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Stem Cells,What is a Stem Cell?In general a stem cell is: A cell that can divide indefinitely A self-replicating cell A cell that can produce the differentiated cells required for functional tissues given the right conditions given the right signals,Human Stem Cells,EmbryonicStem Cells,FetalStem Cells,Infant,Adult,Umbilical Cord Blood Stem Cells,Classification of Human Stem Cells,A. Bongso and E.H. Lee, Stem Cells : from Bench to Bedside, World Scientific Publishing Co. Pte. Ltd., 2005,Potential of Stem CellsTotipotent: can produce all the cells in the embryo and the embryos contribution to the extra-embryonic tissuesPluripotent: can produce all the cell types in the embryoProperMultipotent: contributes cells to several cell lineages(Adapted from Wagers and Weissman, Cell 116:639-648, 2004),Totipotency and pluripotencyEmbryonic cells up to the blastomere stage are considered to be totipotent because one cell can make all of the embryonic and extraembryoniccells.Cells of the inner cell mass of the blastocyst are considered to be pluripotent because one cell can contribute to all cells and tissues in a whole organism. Embryonic stem cells (ES cells) are derived from cells of the inner cell mass.Pluripotency of ES cells was shown by making chimeric mice.,making chimeric mice.,What is Multipotency? Multipotency is defined as: The stem cell itself changing its phenotype The stem cell produce progeny with phenotypes andfunctions different than its own in response to changes in the stem cell niche factors added to cultures new signals in vivo Somatic stem cells from most tissues are now thought to be multipotent.,Examples of Multipotency of Some Somatic Stem CellsType of Stem Cell Type of Cells/Tissue Generated1. Mesenchymal1. Keratinocytes, mesenchymal cells, muscle, blood2. Epidermal2. Keratinocytes, fibroblasts, endothelial, brain, bloodcells, sebaceous3. Neural3. Neurons, oligodendrocytes, skeletal muscle, bloodcells4. Bone Marrow 4. Blood cells, endothelial, cartilage, bone, dermis, liver, adipocytes, gastrointestinal, thymus, pulmonaryepithelial, islet cells5. Muscle/satellite5. Skeletal muscle, bone, cartilage, fat, smooth muscle, cardiac muscle6. Oval Liver Cells 6. Hepatocytes, blood cells7. Testis & Ovarian 7. Gonads, mesenchymal cells8. Pancreatic Acinar 8. Islet cells9. Adipocytic9. Fat, muscle, cartilage, bone,Why are Multipotent Somatic Stem Cells Important?1. The use of embryonic stem cells has legal and ethical problems. Cells from the patient who requires the new tissue will nothave legal or ethical problems.2. Embryonic stem cells potentially carry MHC markers that may cause rejection of tissues made with these cells. There should be no rejection problems if the patients owncells are used.3. Injection of embryonic stem cells has been shown to cause benigntumors, called teratomas, which contain differentiated cells of all thetissues, such as bone, teeth, muscle, etc. Injection of normal somatic cells have not caused theformation of benign or malignant tumors,What are Embryonic Stem Cells? Embryonic stem cells (ES cells) are derived fromthe cells in the inner cell mass of the developingblastocyst Most ES cell work is done with murine ES cells Human ES cells are derived from embryos that developed fromeggs that were fertilized in vitro in an in vitro fertilization clinicThey have been donated for research with informed consent of thedonors. Human ES cells are not derived from eggs fertilized in awomans body.,Embryonic Stem (ES) CellsCulture of ES Cells ES cells can be isolated and maintained in culture Fibroblast feeder layer (STO cells or MEF cells) LIF (leukocyte inhibitory factor) for mouse ES cells LIF is not required for human ES cellsDifferentiation of ES Cells Cultured ES cells can be induced to differentiate into multiple tissues by addition of specific cytokines or growth factors to the culture medium. Once differentiated, ES cells are nolonger pluripotent,Three types of cultured embryonic cells canform normal offspringES cells EG cells EC cells,What are Somatic Stem Cells (adult stem cells)? Somatic stem cells are undifferentiated cells found in a tissue,such as the skin or the brain sometimes called tissue stem cells or adult stem cells, eventhough they are also found in neonatal and embryonic tissues located among differentiated cells in a tissue or organ Somatic stem cells can renew themselves indefinitely in vivo The primary role of somatic stem cells is to produce thedifferentiated cells for maintenance and repair the tissue inwhich they reside The origin of somatic stem cells in mature tissues is unknown There is evidence that they are defined by their environmentalniche,- Bone Marrow Stem Cells- Peripheral Blood Stem Cells- Neuronal Stem Cells (from olfactory bulb, spinal cord)- Muscle Stem Cells- Liver Stem Cells- Pancreatic Stem Cells- Corneal Limbal Stem Cells- Umbilical Cord Blood,Adult Stem Cells,Hematopoietic stem cells were the firstsomatic stem cells functionally identified Hematopoietic stem cells were the first somatic stem cells to be identified. In 1961 Till and McCullough determined that after irradiation only a few cells repopulated the spleen.(Radiat. Res. 14: 213-219,1961). Found in the bone marrow, these stem cells can be induced to differentiate into all functional blood cells (lymphocytes, erythrocytes, megakaryocytes, monocytes, granulocytes, etc.),Hematopoietic stem cells,Patterns of stem cell divisionSymmetric cell division results in two equal daughter cells. This is how ES cells reproduce. During development or under repair circumstances, somatic stem cells may also reproduce by symmetric cell division.Asymmetric cell division results in two daughter cells with different potential. It is thought that somatic stem cells have asymmetric cell division,producing one daughter cell that remains a stem cell and one daughter cell that is committed to differentiate. ES cells may show asymmetric cell division when producing committed cells. Committed progenitor cells may show symmetric cell division for a specific number of cell cycles, producing several cells with equal potential.,Patterns of stem cell division,Stem cell Niche Both ES cells and somatic stem cells are thought to be maintained (and perhaps defined) by the environment produced by the surrounding differentiated cells. Exactly how this stem cell niche is maintained is not known yet. The differentiated cells may: secret specific factors into the surrounding matrix communicate with the stem cells via gap junctions or receptor mediated inducers Such communication may activate specific signaling pathways, such as the Wnt/frizzled (which activates Lef-1/TCF), Notch/delta, orSonic hedgehog/patched pathways. Loss of the stem cell niche can induce a stem cell to divide, die, or differentiate. Change in the niche may induce a stem cell to alter its phenotype and its function.,Stem cell Niche,Summary: Embryonic vs. Somatic Stem CellsEmbryonic Stem CellsSomatic Stem Cells Called ES cells Also called adult stem cells Derived from the inner cell mass of Derived from a specific tissue, such the developing blastocystas the epidermis High plasticity and developmental Developmental potential uncertainpotential Unlimited lifespan in culture Limited lifespan in culture Limited lifespan in vivo May have unlimited lifespan in tissues May be rejected due to allogeneinc High potential for autologous graftsnature Potential for undesired tumor Less likely to form tumorsformation (teratomas) High ethical controversy Less moral controversy Uncertain legal status Less legal controversy,the Scientific Foundations of Cardiac Repair,Stefanie Dimmeler, Andreas M. Zeiher, Michael D. Schneider.The Journal of Clinical Investigation Vol 115 Number 3 March 2005,Review : Recent experimental studies and early-phase clinical trials lend credence to the visionary goal of enhancing cardiac repair as an achievable therapeutic target.,Cell Types : Peripheral blood- derived progenitor cells, bone marrow, skeletal muscle myoblasts, fat tissue derived multipotent stem cells and embryonic stem cells.,Route of Application,Clinical Trials : Intracoronary Progenitor Cells for Acute Myocardial Infarction,Study,N,Cell,Cell No.,Safety,(106 ),Myocardial,function,Strauer et al.,TOPCARE-AMI,10,BMCs,28,+,Regional contractilityendsystolic volumeperfusion,BOOST,Fernandez-Aviles et al,59,20,30,CPCs,BMCs,BMCs,BMCs,Global contractility end systolic volumeviability,Global contractility,Global contractilityend systolic volume,+,+,+,16,213,2,460,78,type,similar results for both cell types,Potential Roles of Bone Marrow-Derived Cells in Renal Protection/ Repair,Krause, D. et al. J. Clin. Invest. 2005;115:1705-1708,Umbilical Cord Blood Cells and Brain Stroke Injury: Bringing in Fresh Blood to Address an Old Problem.,Daniel A. PetersonRosalind and Franklin University of Medicine and Science, North Chicago, USA,The Journal of Clinical Investigation Vol. 114 No.3 July 2004,Review evidence which suggests that delivery of circulating CD34+ human umbilical cord cells can produce functional recovery in an animal stroke model,Morphological Response of Stroke-Injured Brain to Delivery of Umbilical Cord Blood Cells,Peterson, D. A. J. Clin. Invest. 2004;114:312-314,Stem cell transplant helps Brazilian walk again,A Brazilian woman who suffered a brain haemorrhage that left her paralysed on one side has regained her ability to walk and talk after undergoing a stem cell transplant, hospital officials say.,The patients lower limbs were paralyzed after an accident in 1985 damaged her lower back and hips. Afterward she spent her life in bed or in a wheelchairThe stem cell transplantation was performed on Oct. 12, 2004 and in just three weeks she started to walk with the help of a walker.The team was co-headed by Chosun University professor Song Chang-hun, Seoul National University professor Kang Kyung-sun and Han Hoon, Ph.D, from the Seoul Cord Blood Bank (SCB).,The team, headed by Korea Institute of Radiological and Medical Sciences researcher Son Young-sook, revealed the medical technique of using stem cells to mass produce skin cells. We extracted skin stem cells from a burn patients epidermis, cultured them and increased their number by 200 times outside his body in two weeks. Then we transplanted them back to the patient and got a satisfactory result, the 47-year-old Son said.,By Kim Tae-gyu, Staff Reporter,A team of Korean scientists has developed a breakthrough technology to heal skin damage, such as burn injuries, by transplanting skin cells enriched from stem cells.,Stem Cell Therapy for Skin Developed,Stem Cell Therapy for Skin Developed,Current Clinical Applications of Adult Stem Cells.,Cancer Treatment : Brain Tumors, Retinoblastoma, Ovarian Cancer, Testicular Cancer, Breast Cancer, Neuroblastoma,Anemias : Sickle Cell Anemia, Congenital Thrombocytopenia, Thalassemia, Congenital Sideroblastic AnemiaAutoimmune DiseaseStrokeImmunodeficiencyCartilage and Bone DiseaseCorneal ScarringDiseases of Central Nervous System, Heart, Liver,David A. Prentice ,U.S. President George W. Bush has endorsed limited federal funding of embryonic stem cell research. The complex and controversial issue has divided members of his own party and pitted the scientific community against religious leaders. Bush said federal funds would only be used for research on 60 existing embryo stem cell lines where a life-and-death decision has already been made. The embryos for these lines have already been destroyed,Americans Following the Issue of Stem Cell Research,How closely have you been following the issue of stem cell research?,Taking Our Pulse: The PARADE/Research!America Health Poll Charlton Research Company, 2005,Americans Favor Embryonic Stem Cell Research (ESCR),Do you favor or oppose medical research using embryonic stem cells?,Taking Our Pulse: The PARADE/Research!America Health Poll Charlton Research Company, 2005,58%,29