Stem Cell Thearpy
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on Jul 17, 2012 Says :
a great presentation on stem cells.
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Stem Cell Therapy
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Summary Stem Cells – what are they, Hierarchy ? Potency? Different types What are MAPCs Source of Stem Cell Types of Stem cell transplantation Therapeutic, Research and Diagnostic Uses Ethical Issues Conclusions
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Stem Cell – Definition A cell that has the ability to continuously divide and differentiate (develop) into various other kind of cells/tissues
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Stem Cell Biology What are Stem Cell Stem cells have the remarkable potential to develop into many different cell types in the body during early life and growth. In addition, in many tissues they serve as a sort of internal repair system, dividing essentially without limit to replenish other cells as long as the person or animal is still alive. When a stem cell divides, each new cell has the potential either to remain a stem cell or become another type of cell with a more specialized function, such as a muscle cell, a red blood cell, or a brain cell. - NIH WEBSITE
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Stem Cell Transplantation Hematopoietic stem cell transplantation (HSCT) involves the intravenous infusion of autologous or allogeneic stem cells collected from bone marrow, peripheral blood, or umbilical cord blood to re-establish hematopoietic function in patients with damaged or defective bone marrow or immune systems.
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On division, one daughter cell replenishes a whole compartment, and the other remains fully “stem“.
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Potency of Stem Cells Potency specifies the potential to differentiate into different cell types: Totipotent stem cells are produced from the fusion of an egg and sperm cell. Cells produced by the first few divisions of the fertilized egg are also totipotent. These cells can differentiate into embryonic and extraembryonic cell types. Pluripotent stem cells are the descendants of totipotent cells and can differentiate into cells derived from any of the three germ layers. Multipotent stem cells can produce only cells of a closely related family of cells (e.g. hematopoietic stem cells differentiate into red blood cells, white blood cells, platelets, etc.). Unipotent cells can produce only one cell type, but have the property of self-renewal which distinguishes them from non-stem cells (e.g. muscle stem cells)
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Two Kinds of Stem Cells 1) Embryonic stem Cell Derived from the inner cell mass of a blastocyst Pluripotent Can develop into more than 200 different cells Differentiate into cells of the 3 germ cell layers Because of their capacity of unlimited expansion & pluripotency – useful in regenerative medicine.
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Embryonic Stem Cells and Embryonic Stem Cell Lines Cell lines are from one separated cells & the daughter cells are alike and grow indefinitely.
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2) Tissue or Adult stem cells Less versatile & more difficult to identify, isolate, & purify They produce cells specific to the tissue in which they are found They are relatively unspecialized However they are predetermined to give rise to specific cell types when they differentiate Recently, however it was discovered that an adult stem cell from 1 tissue may act as a stem cell for another tissue, i.e. blood to neural Stem cells & progenitor cells act as a repair system for the body, replenishing specialized cells, but also maintain the normal turnover of regenerative organs, such as blood, skin or intestinal tissues Eg: haematopoietic, bone marrow, neural
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Multipotential Adult Progenitor Cell (MAPC) Described in the adult bone marrow with very similar properties to embryonic stem cells Multipotent adult progenitor cells or MAPCs have high telomerase activity.
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ESCs versus MAPCs
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Two Sources of Embryonic Stem Cells 1.Excess fertilized eggs from IVF (in-vitro fertilization) clinics 2.Therapeutic cloning (somatic cell nuclear transfer)
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Stem cells from In Vitro fertilization Tens of thousands of frozen embryos are routinely destroyed when couples finish their treatment. These surplus embryos can be used to produce stem cells. Regenerative medical research aims to develop these cells into new, healthy tissue to heal severe illnesses.
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Somatic Cell Nuclear Transfer The nucleus of a donated egg is removed and replaced with the nucleus of a mature, "somatic cell" (a skin cell, for example). No sperm is involved in this process, and no embryo is created to be implanted in a woman’s womb. The resulting stem cells can potentially develop into specialized cells that are useful for treating severe illnesses.
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Somatic cell nuclear transfer Unfertilized egg Fusion with patient’s cell
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Pros and cons of stem cell sources Type Advantage Problem ES grow well non-self pluripotent directed differentiation, ES contamination in product Ethical Issues ES-self grow well directed differentiation (therapeutic cloning) pluripotent labor intensive, inefficient, self oocyte supply ES contamination in product Cord blood availability, growth, numbers, cell types could be self Adult stem cells unexpected plasticity grow poorly, accessibility could be self numbers, inter-conversions may be very rare
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Types of stem cell for transplantation Autologous adult Allogeneic adult Foetal (cord blood) Embryonic Mesenchymal
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History of BM transplantation 1956 – 1st marrow infusion 1968 – 1st successful BMT 1981 – 1st thalassaemia Tx 1988 – 1st cord blood transplant (Fanconi’s anaemia) Nobel Prizes 1980:Jean Dausset, Baruj Benacerraf and George D. Snell for work on HLA system 1990: Dr E Donall Thomas – Seattle for work in clinical marrow transplantation
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Stem cell harvesting Autologous and allogeneic, from peripheral blood or bone marrow Foetal – placental cord blood “milking” Embryonic Mesenchymal
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Bone marrow harvesting General anaesthetic Marrow aspirated from pelvis (+sternum) Marrow filtered to remove debris Marrow may be administered “fresh” or cryo-preserved
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Peripheral blood harvesting Stem cells mobilised – G-CSF in healthy donors 10 mcg/kg/day Cyclophosphamide + G-CSF Mozobil (plerixafor) + G- CSF approved by the US FDA in Dec 2008 (0.24 mg/kg sc) For Myeloma and HDs On day 5 (donors), day 10 (patients) 3 hours session on stem cell collection machine ~ to apheresis machine Stem cells given fresh or cryopreserved Dose required for engraftment is 1-2 X 106 CD34+ cells/kg Higher doses ? better engraftment, but if 8 X 106 cells are associated with increased risk of extensive GVHD
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Complications of BM donation Bone marrow donors Post operative pain Anaemia Peripheral blood stem cell donors Vs Access site bruising/pain G-CSF induced bone pain – 80% Allergy to g-csf (1 in 300) ARDS and alveolar haemorrhage Patients may experience neutropenic infection Excessive white cell drive – has been linked to splenic rupture (?1 in 4000) Apheresis reactions Cardiovascular events due to plaque inflammation DVT / PE ( hypercoagulability) Flaring of Autoimmune disorders, ophthalmologic events First dose reaction ( < 3hours ) No evidence of increased haematological malignancy
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Stem cell processing and storage Donation divided into 60ml aliquots Cells cooled to 0oC on ice 10% DMSO added Cells frozen to -40oC at rate of -10o/min Frozen bags moved into gaseous phase liquid nitrogen Bags stored in liquid phase nitrogen at approximately -200oC
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Manipulation of Stem Cell Grafts Sophisticated labs &highly trained personnel, & often they are quite expensive. ABO-incompatible allogeneic transplants Removal of isoagglutinins or RBCs from the donor graft prevents hemolysis in the recipient. T-cell depletion in the allogeneic transplantation setting To reduce or eliminate the possibility for the development of GVHD. Is often effective in lowering the morbidity and mortality associated with GVHD, Removal of these accessory cells may be associated with an increase in engraftment failure in up to 10% of transplantations (loss of T-helper cells, which facilitate engraftment). T-cell depletion results in higher relapse rates compared with T-cell–replete grafts
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Stem cell thawing and administration Bags warmed in 37oC waterbath DMSO is toxic to stem cells at >0oC Administer cells as an infusion over <10 mins via a central venous line Pre-treat patient with paracetamol and anti-emetics
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Purpose of Autologous Transplantation To allow administration of high dose (supra-lethal) therapy Use when patient has achieved best response to initial chemotherapy Autologous stem cells “rescue” patient from high dose therapy No immunological conflict
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Disadvantages of Autologous transplant Stem cell donation may be contaminated by tumour cells Pre transplant purging may be used, in-vivo or in-vitro No graft versus tumour effect
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Benefits of Autologous Transplant May provide sufficient anti-tumour effect to leave very few tumour cells Cure can be achieved Low transplant related mortality (TRM) – 3%
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Application of Autologous transplant Myeloma – in 1st remission Lymphomas – in 2nd remission Non-Hodgkin lymphoma Hodgkin disease AML – has greater anti-leukaemic effect, but high risk ALL – no benefit Solid tumours No benefit in breast cancer Occasional use in less common tumours ( Neuroblastoma, Germ cell tumors ) Autoimmune disorders inc. ITP, SLE, systemic sclerosis Neurological disorders inc. MS
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Complications of Autografting Mucositis ( oropharangeal, intestinal) Prolonged and severe pancytopenia Severe thrombocytopenia Infections Procedure related mortality ( related to age) Early relapse may be more aggressive Due to lack of graft vs tumor effect 2nd Cancers
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Allogeneic transplantation Donors: Syngeneic twin Matched sibling donor Mis-matched family donor Matched unrelated donor Cord blood donation “Saviour” sibling “Matched” unrelated cord-blood
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Preparing patient for allograft Achieve best possible disease reduction “Condition” patient to receive donation Conventional high dose chemo/radiotherapy Reduced intensity conditioning RIC (mini-transplant) Administer stem cell/ bone marrow infusion Provide protective isolation and anti-infective prophylaxis
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Myelo-ablation Total body irradiation 10-12 Gy (fractionated) + cyclophosphamide Cyclophosphamide + busulfan Nb 4.5 Gy fatal in 50% exposed individuals
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Complications: Graft versus host disease Counterpart of graft versus tumour effect Acute <100 days May be lethal Chronic >100 days May be disabling Organs affected : Skin, Gut, Liver and Lungs
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Acute GVHD grading
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Prevention and treatment of GVHD Best HLA match ( ABO Compatibility not required) 6/6 T cell depletion But, reduced anti-tumour effect Immune suppression Steroids, cyclosporin, mycophenolate, tacrolimus, azathioprine, methotrexate Mesenchymal stem cell infusions Patients who are candidates for HSCT have an identical twin who serve as a donor. These patients don't require post transplantation immunosuppressive therapy & do not develop GVHD, although they are at a higher risk of relapse compared with similar HLA-matched but non-identical sibling donors, related to the ability of the donor lymphocytes to recognize the recipient tumor cells
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Other procedure related complications Veno-occlusive disease of liver Cyclosporin induced renal failure Cyclosporin induced TTP Sterility due to TBI/high dose chemo Secondary cancers
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Allograft failure May occur due to graft rejection May reflect disease relapse Can be treated by donor lymphocyte infusion (DLI)
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Post-transplant related lympho-proliferative disease (PTLD) Early PTLD EBV driven Late PTLD often EBV negative May be polyclonal and respond to reduced immune suppression Can respond to anti-CD20 therapy (Rituximab) May become high grade lymphoma
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Transplant related mortality in Allograft Syngeneic twin: 3-5% Matched sibling: 10% Unmatched related donor: 18% Matched unrelated donor: 25%
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Applications of allografting Haematological malignancies AML, ALL, CML, CLL, MM, Lymphomas Myeloproliferative disorders, Myelodysplastic syndromes Marrow failure ( Aplastic anemia, Pure red cell aplasia ) Paroxysmal nocturnal hemoglobinuria Fanconi anemia Haemoglobinopathies (Thalassemia major 80 % , Sickle cell anemia 100%) Severe combined immunodeficiency (SCID) Wiskott-Aldrich syndrome Hemophagocytic lymphohistiocytosis (HLH) Inborn errors of metabolism (eg, mucopolysaccharidosis, Gaucher disease, metachromatic leukodystrophies & adrenoleukodystrophies) *Immune deficiency in HIV ( experimental )
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Cord Blood Stem Cells It hold great potential in treating a wide number of diseases and disorders. They are actually much more primitive than bone marrow or peripheral stem cells. Taken from umbilical cord blood shortly after birth; once the umbilical cord has been cut, the blood from the cord can then be frozen and stored in cord blood banks. The stem cells are thawed and ready to use in stem cell therapy.
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Cord Blood Transplantation Advantages It is readily available, Carries less risk of transmission of blood-borne infections It is transplantable across HLA barriers with diminished risk of GVHD Owing to the relative immaturity of the immune system in cord samples, stem cells from this source allow the crossing of immunologic barriers A match of 3-4 out of the 6 HLA-A, HLA-B and HLA-DRB1 antigens is sufficient for transplantation.
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Disadvantage Relatively small volume obtained from cord blood collections, which makes difficult for transplantation in adults as the small volume results in delayed engraftment and increased risk of infections and mortality. The median time to neutrophil recovery after cord blood transplantation is 4 weeks, in contrast to 8-12 days after peripheral blood progenitor cell transplantation. To overcome this, pooled or sequential cord blood transplantation is practiced at some centers and has shown encouraging results The possibility of expanding the cord blood stem cells in vitro is an area of active research
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A to Z of Indications for Cord Blood Indiactions Adrenoleukodystrophy Agnogenic Myeloid Metaplasia(myelofibrosis) Amegakaryocytosis / Congenital Thrombocytopenia Aplastic Anemia (Severe) Ataxia-Telangiectasia Bare Lymphocyte Syndrome Batten disease B- Thalassemia Major Blackfan-Diamond anemia Breast Cancer Cartilage-Hair Hypoplasia Chediak-Higashi Syndrome CGD Common Variable Immunodeficiency DiGeorge Syndrome Dyskeratosis congenita Essential Thrombocythemia Evans syndrome Ewing Sarcoma Gaucher's Disease Glanzmann Thrombasthenia Hemophagocytosis Histiocytosis-X Hunter's Syndrome (MPS-II) & Hurler's Syndrome (MPS-IH) Kostmann's Syndrome Krabbe Disease Langerthans cell histiocytosis Lesch-Nyhan Syndrome Leukocyte Adhesion Deficiency Liposarcoma Maroteaux-Lamy Syndrome (MPS-VI) Metachromatic Leukodystrophy Morquio Syndrome (MPS-IV) Mucolipidosis II (I-cell Disease) Neutrophil Actin deficiency Neuroblastoma Niemann-Pick Disease Osteopetrosis Renal Cell Ca Reticular Dysgenesis Retinoblastoma Sanfilippo Syndrome (MPS-III) Scheie Syndrome (MPS-IS) Severe Combined Immunodeficiency Sickle Cell Anemia Sly Syndrome, Beta-Glucuronidase Deficiency (MPS-VII) Thalassemia Thymic dysplasia Waldenstrom's Macroglobulinemia Wiskott-Aldrich syndrome Wolman Disease X-linked lymphoproliferative Disorder
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Adult Stem Cells Skin Gut Liver Pancreas Brain Heart
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Current Clinical Uses of Adult Stem Cells Cancers—Lymphomas, multiple myeloma, leukemias, breast cancer, neuroblastoma, renal cell carcinoma, ovarian cancer Autoimmune diseases—multiple sclerosis, systemic lupus, rheumatoid, arthritis, scleroderma, Crohn’s disease Anemias (incl.Aplastic anemia sickle cell anemia) Immunodeficiencies Bone/cartilage deformities—children with osteogenesis imperfecta Corneal scarring-generation of new corneas to restore sight Stroke—neural cell implants in clinical trials Repairing cardiac tissue after heart attack—bone marrow or muscle stemcells from patient Parkinson’s Disease — retinal stem cells, patient’s own neural stem cells, injected growth factors Growth of new blood vessels—e.g., preventing gangrene Gastrointestinal epithelia—regenerate damaged ulcerous tissue Skin—grafts grown from hair follicle stem cells, after plucking a few hairs from patient Wound healing—bone marrow stem cells stimulated skin healing Spinal cord injury—clinical trials currently in Portugal, Italy, S. Korea
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Drug Testing Stem cells could allow scientists to test new drugs using human cell line which could speed up new drug development. Only drugs that were safe and had beneficial effects in cell line testing would graduate to whole animal or human testing. It would allow quicker and safer development of new drugs.
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Therapeutic Possibilities of Stem Cells
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Olfactory Bulb Stem Cells Primitive stem cells that normally feed the constant, life-long regeneration of odor-detecting nerves Like embryonic stem cells, they develop into many different types of cells in the right chemical or cellular environment Fairly accessible, readily obtained in all individuals and easy to grow and multiply Potential non-embryonic source for cells that could prove useful in replacing nerve cells lost due to injury or diseases like ALS and Parkinson's Transplant not subject to immune rejection
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Neurological Disorders e.g. ALS, Alzheimer’s disease, Parkinsons Disease, Cord injury Mouse experiments Neuronal stem cells transplanted into spinal cord or brain Significantly prolonged lives by becoming neurons and interacting with existing neurons Symptoms developed at 137 days verses 90 days Treated mice lived 2 months longer
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Spinal Cord Injury Rat Experiments Sensory and motor deficiencies; paralysis Treatment derived from human embryonic stem cells and must occur in the acute phase of spinal stabilization Cells differentiate into early stage oligodendrocytes, the building blocks of myelin Transplanted cells migrated to appropriate neuronal sites in the spinal cord 7 days post injury vs. 10 months post injury
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Heart Disease The heart is an example of a non-regenerative organ frequently injured. Treatment for congestive heart failure and other heart disease Transplantation is the current standard treatment for severe heart disease. Stem cells and blood plasma injected into 25 to 30 sites of the diseased heart (25-45 m. cells) New heart cells and blood vessels Do stem cells take on the functional characteristics of heart cells and blood vessels, or do they recruit other cells and growth factors to help regenerate heart tissue?
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The heart is an example of a non-regenerative organ frequently injured. Approximately one billion heart cells are lost during a serious heart attack. If one survives the initial event, a progressive chronic heart failure often occurs due to the replacement of functional beating heart cells with a tough fibrous scar.
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Instead of replacing the whole organ, why not just replace the lost cells? For tissues incapable of regenerating, we look towards stem cells as a source of functional replacement cells.
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Type I Diabetes Know the genes to make a stem cell into an insulin producing pancreatic cell, and the signals involved in their activation Turn genes on in the right order to get functioning cells Add and remove proteins as needed from the developmental process which may give advantages over less flexible approaches such as gene therapy Bone marrow-derived stem cells may not have the same antigen as pancreatic beta cells, which would eliminate the potential for rejection or a negative immune response
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Bone Repair NJ Institute of Technology – use of stem cells to induce bone repair Adult Stem Cells mixed with biomaterials known as scaffolds to regenerate bone growth Stem Cells from one person can successfully implant in another Diabetes, osteoporosis, cancer surgeries Also testing biomaterials that may repair cartilage, tendons and neuronal tissue It can help in repairing the eroded cartilage in Rheumatoid arthritis
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Cystic Fibrosis: Stem Cell-Gene Therapy Approach Human bone marrow derived stem cells can differentiate into airway epithelial cells Encoding these cells with the gene that is defective in CF restores cellular function Keep airways clear of mucus and air-borne irritants Hope to perform clinical trial in next 2-3 years Huntingtons disease, is next on the list for gene thearpy
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Biological Pacemaker Human Embryonic Stem Cells genetically engineered and coaxed to become heart cells Clusters of cells beat on their own triggered the unified beating of rat heart muscle cells Triggered regular beating when implanted in guinea pigs Cells responded to drugs used to slow or speed up heart rate Use genetic engineering to customize the pacing rate of the cells
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Hemophilia UNC Chapel Hill Medical School treated embryonic stem cells with fibroblast growth factor for seven days prior to injection Differentiate into early endoderm precursors Engraft, persist, differentiate further and function following injection - resulting in persistent production of Factor IX (hepatocytes) Engrafted in the liver and not recognized as foreign by immune system Cells became hepatocytes 4 months later mice still producing Factor IX without immune rejection or suppression Low incidence of teratoma
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Hearing Impairment Indiana University School of Medicine transformed adult bone marrow stem cells into cells with many characteristics of sensory nerve cells found in the ears Marrow-stromal cells develop into fat, bone and cartilage Autologous cell-based therapy to stimulate growth of nerve cells often missing in the inner ear of patients with profound hearing loss
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Tooth Replacements Adult stem cells harvested from baby or wisdom teeth to grow new teeth naturally Contain rich supplies of stem cells that can develop into a variety of cell types including tooth generating cells Gingivitis and periodontis
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Cosmetic and Reconstructive Surgery Conventional soft tissue implants lose 40 to 60% of volume Stem cell generated natural tissues instead of synthetic implants Avoid problems of saline and silicon Won’t shrink or lose shape Mouse experiments: bone marrow stem cells placed under the skin for four weeks; stem cells differentiated into fat generating cells and implants retained original size and shape Breast cancer surgery, post-cancer facial soft tissue reconstruction, trauma surgeries
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Retinal Degeneration Mice predisposed for Retinitis Pigmentosa Injected bone marrow derived stem cells into the back of mouse eyes during development Dramatically curtailed retinal degeneration Completely normal vasculature, improved retinal tissue & light response Disorders of the retina that have vascular and neuronal degeneration: genetic disorders known collectively as retinitis pigmentosa Corneal Regeneration is also being tried using bone marrow stem cell LV PRASAD EYE INSTITUTE OF HYDERABAD
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Limbal stem Cell therapy The treatment is known as limbal stem cell therapy, and the patients who received the treatment suffered from chemical burn or genetic disease ( aniridia ) By replacing the limbal stem cells, the cornea begins to clear up as the cells are replaced with the healthy transparent layer again. Moorfields Eye Hospital in London, surgeons restored eye sight for six patients
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Other Disorders where presently used on experimental basis Baldness ( Commonly available though ) As Anti-aging Erectile dysfunction Cerebral palsy Autism Inclusion body myositis Hypertension
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Law interferes in Stem Cell Therapy
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Ethical debate Harvesting ES cells destroys the blastocyst “This is murder” ES cell research requires human cells Could create a commercial market for human cells “This devalues life” Reproduced by permission of Dave Catrow and Copley News Service
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STEM CELL THEARPY
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