Stem Cells: A Global Perspective...(Kondo et al. Cell Stem Cell, 2013) + + Background: Parkinson’s...

Stem Cells: A Global Perspective

Ole Isacson, M.D.–Ph.D.

Harvard Medical School

IMI Stakeholder Forum – 21 May 2014 - Brussels

Heart and vascular disease

O Isacson

Diabetes

(β-cells)

Aging Processes

(Oxidative stress,…)

Neurological Diseases

(Alzheimer’s…)

Parkinson’s disease (DA cells, etc.)

Regenerative Medicine:

Regeneration in Planaria – flatworm

Regenerative Medicine:

Stem Cell based options

• Mechanism of disease

• Drug screening

• Cell therapy

Study of disease and drug screening

Restorative and cell therapy

What is a stem cell and an iPS cell?

Embryonic Stem Cells

IMI Stakeholder Forum- 21 May 2014 - Brussels

http://learn.genetics.utah.edu/content/tech/stemcells/quickref/isolatingEScells.jpg

(1) Sperm and egg join

(2) Embryo develops for 5-7 days

Blastocyst

(3) Remove inner cell mass (4) Grow in dish

(5) Change culture conditions to stimulate cells to differentiate into a variety of cell types

Skin cells Skeletal muscle cells

Neural cells

Generation of human induced pluripotent stem cells

Davis et al., Trends in Mol Med (2012)

Why are iPS cells so important?

Electrophysiological differences between adult human and mouse

Cardiomyocytes

Davis et al., Trends in Mol Med (2012)

Medicines withdrawn from the market due to cardiotoxicity

Braam et al., Trends in Pharmacological Sciences (2009)

Human iPS cell derivation, differentiation and applications

Bellin et al., Nature Reviews: Mol Cell Biol (2012)

The global advancement of medical research & treatment

Latest developments in stem cell research

Disease modeling using Alzheimer’s disease patient iPSCs

Patient iPSCs would be useful for precision early diagnosis

Monomer

Tetramer

Endosome

ER stress

Oxidative stress ROS↑

BiP↑

PRDX4↑

Amyloidβoligomer

(Kondo et al. Cell Stem Cell, 2013)

Background: Parkinson’s disease disease

VTA/A10

SNc/A9

SNc and VTA relevance to Parkinson’s disease

Isacson, O IMI Stakeholder Forum – 21 May 2014 - Brussels

The most vulnerable midbrain DA neuron type (A9) in PD -- allowing

basal gangliamovement initiation -- has specific connections,

physiology, cell biology and gene expression

1. Cell type specific gene expression of midbrain dopaminergic neurons.. vulnerability and protection. Chung CY et al Hum. Mol. Genet. 2005

2. Cell type analysis of functional fetal dopamine cell suspension transplants in patients with Parkinson's disease Mendez I et al Brain 2005

Pre-symptomatic stage

Symptomatic stage

Neuroprotective therapies

Small molecules

Gene therapy

Transplantation and restoration strategies

DA agonists L-DOPA and pharmacology

Isacson, O

Initiation, progression and treatments of midbrain dopaminergic (DA) synaptic and cellular loss in

Parkinson’s disease

Cell Therapy

Parkinson’s Disease Patients:

Causes and diagnostically defined

human populations

Pure genetic forms are rare but provide contexts For approaches using PD iPS cells

Goal: Matching high risk individuals by iPS cell-derived cell function analyses and drug responsiveness

Efficacy

Toxicity

Strategies for disease modeling in

a dish using iPSCs

Adult cell

Reprogrammed cell (iPSC)

Disease Simulation Process

Readout: Disease outcome/pathology of adaptive responses

1 2 a) none

b) known genetic inherited

a) chemically induced b) genetically induced c) combined a & b

Cell, organelle and molecular phenotypes

Isacson O

PD patients iPSC derived neural cells: Spontaneous cellular phenotypic changes in dish

Validation and standardization of individuals’ PD iPS cells

Cooper et al. Science Translational Medicine, 2012

1. Mitochondrial function and aging

Lysosomal function & autophagy

Immune response

Nuclear transcription response and expression patterns (epigenetic & aging response)

Electrophysiological parameters

3. Transport, cytoskeletal & neurite extension/retraction responses Adaptive electrophysiological response

2. Golgi to Endoplasmic reticulum unfolded protein response and function

Membrane integrity

Dendritic input and neurite morphology

PDiPSC derived neurons can be used to reveal gene or disease specific cell responses

Isacson O

1. Mitochondrial function and aging

Lysosomal function & autophagy

Immune response

Nuclear transcription response and expression patterns (epigenetic & aging response)

Electrophysiological parameters

Transport, cytoskeletal & neurite responses

Adaptive electrophysiological response

Golgi to Endoplasmic reticulum response and function

Membrane integrity

Dendritic input

Isacson O

PDiPSC derived neurons can be used to reveal gene or disease specific cell responses

Sanders L et al, 2013

PD patients iPSC derived neural cells: Cellular phenotypic responses after

challenge in dish

PINK1 PD iPS cell-derived neuronal cells produce much higher levels of free-radical species after

mitochondrial K+ depolarization than sibling controls

Unstained Healthy Subject Val 1mM

PINK1 Val 1mM

Genetically linked PD Neural cells from iPS cells are more sensitive to cellular mitochondrial

stress than fibroblasts

Chemical stressors produce both specific and converging responses from different genetic forms of PD

Rescue of PD patient neural cell by antioxidant-like and other drugs

PD patients iPSC derived human

neurons transplanted as an in vivo brain assay

Transplanted PDiPSC SNCA3x neurons have reduced neurite extension in brain for the

1st month in vivo

In vitro differentiated then transplanted hPDiPS cells: human specific alpha syn and TH/DA

stained after 6 months in vivo

Patients iPSC derived cells in a dish: Summary and Outlook

Strategies for disease modeling in

a dish using iPSCs

Adult cell

Reprogrammed cell (iPSC)

Disease Simulation Process

Readout: Disease outcome/pathology of adaptive responses

1 2 a) none

b) known genetic inherited

a) chemically induced b) genetically induced c) combined a & b

Cell, organelle and molecular phenotypes

Isacson O

Pre-symptomatic stage

Symptomatic stage

Neuroprotective therapies

Small molecules

Gene therapy

Transplantation and restoration strategies

DA agonists L-DOPA and pharmacology

Isacson, O

Cell Therapy

Outlook: iPSC derived neurons can be used to discover cellular pre-symptomatic or pre-disposing neurobiology and neuroprotective treatments

Promises and hurdles in using human iPS cells for disease

modeling and drug discovery

• Controls: Human induced pluripotent stem (iPS) cells from the same patient can show biological variability

• Drug discovery and toxicity: Early risk prediction for new drugs reduces attrition rates and costs

• Cell-autonomous versus non-cell-autonomous: Human iPS cells are most suitable for investigating monogenetic diseases with complete penetrance that display cell-autonomous defects on differentiated cells

• Immaturity of differentiated cells: Differentiated cells from human pluripotent stem cells are immature

• Effects of genetic and ethnic backgrounds: Many diseases manifest with incomplete penetrance so that patients harbouring the same mutation have different phenotypes

• Novel biological insights: A key challenge in human iPS cell biology is to generate new (patho)physiological insights.

Bellin et al., Nature Reviews: Mol Cell Biol (2012)

Penny Hallett Teresia Osborn Oliver Cooper Maria Sundberg Jesse McLean Gaynor Smith Emily Mangano Johan Jansson Tristan Lawson Sarah Izen Eduardo Perez-Torres Jon Beagan Hyemyung Seo Michela Deleidi Gunnar Hargus

Neuroregeneration Laboratory

U Pittsburgh J. Timothy Greenamyre Laurie Sanders Parkinson’s Institute, CA Birgitt Schuele

Harvard University

Kevin Eggan Lee Rubin Paola Arlotta

NINDS PDiPS Consortium

Thank you

Stem Cells: A Global Perspective...(Kondo et al. Cell Stem Cell, 2013) + + Background: Parkinson’s...

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