restorative neurology Essay Submitted of Partial Fulfillment of Master Degree In Neuropsychiatry By Samy Moussa Selim Under Supervision of Prof. Dr./ Mohamed Yasser Metwally Professor of Neuropsychiatry www.yassermetwally.com Prof. Dr./ Naglaa Mohamed El-Khayat Professor of Neuropsychiatry Dr./ Haitham Hamdy Salem Lecturer of Neuropsychiatry Faculty of Medicine Ain Shams University 2011
Aim of The work <ul><li>To study and summarize recent progress in stem cells therapies aimed at neuro-degenerative disorders and illustrate how some of the aforementioned methods and strategies are being utilized to formulate clinically valuable treatment </li></ul>
The stem cells are progenitor cells that have the ability for generation and cell division & renewal (Metwally, 2009) . The stem cells are divided into two main types Adult Stem Cells Embryonic Stem Cells
Embryonic Stem Cells Embryonic Stem Cells (ESCs) were discovered by the early work of Kleinsmith and Pierce (1964). They are derived from the Inner Cell Mass (ICM) of cultured blastocyst stage embryos (Aoki et al., 2007) .
<ul><ul><li>The blastocyst includes three structures: </li></ul></ul><ul><li>The Trophoblast , which is the layer of cells that surrounds the blastocyst . </li></ul><ul><li>The Blastocoel , which is the hollow cavity inside the blastocyst </li></ul><ul><li>The Inner Cell Mass , which is a group of approximately 30 cells at one end of the Blastocoel (Avasthe et al., 2008). </li></ul>
<ul><li>(ESCs) are either </li></ul><ul><li>Totipotent (able to generate all cell types in an organism except placenta ( </li></ul><ul><li>Pluripotent (able to yield mature cell types from all different germ layers) </li></ul><ul><li>Multipotent (able to give rise to all cells within an organ). </li></ul><ul><li>) ESCs) do not appear to undergo replicative senescence, and thus appear to be immortal in culture (Svendsen and Ebert, 2008) . </li></ul>
Adult Stem Cells Somatic stem cells are the building blocks of organ They are undifferentiated cells found among differentiated cells in an organ & can differentiate to maintain and repair the tissue in which they are found (Joanna et al., 2009).
Hematopoietic stem cells (HSCs) <ul><li>HSCs are presented in umbilical cord blood. They are capable of unlimited cell proliferation in bone marrow and must undergo at least 20 to 23 divisions on their way to produce mature blood cells, even assuming no cell death along the way (Emerson et al., 2008). </li></ul>
Bone marrow stromal cells (BMSC). These cells were discovered by Friedenstein, et al. (1968) they can easily be obtained following a simple bone marrow aspiration procedure. They can give rise to a variety of cell types: Bone cells (Osteocytes), Cartilage cells (Chondrocytes), Fat cells (Adipocytes), and other kinds of connective tissue cells such as those in tendons (Svendsen and Ebert, 2008).
<ul><li>Neural stem cells(NSCs). </li></ul><ul><li>In the adult brain generation of new neurons from neuronal stem and progenitor cells predominantly occurs in two brain regions: </li></ul><ul><li>The Subventricular Zone (SVZ) of the lateral ventricle. </li></ul><ul><li>The Subgranular zone of the dentate gyrus (Song et al., 2007). </li></ul>
<ul><li>Stem cells differ from other kinds of cells in the body. </li></ul><ul><li>All stem cells have three general properties regardless of their source: - </li></ul><ul><li>1) They are capable of dividing and renewing themselves for long period. </li></ul><ul><li>2) They are unspecialized. </li></ul><ul><li>3) They can give rise to specialized cell types. </li></ul><ul><li>(Caplan, 2011). </li></ul>
<ul><li>Peripheral blood stem cells are collected by Aphaeresis, a process in which the stem cells are collected from the peripheral blood. </li></ul><ul><li>Mobilization, or priming, is the process used to stimulate the donor’s marrow to produce extra stem cells and release them into the peripheral blood. This is done by giving a growth factor called Colony Stimulating Factor G (G-CSF). </li></ul><ul><li>The ideal number is 5–10 million stem cells per kilogram of the recipient’s weight per transplant dose (Emerson et al., 2008). </li></ul>
<ul><li>Parkinson disease, is a debilitating neurodegenerative disorder characterized by the selective loss of nigrostriatal dopaminergic neurons and loss of dopamine in the striatum </li></ul><ul><li>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 </li></ul><ul><li>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). </li></ul>
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).
<ul><li>In demylinating diseases as MS stem cells has two therapeutic approaches to induce remyelination: </li></ul><ul><li>Promotion of endogenous remyelination by growth factors therapy. </li></ul><ul><li>Transplantation of myelin forming cells is a mode of delivering the entire “cell factory” that manufactures myelin (johnson, 2011). </li></ul>
<ul><li>The concept of a cell based therapy in muscular dystrophies (MD) is to promote muscle regeneration, particularly in recessive types of MD, originated with the observation of the intrinsic ability of myofibers to fuse to each other (David, 2009). </li></ul>
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).
<ul><li>Stem cell based gene therapy could deliver factors modifying the course of AD and may be advantageous because of the capacity of stem cells to migrate and reach large areas of the brain. It counteracts cholinergic neuronal death, stimulate cell function and improve memory in animal models of AD (Zhao et al., 2008). </li></ul>
<ul><li>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: </li></ul><ul><li>photoreceptor survival promoted by restoring the supportive functions of retinal pigment epithelial cells (RPECs), </li></ul><ul><li>directly replacing lost photoreceptors with transplanted stem cells and retinal precursor cells (Svendsen and Ebert, 2008). </li></ul>
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).
<ul><li>Autism spectrum disorders are a group of biologically based neurodevelopmental disorders characterized by impairments in three major domains: socialization, communication, and behavior, stem cells induce angiogenesis and neurogenesis in areas of cerebral hypoperfusion, their ability to constitutively secrete immune inhibitory factors leads to Immune modulation (Augustyn et al., 2011). </li></ul>
<ul><li>Cell-based approaches in spinal cord injury have the most imminent translational potential for spinal cord functional repair center on two fundamental directions that are not mutually exclusive: restitution of white matter long-tracts (to be referred to as “regenerative” approaches) and cellular (i.e., neuronal or oligodendrocyte) replacement (Lindvall and Kokaia, 2010). </li></ul>
<ul><li>In peripheral nerve injury stem cells not only improved survival of nerve cells but also augmented nerve regeneration (Metwally, 2009). </li></ul><ul><li>effectiveness of precursor transplantation could be improved using technology that exists to directly alter the regenerative microenvironment by continuous delivery of neuregulins, forskolin, or other differentiation-promoting factors (Svendsen and Ebert, 2008). </li></ul>
Summary <ul><li>Stem cell therapy has been used successfully to rebuild damaged neural tissues (neurorestoration) as repair of spinal cord injuries, strengthen a weakened immune system, treat autoimmune diseases and help patients with neurodegenerative disorders such as Parkinson's disease (PD), HD, stroke and Alzheimer's disease and further uses have shown positive results in the treatment of a wide range of chronic conditions such as arteriosclerosis and muscular dystrophies. </li></ul>