
thereby aiding to turn the degenerating nerve segment into an environment that
would support regeneration of neurons; nonetheless the phagocytic role for SC
has been reported long before in many animals.
synthesize some of the most important Neurotrophic Factors (NTFs) & Growth
Factors (GFs) like Nerve Growth Factor, Brain Derived Neurotrophic Factor,
Ciliary Neurotrophic Factor, Fibroblast Growth Factor,
Growth Factor, and Platelet Derived Growth Factor27-30,
reexpress a galaxy of receptors for many NTFs, Neurite Promoting Factors (NPFs)
elaborate Cell Adhesive Molecules (CAMs)4;
and synthesize, secrete & assemble basal membrane (BM) components9,18
The neurotrophic requirements for cells (motor, sensory & sympathetic)
contributing to the formation of peripheral nerves differ among them but SC
& only the SC produce all these factors to effectively help regenerate the
peripheral nerve axons34.
The SC conditioned extracellular fluid has been reported to stimulate SC
proliferation, adhesion & migration5,35.
Recently a novel NPA has been reported34,
not particular for any class of neuron, in the SC from adult rat Sciatic Nerve
& immortal SC clone which is not related to all of the previously known
NTFs/NPFs, indicating a new cytokine or a novel NTF or combinatorial effect of
the known NTFs. Leaving aside the NTFs, GFs, NPFs, CAMs, & BL components,
they present perhaps the most abundant receptor sites on their surfaces. They
synthesize Growth Associated Protein (GAP)36,
express c-met mRNA37,
Glia Fibrillary Associated Protein (GFAP) & myelin proteins38,
fact, SC neurite regenerating potentials have unjustifiably overshadowed their
other so many unique & singular contributions to the development of the
nervous system, its regeneration, reorganization & proper coordinated
functioning. They have automitogenic activity44,45
in long term cultures, while autoinhibitory action in short term cultures46,47.
They are extensively involved in neurite directionality. The range of their
fostering neurotrophic activities involves a wide range of cells including
dopaminergic neurons, sensory, motor (both PNS & CNS) & sympathetic
They are indispensable for the
proper functions of rapid axonal conduction, axonal protection, maintenance
& formation of myelin, remyelination of injured PNS as well as CNS axons49,
regulation of axoplasmic flow & metabolic activities. The myelin sheath,
in addition to its insulating & conduction facilitating actions, is
closely related to the molecular exchanges between axon & extracellular
one looks at the unbelievable synthesizing & expressing potentials of the
SC, it leaves little doubt about their versatile functions. Also worth
mentioning is their changing scenario of functional activities under different
conditions. They promptly change their expressing activities & phenotypic
characteristics at different stages of life as & when required.
other glial (astrocytes) & non-glial (macrophages) cells, reportedly play
roles in the regenerative process but neither of them as well as none of the
other glial cells can snatch the credit which for almost a century belongs to
SC & would remain to give the distinction to them in the future50.
None of the other glial cells have ever attempted to interfere in the domain
of SC. These are the daring efforts of the SC which have effectively &
successfully encroached upon the CNS boundaries by challenging the hostile
resident cues. SC deserve to be crowned as the true candidate for leading the
team of glia.
at the efforts on SC transplantation & their evaluation to determine the
extent of SC as a therapeutic tool, for alleviating the impoverishing miseries
caused by the nervous system injuries or certain incurable diseases with
unknown aetiology, it does not seem too distant that the SC would one day
assume the role of an established therapeutic agent for incapacitating &
paralyzing disabilities. We should join our hands to bring that day
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