Abstract: forming a dense myelin sheath around the

Abstract:

Multiple sclerosis
(MS) is a chronic, inflammatory, demyelinating disease of the central nervous
system, whose etiology remains unknown. MS destroys oligodendrocytes, which are
the cells responsible for creating and maintaining the myelin sheath, which helps
the neurons carry electrical signals. This work aimed to evaluate the treatment
of experimentally induced MS in dogs using laser activated non expanded adipose
derived stem cells. Twenty-four animals were used in study divided. All animals
received intraspinal injection of 20 µl of 0.1 % Ethidium bromide in the
lateral columns using a microneedle syringe attached to a capillary tube
through a drilled hole at the first lumbar vertebra. Treatment using prepared Stem
cell preparation was applied by injection of (10 X106 nucleated
cells) directly in the CSF at the day 14 from the induction of the MS. Results
showed showed amelioration of the clinical signs over time confirmed by the
resolution of the previous lesions on MRI. The electron microscopy showed the
remyelination sequence till forming a dense myelin sheath around the axons. From
the forementioned results we concluded that treatment using laser activated
stem cells holds a promising therapeutic option for treatment of MS.

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Keywords:

Multiple sclerosis;
demyelination; spinal cord; Dog model; Adipose derived stem cells; low level
Laser irradiation.

 

 

 

 

 

 

 

 

Introduction:

Multiple sclerosis
(MS) is a chronic, inflammatory, demyelinating disease of the central nervous
system (CNS), whose etiology remains unknown. MS is characterized by the
presence, within the CNS, of patchy demyelination and axonal loss (1), causing numerous physical and
mental symptoms, and often progresses to physical and cognitive disability (2). MS affects the areas of the brain
and spinal cord known as the white matter. Specifically, MS destroys
oligodendrocytes, which are the cells responsible for creating and maintaining
the myelin sheath, which helps the neurons carry electrical signals. MS results
in a thinning or complete loss of myelin and, less frequently, transection of
axons (3) causing paralysis of the limbs,
sensation, visual and sphincter problems.

 

The
precise cause of MS is unknown, but the current evidence suggests that it can be
linked to both genetic predisposition and environmental factors. Damage to this
myelin sheath protecting the nerve cells in the brain and spinal cord leads to
retardation, distortion, or loss of messages from the brain and presents as a relapse
of neurological disability, a flare-up of symptoms lasting anywhere from 24
hours to several months (3). Damage or destruction of these
important axons (nerve fibers) over time can also lead to irreversible
neurodegeneration, causing progression of the disease and an increase in
disability(4).

 

Unfortunately,
there is no cure for MS and current remedies only help in alleviating the
symptoms and halting the immune attack (5). But Stem cell
therapies offers a new hope for treatment of such neurological diseases, as
stem cells was efficiently proven to differentiate effectively into
oligodendrocytes and astrocytes in vitro and in vivo (6) and secretes
neurotrophic factors having immunomodulatory effects preventing further damage
and creating a regenerative microenvironment for remyelination (7). Based on
these results, several small pilot clinical trials in subjects with advanced MS
have demonstrated that Mesenchymal Stem Cells (MSCs) administration is safe and
provided an early signal of clinical effectiveness (8).

Adipose
Derived Stem Cells (ADSCs) is a population of MSCs which have a much higher
frequency in the adipose tissue than in bone marrow (approximately 500-fold
more). Moreover, ADSCs can be harvested by minimally invasive procedures that
should facilitate their use in cell transplantation (9). These cells
are capable to differentiate to other cells outside their lineage, such as
neural progenitors and oligodendrocytes. Many of the neurotrophic factors have
been identified as secretome of ADSCs (10). Therefore,
ADSCs transplantation can induce nerve repair and provide a practical way for
remyelination in neurodegenerative diseases.

In
order to maximize the cellular proliferation efficiency of ADSCs, low level
laser irradiation was used to activate the cells. Laser irradiation at
different intensities has been recognized to inhibit and/or stimulate cellular
processes. Recent findings suggest that at the cellular level, laser energy of a
particular wavelength can initiate signaling cascades, such as those that
promote cellular proliferation (11).

Recently,
successful cell transplantation and important experimental results proposed
considerable therapeutic potential of Adipose Derived Stem Cells (ADSCs) for
cellular replacement in MS. The results of previous studies suggested that
ADSCs may be an ideal cell source for regenerative cure because can ameliorate
the neuropathological signs and improve motor function in experimental models
of MS (12). Other findings confirm that these
cells may promote remyelination process by either differentiation into mature
oligodendrocyte or indirectly by promoting the survival of endogenous precursor
cells via production of neurotrophic factors (13). Also reported that ADSCs
trans-differentiation into a Schwann cells phenotype cells and transplantation
in a rat model of chronic denervation, enhanced nerve regeneration and motor
functional recovery through promoting remyelination process (14). Other studies results
demonstrated that ADSCs administration into Experimental Autoimmune  Encephalomyelitis (EAE) model of MS can
greatly reduce attack immune cells into the CNS and ameliorate severity of
clinical scores due to their immunomodulative and neuroprotective effects (15,16). It has been reported that
transplantation of ADSCs can play a significant role in tissue repair processes
through migration to the lesion areas and suppression of inflammatory responses
in chronic progressive and relapsing remitting EAE models of MS (17).

 

The stromal vascular fraction (SVF) of adipose tissue is known to
contain MSC, T regulatory cells, endothelial precursor cells, preadipocytes, as
well as anti -inflammatory M2 macrophages. Safety of autologous adipose tissue
implantation is supported by extensive use of this procedure in cosmetic
surgery, as well as by ongoing studies using in vitro expanded adipose derived
MSC and its uses in Equine and Canine studies showed promising regenerative
effects. SVF can be used as a rapid safe autologous therapeutic modality for
clinical regenerative medicine without the further need for culture, expansion
of pure MSC offering an early interference avoiding the progressive damage of
the disease which is required in neurological diseases.

 

This work aimed to evaluate the
transplantation of non-expanded Laser activated Adipose derived SVF in a Dog
Model of Toxin induced MS.

 

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