Therapeutic and Research Potential of Human

Stem Cells

Dr Stephen L MingerDr Stephen L MingerDirector, Stem Cell Biology LaboratoryDirector, Stem Cell Biology Laboratory

Wolfson Centre for Age-Related DiseasesWolfson Centre for Age-Related DiseasesKing’s College LondonKing’s College London

Senior Editor – Regenerative MedicineSenior Editor – Regenerative Medicine

Stem Cell Expert – UK Gene Therapy Stem Cell Expert – UK Gene Therapy Advisory Committee (GTAC)Advisory Committee (GTAC)

Parkinson’s Disease and the Parkinson’s Disease and the BrainBrain

Progressive and sustainedimprovement in transplantfunction over ten years inhuman graft recipient

Piccini et al, 1999, NatureNeurosci, 2

Stem Cells – Types, Flavours and Sources

Pluripotent Multipotent

Multipotent

Multipotent

Adult Neurogenesis

Human adult braincontains proliferativeneural stem cells in dentate gyrus and lateral ventricle wall (SVZ) that generate new neurons throughout life

Eriksson et al, 1998, NatureMed, 4, 1313

Regulators of Adult Regulators of Adult NeurogenesisNeurogenesis

PositivePositive

Enriched EnvironmentEnriched Environment Physical Activity (e.g. Physical Activity (e.g.

Running)Running) AntidepressantsAntidepressants Caloric RestrictionCaloric Restriction LearningLearning Modulation of ExcitationModulation of Excitation Ischaemia (experimental)Ischaemia (experimental) Pregnancy (Prolactin)Pregnancy (Prolactin) Inflammatory Blockade Inflammatory Blockade

(NSAIDS)(NSAIDS) VEGF, G-CSF, NO, SCFVEGF, G-CSF, NO, SCF Statins (Anti-hypertensives)Statins (Anti-hypertensives) LithiumLithium

NegativeNegative

OpiatesOpiates MethamphetamineMethamphetamine SeizuresSeizures AgingAging Stress (Glucocorticoids)Stress (Glucocorticoids) 5-HT Depletion 5-HT Depletion Nitric OxideNitric Oxide Inflammation Inflammation (Microglial (Microglial

Activation)Activation) Interleukin-6 (from activated Interleukin-6 (from activated

microglia)microglia) IrradiationIrradiation Nicotine Nicotine

84-year old womanwith progressive

vasculardisease

Stoke 2 weeks prior to death

Minger et al, 2007

Adult Human SVZ Neural Progenitor Cells

Austin Smith, 2003

Human Embryo Research in Human Embryo Research in UKUK

Human Fertilisation and Embryology Authority Human Fertilisation and Embryology Authority Created in 1990Created in 1990

All Reproductive Medicine & Human Embryo All Reproductive Medicine & Human Embryo Research must be licensed by HFEAResearch must be licensed by HFEA

HFEA-Licensed Embryo Research AreasHFEA-Licensed Embryo Research Areas Treatment of InfertilityTreatment of Infertility Causes of Congenital DiseasesCauses of Congenital Diseases Causes of MiscarriageCauses of Miscarriage Development of more Effective ConceptionDevelopment of more Effective Conception Improvements in Preimplantation Genetic DiagnosisImprovements in Preimplantation Genetic Diagnosis Provide Understanding of Human DevelopmentProvide Understanding of Human Development Provide Understanding of Human DiseaseProvide Understanding of Human Disease Enable Development of Therapies of Human DiseaseEnable Development of Therapies of Human Disease

License for Derivation of Human License for Derivation of Human ES cells from UK Human ES cells from UK Human

Fertilisation and Embryology Fertilisation and Embryology AuthorityAuthority

Awarded to Drs Susan Pickering, Stephen Awarded to Drs Susan Pickering, Stephen Minger & Professor Peter Braude in May 2002 – Minger & Professor Peter Braude in May 2002 – renewed in 2005 for three additional yearsrenewed in 2005 for three additional years

Derivation from donated embryos with informed Derivation from donated embryos with informed consentconsentNo financial inducement for donationNo financial inducement for donationCannot create embryos for stem cell derivationCannot create embryos for stem cell derivationAll cell lines must be deposited in UK Stem Cell Bank All cell lines must be deposited in UK Stem Cell Bank and made and made freely available to other research groupsfreely available to other research groupsCell Nuclear Replacement (Therapeutic) permitted with Cell Nuclear Replacement (Therapeutic) permitted with licenselicenseCell Nuclear Replacement (Reproductive) banned with Cell Nuclear Replacement (Reproductive) banned with criminal criminal penaltiespenalties

Early human development in vitro

Late Day 1 2- cells

Day 1

Day 2 4-cells Day 3 8-cells

Day 4 Morula

Blastocyst Day 5

Hatching Day 6Hatched Late Day 6

ICM

Day 4

ICM

The inner cell mass - contains pluripotent stem cells

With Good Karma, Embryos, andCulture Conditions, Human ESCells Can Be Established At Frequency of ~10%

A, B, Cystic Fibrosis Line (CF-1)C HES Cell Line (WT-4)

A B

CC

Oct-4

-Tubulin(ectoderm)

Smooth Muscle Actin (mesoderm) Albumin (endoderm)

Stem Cell Biology Laboratory Stem Cell Biology Laboratory Therapeutic TargetsTherapeutic Targets

CNS DisordersCNS Disorders Spinal Cord (McMahon, Bradbury) - traumatic injury, Multiple SclerosisSpinal Cord (McMahon, Bradbury) - traumatic injury, Multiple Sclerosis Parkinson’s disease (Duty, Jenner) Parkinson’s disease (Duty, Jenner) Stroke/Vascular Disease (Ballard) – adult neurogenesisStroke/Vascular Disease (Ballard) – adult neurogenesis

Cardiac RegenerationCardiac Regeneration Heart Failure/Heart Attack (Mathur/Hirschi & Cardiac Cell Therapy Heart Failure/Heart Attack (Mathur/Hirschi & Cardiac Cell Therapy

Consortium)Consortium) Retinal RegenerationRetinal Regeneration

Macular Degeneration, Retinitis Pigmentosa (Ali, Institute of Ophthalmology)Macular Degeneration, Retinitis Pigmentosa (Ali, Institute of Ophthalmology) Endocrine DisordersEndocrine Disorders

Type I Diabetes (Jones, Persuad & King’s Islet Transplant Programme)Type I Diabetes (Jones, Persuad & King’s Islet Transplant Programme) Hepatic RegenerationHepatic Regeneration

Hepatic Insufficiency (King’s Liver Transplant Programme)Hepatic Insufficiency (King’s Liver Transplant Programme) Joint and Bone DestructionJoint and Bone Destruction

Cartilage Repair ( De Bari, Dell’Accio)Cartilage Repair ( De Bari, Dell’Accio) Bone Replacement (Grigoriadis)Bone Replacement (Grigoriadis)

Epithelial CellsEpithelial Cells Lung Differentiation (Novartis)Lung Differentiation (Novartis) Skin Cells for Genetic Skin Disorders (McGrath)Skin Cells for Genetic Skin Disorders (McGrath)

Stem Cell BioprocessingStem Cell Bioprocessing Bioengineering/Scale up (Mason, UCL)Bioengineering/Scale up (Mason, UCL)

Developments Required for Therapeutic Developments Required for Therapeutic Application of Human ES Cells To Application of Human ES Cells To Parkinson’s Disease – Preclinical Parkinson’s Disease – Preclinical

Generation of A9-Mesencephalic Dopaminergic Neural Stem Cells Generation of A9-Mesencephalic Dopaminergic Neural Stem Cells by Genetic Engineering – not A10by Genetic Engineering – not A10

Characterisation of Dopaminergic Progenitor CellsCharacterisation of Dopaminergic Progenitor Cells Testing of A9 Stem Cells in Rat PD Models Testing of A9 Stem Cells in Rat PD Models Identification of Cell-Surface Proteins Unique to A9 Dopa Stem Cells Identification of Cell-Surface Proteins Unique to A9 Dopa Stem Cells

by Mass Spectroscopy (if required)by Mass Spectroscopy (if required) Selection of A9 Neural Stem Cells by SortingSelection of A9 Neural Stem Cells by Sorting Long-term Safety and Efficacy Testing of A9 Cells in Rodent -> Long-term Safety and Efficacy Testing of A9 Cells in Rodent ->

Primate Models of PDPrimate Models of PD

Developments Required for Therapeutic Developments Required for Therapeutic Application of Human ES Cells To Application of Human ES Cells To

Parkinson’s Disease Therapy – Clinical IssuesParkinson’s Disease Therapy – Clinical Issues

Delivery of Cells for Therapeutic Applications – Good Delivery of Cells for Therapeutic Applications – Good Experience with Foetal Cell Transplantation, Efficacy Experience with Foetal Cell Transplantation, Efficacy Proportional to Number of DA Neurons Implanted Proportional to Number of DA Neurons Implanted

Need for Standardised Neurosurgical Protocol Need for Standardised Neurosurgical Protocol Requirement for Strict Inclusion/Exclusion Criteria Requirement for Strict Inclusion/Exclusion Criteria

for Patient Selection – Reduce Variability between for Patient Selection – Reduce Variability between PatientsPatients

Generation of Animal-Free, Chemically Defined Generation of Animal-Free, Chemically Defined Culture Conditions -> No XenoproductsCulture Conditions -> No Xenoproducts

Generation of Therapeutic-Grade Lines – Requires Generation of Therapeutic-Grade Lines – Requires Specialised GMP-Level Facilities – King’s 2008Specialised GMP-Level Facilities – King’s 2008

Immune Response – Short term (2-3 yrs) minimal Immune Response – Short term (2-3 yrs) minimal immunosuppression supportive/required for graft immunosuppression supportive/required for graft survivalsurvival

Somatic Cell NuclearReplacement

(Cloning)

Can it work in Humans?

Should it be allowed?

How can we use this technology for therapy and/or research?

Strengths of UK Stem Cell Strengths of UK Stem Cell ResearchResearch

World-class academic research centresWorld-class academic research centres Tight regulation on Assisted Reproduction & Tight regulation on Assisted Reproduction &

Human Embryo Research by HFEAHuman Embryo Research by HFEA Government Commitment to Stem Cell Research Government Commitment to Stem Cell Research

(~£45 million – 2003-2004); £350-800 million 10-(~£45 million – 2003-2004); £350-800 million 10-year strategy from Chancellor’s Office announced year strategy from Chancellor’s Office announced Dec 2005 Dec 2005

Government Funded UK Stem Cell Bank for foetal, Government Funded UK Stem Cell Bank for foetal, adult & embryonic human stem cell linesadult & embryonic human stem cell lines

London Regenerative Medicine Network – drive London Regenerative Medicine Network – drive towards clinical applicationstowards clinical applications

UK Stem Cell Network – integration of all UK UK Stem Cell Network – integration of all UK regional networkregional network

Stem Cell Biology LaboratoryWolfson Centre for Age-Related Diseases

Sarah PringleSarah PringleSiobhán ConnorSiobhán Connor Zhenling LuoZhenling LuoKaterina VaranouKaterina VaranouWoojin LeeWoojin Lee

Julie GhoshJulie GhoshDaniel WebberDaniel WebberJessica CookeJessica CookeHannah TaylorHannah Taylor

Antigoni EkonomouAntigoni EkonomouSH CedarSH CedarChetan ShatapathyChetan ShatapathyYue WuYue Wu

Stem Cell Biology Laboratory CollaboratorsStem Cell Biology Laboratory CollaboratorsHuman ES CellsHuman ES CellsPeter BraudePeter BraudeSara HallSara HallGlenda CornwallGlenda CornwallEmma StephensonEmma Stephenson

Spinal Cord RepairSpinal Cord RepairSteve McMahonSteve McMahonLiz BradburyLiz BradburyPaul FeltsPaul FeltsMerion Davies Merion Davies

Retinal RegenerationRetinal Regeneration Robin Ali (UCL/Moorfields)Robin Ali (UCL/Moorfields)

Pancreatic Islet Pancreatic Islet Cells Cells Peter JonesPeter JonesShanta PersaudShanta Persaud

Parkinson’s DiseaseParkinson’s Disease Peter JennerPeter JennerSusan DutySusan Duty

Tooth ReplacementTooth ReplacementPaul SharpePaul Sharpe

Neural DifferentiationNeural DifferentiationJonathan CorcoranJonathan CorcoranBia GonclavesBia Gonclaves

BioprocessingBioprocessingChris Mason (UCL)Chris Mason (UCL)

Medical Research Council, Edmond J Safra Foundation, BBSRC, ESRC, EPSRC, Medical Research Council, Edmond J Safra Foundation, BBSRC, ESRC, EPSRC, European Commission, Oliver Bird Foundation, UK DTI, European Commission, Oliver Bird Foundation, UK DTI, Francesca Patrizi,Francesca Patrizi,

High Q Foundation, Wellcome Trust, Huntington’s Disease SocietyHigh Q Foundation, Wellcome Trust, Huntington’s Disease Society, John &, John & Helen Helen Robertson, Alzheimer’s Research Trust, Liz & John Hancock, Guy’s & St Thomas’ Robertson, Alzheimer’s Research Trust, Liz & John Hancock, Guy’s & St Thomas’

Charitable TrustCharitable Trust

Adult NeurogenesisAdult NeurogenesisClive BallardClive BallardOmar PathmanabanOmar PathmanabanChirstos ToliasChirstos ToliasElaine Perry (Newcastle)Elaine Perry (Newcastle)Robert Perry (Newcastle)Robert Perry (Newcastle)Aaron Cheung (GSK)Aaron Cheung (GSK)

Vascular DevelopmentVascular DevelopmentKaren Hirschi (Baylor)Karen Hirschi (Baylor)Qingbo XuQingbo Xu

Blood Stem CellsBlood Stem CellsPaul Fairchild (Oxford)Paul Fairchild (Oxford)Karl Karlsson (Oxford)Karl Karlsson (Oxford)

Lung DifferentiationLung DifferentiationCarol Jones (Novartis)Carol Jones (Novartis)Phil Kemp (Novartis)Phil Kemp (Novartis)

Bioethics & PoliticsBioethics & PoliticsClaire WilliamsClaire WilliamsSteve WainrightSteve WainrightSarah Franklin (LSE)Sarah Franklin (LSE)Brian Salter (Norwich)Brian Salter (Norwich)Herbert Gottweis (Vienna)Herbert Gottweis (Vienna)

ElectrophysiologyElectrophysiologyReginald DochertyReginald Docherty

Cardiac RepairCardiac RepairAnthony Mathur Anthony Mathur (Barts)(Barts)Matthew Lovell (Barts)Matthew Lovell (Barts)

ProteomicsProteomicsTony NgTony NgSimon Ameer-BegSimon Ameer-Beg Sukhi BansalSukhi BansalGiampietro Schiavo (CRUK)Jonas Bergquist (Uppsala)

Huntington’s DiseaseHuntington’s DiseaseGillian BatesGillian BatesEva SirinathsinghjiEva Sirinathsinghji

Cartilage GenerationCartilage GenerationCosimo De BariCosimo De BariFrancesco Dell’AccioFrancesco Dell’Accio

Hepatic Stem CellsHepatic Stem CellsAnill DhawanAnill DhawanRobin HughesRobin HughesRagai MitryRagai Mitry

Bone DevelopmentBone DevelopmentAgi GrigoriadisAgi Grigoriadis

Skin DifferentiationSkin DifferentiationJohn McGrath