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Stem/cell/systematics/ and/potentials/for/modeling/and/therapy/ Poul Hyttel University/of/Copenhagen The$Anatomy$Building University$of$Copenhagen,$Frederiksberg Contents Stem*cell*definitions Cell*differentiation*potency

  1. Stem/cell/systematics/ and/potentials/for/modeling/and/therapy/ Poul Hyttel University/of/Copenhagen

  2. The$Anatomy$Building University$of$Copenhagen,$Frederiksberg

  3. Contents • Stem*cell*definitions • Cell*differentiation*potency • The*stem*cell*hierarchy:*Pluripotent,*multipotent*and* unipotent*stem*cells • Induced*pluripotent*stem*cells*for*disease*modeling • Stem*cell*therapy • Conclusions

  4. Contents • Stem*cell*definitions • Cell*differentiation*potency • The*stem*cell*hierarchy:*Pluripotent,*multipotent*and* unipotent*stem*cells • Induced*pluripotent*stem*cells*for*disease*modeling • Stem*cell*therapy • Conclusions

  5. Stem'cell'definitions • Self:renew'(indefinite'multiplication) • Differentiate'into'specialized'cell'types' (differentiation'potency) Self:renewal Stem'cell Limited expansion Intermediate'progenitors Conrad' Waddington' (1957) Terminally'differentiated

  6. Contents • Stem*cell*definitions • Cell*differentiation*potency • The*stem*cell*hierarchy:*Pluripotent,*multipotent*and* unipotent*stem*cells • Induced*pluripotent*stem*cells*for*disease*modeling • Stem*cell*therapy • Conclusions

  7. Cell$differentiation$potency Totipotency • Totipotency:$All$ hED1 hED2 hED1.5 embryomic and$ extraCembryonic$ cell$types • Pluripotency:$All$ embryonic$cell$ types • Multipotency:$ Several$cell$types • Unipotency:$A$ single$cell$type Multipotency Pluripotency hED3 hED5 hED7 pED11

  8. Contents • Stem*cell*definitions • Cell*differentiation*potency • The*stem*cell*hierarchy:*Pluripotent,*multipotent*and* unipotent*stem*cells • Induced*pluripotent*stem*cells*for*disease*modeling • Stem*cell*therapy • Conclusions

  9. Most%common%stem%cell%types • Pluripotent%stem%cells%(PSCs) – Embryonic%stem%cells%(ESCs) – Induced%pluripotent%stem%cells%(iPSCs) • Multipotent%stem%cells – Multipotent%stem%cells%are%often%referred%to%as%adult%stem%cells% (even%though%they%are%also%found%in%embryos) – Hematopoietic%stem%cells%(HSCs) – Mesenchymal%stem%cells%(MSCs) – Neural%stem%cells%(NSCs) • Unipotent%stem%cells – Epidermal%stem%cells%(EpiSCs)

  10. Most%common%stem%cell%types • Pluripotent%stem%cells%(PSCs) – Embryonic%stem%cells%(ESCs) – Induced%pluripotent%stem%cells%(iPSCs) • Multipotent%stem%cells – Multipotent%stem%cells%are%often%referred%to%as%adult%stem%cells% (even%though%they%are%also%found%in%embryos) – Hematopoietic%stem%cells%(HSCs) – Mesenchymal%stem%cells%(MSCs) – Neural%stem%cells%(NSCs) • Unipotent%stem%cells – Epidermal%stem%cells%(EpiSCs)

  11. Embryonic*stem*cells*(ESCs) Ectoderm Mesoderm Endoderm

  12. Human&embryonic&stem&cells&(hESCs)&7 1998 Thompson&et&al.&(1998)

  14. Most%common%stem%cell%types • Pluripotent%stem%cells%(PSCs) – Embryonic%stem%cells%(ESCs) – Induced%pluripotent%stem%cells%(iPSCs) • Multipotent%stem%cells – Multipotent%stem%cells%are%often%referred%to%as%adult%stem%cells%(even% though%they%are%also%found%in%embryos) – Hematopoietic%stem%cells%(HSCs) – Mesenchymal%stem%cells%(MSCs) – Neural%stem%cells%(NSCs) • Unipotent%stem%cells – Epidermal%stem%cells%(EpiSCs)

  15. Induced pluripotent stem&cells (iPSCs) Mouse& fibroblasts Oct4 Sox2 Klf4 C-Myc Shinya Yamanaka Induced pluripotent& stem&cells (iPSC)

  16. Cell$differentiation$potency Conrad$ Waddington (1957) somatic$cells + Reprogramming$factors

  17. Nobelprize 2012-in-medicine John-B-Gurdon Shinya Yamanaka

  18. Most%common%stem%cell%types • Pluripotent%stem%cells%(PSCs) – Embryonic%stem%cells%(ESCs) – Induced%pluripotent%stem%cells%(iPSCs) • Multipotent%stem%cells – Multipotent%stem%cells%are%often%referred%to%as%adult%stem%cells% (even%though%they%are%also%found%in%embryos) – Hematopoietic%stem%cells%(HSCs) – Mesenchymal%stem%cells%(MSCs) – Neural%stem%cells%(NSCs) • Unipotent%stem%cells – Epidermal%stem%cells%(EpiSCs)

  19. Most%common%stem%cell%types • Pluripotent%stem%cells%(PSCs) – Embryonic%stem%cells%(ESCs) – Induced%pluripotent%stem%cells%(iPSCs) • Multipotent%stem%cells – Multipotent%stem%cells%are%often%referred%to%as%adult%stem%cells% (even%though%they%are%also%found%in%embryos) – Hematopoietic%stem%cells%(HSCs) – Mesenchymal%stem%cells%(MSCs) – Neural%stem%cells%(NSCs) • Unipotent%stem%cells – Epidermal%stem%cells%(EpiSCs)

  20. Hematopoietic*stem*cells*(HSCs) Reside*in*bone*marrow Most*well*defined*stem*cell*hierarchy,* but*still*developing Transplantation*of*bone*marrow@ derived*hematopoietic*stem*cells* commonly*used Eaves*(2015)

  21. Most%common%stem%cell%types • Pluripotent%stem%cells%(PSCs) – Embryonic%stem%cells%(ESCs) – Induced%pluripotent%stem%cells%(iPSCs) • Multipotent%stem%cells – Multipotent%stem%cells%are%often%referred%to%as%adult%stem%cells% (even%though%they%are%also%found%in%embryos) – Hematopoietic%stem%cells%(HSCs) – Mesenchymal%stem%cells%(MSCs) – Neural%stem%cells%(NSCs) • Unipotent%stem%cells – Epidermal%stem%cells%(EpiSCs)

  22. Mesenchymal+stem+cells+(MSCs) BMIMSCs+and+ADIMSCs+ fundamentally+different+cells+ Reside+in+different+organs types+albeit+with+same+ differentiation+potentials Definition • Adhere+to+plastic • Positive+for+CD73,+CD90+and+CD105 • Negative+for+CD14,+CD34,+CD45+and+ HLAIDR • In+vitro+differentiation+into • Chondroblasts • Osteoblasts • Adipocytes • Further+differentiation+potentials • Myocytes • Neurons • Oligodendrocytes • Hepatocytes • Pancreocytes Oryan et+al.+(2017)Q+Ullah+et+al.+(2015)Q+Noël+et+al.+(2008)

  23. Most%common%stem%cell%types • Pluripotent%stem%cells%(PSCs) – Embryonic%stem%cells%(ESCs) – Induced%pluripotent%stem%cells%(iPSCs) • Multipotent%stem%cells – Multipotent%stem%cells%are%often%referred%to%as%adult%stem%cells% (even%though%they%are%also%found%in%embryos) – Hematopoietic%stem%cells%(HSCs) – Mesenchymal%stem%cells%(MSCs) – Neural%stem%cells%(NSCs) • Unipotent%stem%cells – Epidermal%stem%cells%(EpiSCs)

  24. Neural'stem'cells'(NSCs) Reside'in'CNS Differentiate'into • Neuronal'subtypes • Astrocytes • Oligodendrocytes

  25. Most%common%stem%cell%types • Pluripotent%stem%cells%(PSCs) – Embryonic%stem%cells%(ESCs) – Induced%pluripotent%stem%cells%(iPSCs) • Multipotent%stem%cells – Multipotent%stem%cells%are%often%referred%to%as%adult%stem%cells% (even%though%they%are%also%found%in%embryos) – Hematopoietic%stem%cells%(HSCs) – Mesenchymal%stem%cells%(MSCs) – Neural%stem%cells%(NSCs) • Unipotent%stem%cells – Epidermal%stem%cells%(EpiSCs)

  26. Epidermal*stem*cells*(EpiSC) Reside*in*skin Differentiate*into • Keratinocytes

  27. Contents • Stem*cell*definitions • Cell*differentiation*potency • The*stem*cell*hierarchy:*Pluripotent,*multipotent*and* unipotent*stem*cells • Induced*pluripotent*stem*cells*for*disease*modeling • Stem*cell*therapy • Conclusions

  28. How$can$iPSCs$ help$modeling$dementia? Access%to%the% human%target: iPSC4derived% patient4specific% neurons

  29. Frontotemporal+dementia+ localized+to+chromosome+3+(FTD3) Mutation+in CHMP2B' on+ chromosome+3+ resulting+in+ dementia+with+ early+onset FReJa Consortium CHMP2B mutation

  30. iPSC4based6modeling6of6FTD3 CRISPR/Cas9 Plasmid%iPSC% reprogramming Gene% FTD3% corrected% iPSC iPSC Neural% differentiation Skin% fibroblasts Gene% FTD3% corrected% neurons neurons Rescue%from% Identification6of6 disease% ROS FTD36phenotype6 phenotype ROS and6 therapeutic6targets Endosomes Endosomes Mitochondria Mitochondria FTD3%patient

  31. iPSC4based6modeling6of6FTD3 CRISPR/Cas9 Plasmid%iPSC% reprogramming Gene% FTD3% corrected% iPSC iPSC Neural% differentiation Skin% fibroblasts Gene% FTD3% corrected% neurons neurons Rescue%from% Identification6of6 disease% ROS FTD36phenotype6 phenotype ROS and6 therapeutic6targets Endosomes Endosomes Mitochondria Mitochondria FTD3%patient

  32. Generation)of)integration,free patient,specific)iPSCs Fibroblasts from)skin)biopsy iPSC Day)26 L1MYC LIN28 OCT3/4 Shp53+ SOX2 KLF4 Okita et)al.)2011 Rasmussen)et)al.)2011 Mikkel Rasmussen,)Kristine)Freude and)Yu)Zhang

  33. iPSC4based6modeling6of6FTD3 CRISPR/Cas9 Plasmid%iPSC% reprogramming Gene% FTD3% corrected% iPSC iPSC Neural% differentiation Skin% fibroblasts Gene% FTD3% corrected% neurons neurons Rescue%from% Identification6of6 disease% ROS FTD36phenotype6 phenotype ROS and6 therapeutic6targets Endosomes Endosomes Mitochondria Mitochondria FTD3%patient

  34. Importance+for+gene+editing+in+iPSC disease+modeling + r e d n e g + d l n o a r t + n e g o c A + d e h c t a m Isogenic/gene+edited+ control Courtesy+of+Kristine+Freude

  35. Gene'editing'of'iPSCs Courtesy'of' Jacob'Corn' Trinity'College,'Dublin

  36. Gene$editing$of$iPSCs FTD3$iPSC Gene3corrected iPSC ssODN with$correct$template$sequence C/T GuideRNA Cas9 T Anna$Poon,$Benjamin$Schmid and$Kristine$Freude

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