restorative neurology

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Page 1: Restorative neurology

الرحمن الله الرحمن بسم الله بسمالرحيمالرحيم

Page 2: Restorative neurology

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

Page 3: Restorative neurology

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

Page 4: Restorative neurology

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

Page 5: Restorative neurology

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)..

Page 6: Restorative neurology

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).

Page 7: Restorative neurology

(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)..

Page 8: Restorative neurology
Page 9: Restorative neurology

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).

Page 10: Restorative neurology

Hematopoetic stem cells ( HSCs)

Bone marrow stromal cells ( BMSC)

Neural stem cells( NSCs)

Page 11: Restorative neurology

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).

Page 12: Restorative neurology
Page 13: Restorative neurology

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).

Page 14: Restorative neurology
Page 15: Restorative neurology

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).

Page 16: Restorative neurology

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).

Page 17: Restorative neurology

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).

Page 18: Restorative neurology

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).

Page 19: Restorative neurology

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).

Page 20: Restorative neurology

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).

Page 21: Restorative neurology

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).

Page 22: Restorative neurology

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).

Page 23: Restorative neurology

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).

Page 24: Restorative neurology

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).

Page 25: Restorative neurology

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).

Page 26: Restorative neurology

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).

Page 27: Restorative neurology

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).

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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).

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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).

Page 30: Restorative neurology

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.

Page 31: Restorative neurology