Download - Restorative neurology
الرحمن الله الرحمن بسم الله بسمالرحيمالرحيم
restorative neurologyEssay
Submitted of Partial Fulfillment of Master Degree In Neuropsychiatry
By
Samy Moussa Selim
Under Supervision of
Prof. Dr./ Mohamed Yasser Metwally Professor of Neuropsychiatrywww.yassermetwally.com
Prof. Dr./ Naglaa Mohamed El-Khayat Professor of Neuropsychiatry
Dr./ Haitham Hamdy Salem Lecturer of Neuropsychiatry
Faculty of MedicineAin Shams University
2011
Aim of The workAim of The work
To study and summarize recent progress in To study and summarize recent progress in stem cells therapies aimed at neuro-stem cells therapies aimed at neuro-degenerative disorders and illustrate how some degenerative disorders and illustrate how some of the aforementioned methods and strategies of the aforementioned methods and strategies are being utilized to formulate clinically valuable are being utilized to formulate clinically valuable treatmenttreatment
The stem cells are progenitor cells that The stem cells are progenitor cells that have the ability for generation and cell have the ability for generation and cell division & renewaldivision & renewal (Metwally, 2009)(Metwally, 2009)..
The stem cells are divided into two main typesThe stem cells are divided into two main types
Adult Stem CellsAdult Stem Cells Embryonic Stem CellsEmbryonic Stem Cells
Embryonic Stem Cells (ESCs) were Embryonic Stem Cells (ESCs) were
discovered by the early work of discovered by the early work of
Kleinsmith and Pierce (1964). Kleinsmith and Pierce (1964).
They are derived from the Inner Cell They are derived from the Inner Cell
Mass (ICM) of cultured blastocyst Mass (ICM) of cultured blastocyst
stage embryos stage embryos (Aoki et al., 2007)(Aoki et al., 2007)..
The blastocyst includes three The blastocyst includes three structures:structures:
TheThe TrophoblastTrophoblast, which is the layer of , which is the layer of cells that surrounds the blastocystcells that surrounds the blastocyst ..
TheThe BlastocoelBlastocoel, which is the hollow , which is the hollow cavity inside the blastocystcavity inside the blastocyst
TheThe Inner Cell MassInner Cell Mass, which is a group of , which is a group of approximately 30 cells at one end of the approximately 30 cells at one end of the Blastocoel Blastocoel (Avasthe et al., 2008).(Avasthe et al., 2008).
(ESCs) are either(ESCs) are eitherTotipotentTotipotent
(able to generate all cell types in an (able to generate all cell types in an organism exceptorganism except placentaplacenta((
PluripotentPluripotent (able to yield mature cell types from all (able to yield mature cell types from all
different germ layers)different germ layers) MultipotentMultipotent
(able to give rise to all cells within an organ). (able to give rise to all cells within an organ).
))ESCs) do not appear to undergo replicativeESCs) do not appear to undergo replicative senescence, and thus appear to be immortal senescence, and thus appear to be immortal in culturein culture (Svendsen and Ebert, 2008)(Svendsen and Ebert, 2008)..
Somatic stem cells are the building blocks of Somatic stem cells are the building blocks of
organorgan They are undifferentiated cells found They are undifferentiated cells found
among differentiated cells in an organ & can among differentiated cells in an organ & can
differentiate to maintain and repair the tissue in differentiate to maintain and repair the tissue in
which they are found which they are found (Joanna et al., 2009).(Joanna et al., 2009).
Hematopoetic stem cells ( HSCs)
Bone marrow stromal cells ( BMSC)
Neural stem cells( NSCs)
Hematopoietic stem cells (HSCs)Hematopoietic stem cells (HSCs)
HSCs are presented in umbilical cord blood. They HSCs are presented in umbilical cord blood. They
are capable of unlimited cell proliferation in bone are capable of unlimited cell proliferation in bone
marrow and must undergo at least 20 to 23 marrow and must undergo at least 20 to 23
divisions on their way to produce mature blood divisions on their way to produce mature blood
cells, even assuming no cell death along the cells, even assuming no cell death along the
way way (Emerson et al., 2008).(Emerson et al., 2008).
Bone marrow stromal cells (BMSC).Bone marrow stromal cells (BMSC). These cells were discovered by These cells were discovered by Friedenstein, et al. (1968) they can easily be Friedenstein, et al. (1968) they can easily be obtained following a simple bone marrow obtained following a simple bone marrow aspiration procedure. aspiration procedure.
They can give rise to a variety of cell types: They can give rise to a variety of cell types: Bone cells (Osteocytes), Cartilage cells Bone cells (Osteocytes), Cartilage cells (Chondrocytes), Fat cells (Adipocytes), and (Chondrocytes), Fat cells (Adipocytes), and other kinds of connective tissue cells such as other kinds of connective tissue cells such as
those in tendons those in tendons (Svendsen and Ebert, 2008).(Svendsen and Ebert, 2008).
Neural stem cells(NSCs).Neural stem cells(NSCs).
In the adult brain generation of new neurons from In the adult brain generation of new neurons from
neuronal stem and progenitor cells predominantly neuronal stem and progenitor cells predominantly
occurs in two brain regions:occurs in two brain regions:
The Subventricular Zone (SVZ) of the lateral The Subventricular Zone (SVZ) of the lateral
ventricle.ventricle.
The Subgranular zone of the dentate gyrus The Subgranular zone of the dentate gyrus (Song et (Song et
al., 2007).al., 2007).
Stem cells differ from other kinds of cells in the body. Stem cells differ from other kinds of cells in the body. All stem cells have three general properties regardless All stem cells have three general properties regardless
of their source: -of their source: -
1)1) They are capable of dividing and renewing They are capable of dividing and renewing themselves for longthemselves for long period.period.
2)2) They are unspecialized.They are unspecialized.
3)3) They can give rise to specialized cell types.They can give rise to specialized cell types.
(Caplan, (Caplan,
2011).2011).
Peripheral blood stem cells are collected by Peripheral blood stem cells are collected by
Aphaeresis, a process in which the stem cells are Aphaeresis, a process in which the stem cells are
collected from the peripheral blood. collected from the peripheral blood.
Mobilization, or priming, is the process used to Mobilization, or priming, is the process used to
stimulate the donor’s marrow to produce extra stem stimulate the donor’s marrow to produce extra stem
cells and release them into the peripheral blood. This cells and release them into the peripheral blood. This
is done by giving a growth factor called Colony is done by giving a growth factor called Colony
Stimulating Factor G (G-CSF). Stimulating Factor G (G-CSF).
The ideal number is 5–10 million stem cells per The ideal number is 5–10 million stem cells per
kilogram of the recipient’s weight per transplant kilogram of the recipient’s weight per transplant
dose dose (Emerson et al., 2008).(Emerson et al., 2008).
Parkinson disease, is a debilitating neurodegenerative
disorder characterized by the selective loss of nigrostriatal
dopaminergic neurons and loss of dopamine in the striatum
cell based therapies have been developed transplanting of
readily available cell sources, such as catecholominergic
adrenal medullary tissue into the striatum has limited
clinical benefits
A major advancement come with the use of fetal ventral
mesencephalic tissues as a cell source for transplantation.
ESCs may provide an optimal and unlimited source of
dopamine neurone for transplantation (Lane et al., 2008).
Stroke at present is the third leading cause of death and
the most common cause of serious adult disability in the
United States
The role of neural stem cells in stroke:
1) proliferation either symmetrical (2 stem cells) or
asymmetrical (1 stem or progenitor cell). A plethora of
growth factors are expressed by the ischemic tissue
may be responsible for neurgenesis;
2) migration ischemia induce the migration of
neuroblasts into the striatum and cerebral cortex
3) can be differentiated into neurons, astrocytes, and
oligodenderocytes (caplan, 2011).
In demylinating diseases as MS stem cells has two In demylinating diseases as MS stem cells has two
therapeutic approaches to induce remyelination: therapeutic approaches to induce remyelination:
Promotion of endogenous remyelination by growth Promotion of endogenous remyelination by growth
factors therapy.factors therapy.
Transplantation of myelin forming cells is a mode of Transplantation of myelin forming cells is a mode of
delivering the entire “cell factory” that manufactures delivering the entire “cell factory” that manufactures
myelin myelin (johnson, 2011).(johnson, 2011).
The concept of a cell based therapy in muscular The concept of a cell based therapy in muscular
dystrophies (MD) is to promote muscle dystrophies (MD) is to promote muscle
regeneration, particularly in recessive types of regeneration, particularly in recessive types of
MD, originated with the observation of the MD, originated with the observation of the
intrinsic ability of myofibers to fuse to each other intrinsic ability of myofibers to fuse to each other
(David, 2009).(David, 2009).
The aim of stem cell therapy in HD is the use of
growth factors or transplanted cells to protect
the neurons susceptible to disease and/or
death
stem cells release neuroprotective trophic factors
such as brain derived neurotrophic factor
(BDNF), ciliary neurotrophic factor (CNTF) and
glial cell line-derived neurotrophic factor
(GDNF) (Johann et al., 2007).
Amytrophic lateral sclerosis (ALS), also known as Lon
Ghring’s disease, is a progressive disease that manifests
as a gradual evolution and spread of weakness and
wasting of affected patient’s muscles. It leads to
disfunction, disability, and ultimately death or chronic
ventilator dependency
Stem cells could help patients with ALS by its differentiation
into lower motor neurons in order to replace those
neurons that die (Crosta, 2010).
Stem cell based gene therapy could deliver factors Stem cell based gene therapy could deliver factors
modifying the course of AD and may be modifying the course of AD and may be
advantageous because of the capacity of stem advantageous because of the capacity of stem
cells to migrate and reach large areas of the cells to migrate and reach large areas of the
brain. It counteracts cholinergic neuronal death, brain. It counteracts cholinergic neuronal death,
stimulate cell function and improve memory in stimulate cell function and improve memory in
animal models of ADanimal models of AD (Zhao et al., 2008). (Zhao et al., 2008).
In neuroretinal degenerative diseases There have been 2
general approaches to the transplantation of stem cell
or cell-derived cells to rescue the degenerating retina:
photoreceptor survival promoted by restoring the
supportive functions of retinal pigment epithelial cells
(RPECs),
directly replacing lost photoreceptors with transplanted
stem cells and retinal precursor cells (Svendsen and
Ebert, 2008).
Cerebral palsy is defined as a persistent disorder of
movement and posture caused by non-progressive defects
or lesions of the immature brain,
Umbilical cord derived stem cells have the ability to help
repair the entire system by:
1) stimulating angiogenesis;
2) repairing the white matter through production of glial cells
3)repairing of grey matter through the stimulation of growth
factors and neurogenesis;
4) dividing into new neurons;
5) strengthening of muscle tissue; and
6) improving immune function (Battler and Leor, 2006).
Autism spectrum disorders are a group of biologically Autism spectrum disorders are a group of biologically
based neurodevelopmental disorders characterized by based neurodevelopmental disorders characterized by
impairments in three major domains: socialization, impairments in three major domains: socialization,
communication, and behavior, stem cells induce communication, and behavior, stem cells induce
angiogenesis and neurogenesis in areas of cerebral angiogenesis and neurogenesis in areas of cerebral
hypoperfusion, their ability to constitutively secrete hypoperfusion, their ability to constitutively secrete
immune inhibitory factors leads toimmune inhibitory factors leads to Immune modulation Immune modulation
(Augustyn et al., 2011).(Augustyn et al., 2011).
Cell-based approaches in spinal cord injury have the most Cell-based approaches in spinal cord injury have the most
imminent translational potential for spinal cord functional imminent translational potential for spinal cord functional
repair center on two fundamental directions that are not repair center on two fundamental directions that are not
mutually exclusive: restitution of white matter long-tracts mutually exclusive: restitution of white matter long-tracts
(to be referred to as “regenerative” approaches) and (to be referred to as “regenerative” approaches) and
cellular (i.e., neuronal or oligodendrocyte) replacement cellular (i.e., neuronal or oligodendrocyte) replacement
(Lindvall and Kokaia, 2010).(Lindvall and Kokaia, 2010).
In peripheral nerve injury stem cells not only improved In peripheral nerve injury stem cells not only improved
survival of nerve cells but also augmented nerve survival of nerve cells but also augmented nerve
regeneration regeneration (Metwally, 2009).(Metwally, 2009).
effectiveness of precursor transplantation could be effectiveness of precursor transplantation could be
improved using technology that exists to directly alter the improved using technology that exists to directly alter the
regenerative microenvironment by continuous delivery of regenerative microenvironment by continuous delivery of
neuregulins, forskolin, or other differentiation-promoting neuregulins, forskolin, or other differentiation-promoting
factorsfactors (Svendsen and Ebert, 2008). (Svendsen and Ebert, 2008).
SummarySummary
Stem cell therapy has been used successfully to Stem cell therapy has been used successfully to rebuild damaged neural tissues rebuild damaged neural tissues (neurorestoration) as repair of spinal cord (neurorestoration) as repair of spinal cord injuries, strengthen a weakened immune injuries, strengthen a weakened immune system, treat autoimmune diseases and help system, treat autoimmune diseases and help patients with neurodegenerative disorders such patients with neurodegenerative disorders such as Parkinson's disease (PD), HD, stroke and as Parkinson's disease (PD), HD, stroke and Alzheimer's disease and further uses have Alzheimer's disease and further uses have shown positive results in the treatment of a wide shown positive results in the treatment of a wide range of chronic conditions such as range of chronic conditions such as arteriosclerosis and muscular dystrophies. arteriosclerosis and muscular dystrophies.