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04/04/16 STEMCELLS Symmetriccelldivision Atthebeginningofembryonic development,stemcellsundergo symmetriccelldivision. 04/04/16 2 1 04/04/16 Asymmetriccelldivision 1. Self-renews 2. DifferenBates Thenatblastocyst forma:onand gastrula:onthe stemcellsstartto Progenitor cell divide asymmetrically 04/04/16 Stem cell Stem cell 3 Whatisastemcell? Stem cell SELF-RENEWAL (copying) Identical stem cells Stem cell DIFFERENTIATION (specializing) Specialized cells 2 04/04/16 (Embryonicstemcells)EScellshavetwoimportantproperBes.Thefistoneistheirnearlyinfiniteprolifera:on.Wecan expandthenumbersofEScellsasmuchaswewant.Theotherimportantpropertyispluripotency,theabilityto differenBateintonearlyalltypesofsomaBccellsthatexistinbody,suchasmusclecellsandnervecells.WefoundthatNAT1 isindispensableforthepluripotencyofmouseEScells.WhenwedisruptedtheNAT1funcBon,EScellsbecameunableto differenBte.Becauseofthisunexpectedresult,myresearchinterestshiQedfromcancertostemcells.ShinyaYamanaka 04/04/16 5 Whyself-renewANDdifferen:ate? 1stemcell 1stemcell Selfrenewal-maintains thestemcellpool 4specializedcells Differen:a:on-replacesdeadordamaged cellsthroughoutyourlife 3 04/04/16 Stemcelljargon Potency Pluripotent Ameasureofhowmanytypesofspecializedcellastemcell canmake Canmakealltypesofspecializedcellsinthebody Embryonicstemcellsarepluripotent Mul:potent Canmakemul:pletypesofspecializedcells,butnotalltypes Tissuestemcellsaremul:potent Typesofstemcell: 1)Embryonicstemcells 4 04/04/16 9 04/04/16 Embryonic stem (ES) cells: Challenges u grow di con nder grow under cond embryonicstemcells grow u gro w itions B nder cond i un de ? skin A Bons rc on Bons C neurons blood dit ion sD liver 5 04/04/16 Types of stem cell: 2) Tissue stem cells Tissue stem cells: Where we find them surfaceoftheeye skin tesBcles muscles brain breast intesBnes(gut) bonemarrow 6 04/04/16 Tissue stem cells: What they can do bloodstemcell differenBaBon foundin bonemarrow MULTIPOTENT onlyspecializedtypesofbloodcell: redbloodcells,whitebloodcells, platelets Types of stem cell: 3)Induced pluripotent (iPS) stem cells 7 04/04/16 ShinyaYamanaka DepartmentofStemCellBiology, InsBtuteforFronBerMedical Sciences,KyotoUniversity,Kyoto 606-8507,Japan 04/04/16 15 ShinyaYamanaka 04/04/16 16 8 04/04/16 Inducedpluripotentstemcells(iPScells) geneBcreprogramming =addcertaingenestothecell cellfromthebody inducedpluripotentstem(iPS)cell behaveslikeanembryonicstemcell differenBaBon cultureiPScellsinthelab Advantage:noneedforembryos! allpossibletypesof specializedcells Adult(:ssue)stemcellsareuseful in:ssueandorganregenera:on: •Blood-formingstemcellstoregenerate bloodandimmunesystems. •Brain-formingstemcellstoregenerate neuroprotecBvepotenBalinbrain. •Skin-formingstemcells/burns. •Skeletalmusclestemcellsformuscular dystrophies. •Mesenchymalcellculturesmakescar,fat, boneandcarBlage;notanyotherBssues. 9 04/04/16 Tissue stem cells: Haematopoietic stem cells (HSCs) NKcell Tcell Bcell dendriBccell megakaryocyte platelets HSC erythrocytes macrophage neutrophil bonemarrow eosinophil basophil commiWedprogenitors specializedcells Cellinvolvedinosteogenesis 10 04/04/16 Tissue stem cells: Mesenchymal stem cells (MSCs) Bone(osteoblasts) CarBlage(chondrocytes) MSC bonemarrow Fat(adipocytes) commiWedprogenitors specializedcells 11 04/04/16 12 04/04/16 13 04/04/16 Methodology for iPSCs generation 14 04/04/16 Applications of iPSCs DISEASE MODELING 15 04/04/16 REGENERATIVE MEDICINE InregeneraBvemedicinetheinjured ordegeneratedBssuesarerepaired bythegeneraBonofthoseBssues withthehelpofiPSCsinlabsand thentransplanBngthemtothesite ofinjuryordegeneraBon. REGENERATIVE MEDICINE DifferentinjuriesasaresultofhumanacBviBes, accidentsornaturalcalamiBescanalsobetreatedbythe genetherapyuBlizingiPSCs.ThevariouscondiBonsthat canbetreatedare: Hematopoie:cdisorders, Musculoskeletalinjury, Spinalcordinjury, liverdamagebythegenera:onofspecific cellswiththehelpofiPSCs (Liuetal.,2011b;Norietal.,2011;Tanetal.,2012; Suzukietal.,2013). 16 04/04/16 REGENERATIVE MEDICINE Kazukietal.correctedthegeneBcdeficiency iniPSCsfromahumanDuchheneMuscular Dystrophy(DMD)pa:ent.TheyusedHuman Ar:ficialChromosome(HAC)fortheexpressionof completesequenceofDystrophin(DYS).Theyused fibroblastsfromtheDMDpaBentforthegeneraBonof iPSCs.HACwasusedforthecorrecBoninthedeleBon ormutaBonintheDystrophingenepresentiniPSCs bytransferofDYS-HAC(completegenomicsequence ofdystrophininHAC)usingMicrocell-mediated chromosometransfer(MMCT)(Kazukietal.,2009). REGENERATIVE MEDICINE Recently,thereareaccumulaBngdataon theuseofiPSCforex-vivoblood expansionofvariousblood components.Theycanbeusedfor thegenera:onofRedBloodCells (RBCs)whichcouldbeuBlizedforthe generaBonofbloodthatisrequiredover theglobeforthepurposeoftreatmentof variousdamagesordiseases. 17