how to make a heart: towards pluripotent cell-based heart stem cell therapeutics
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How to Make a Heart: Towards Pluripotent Cell-Based Heart Stem Cell Therapeutics. ACI 2011 BCIS Meeting London Hilton Metropole London, UK January 28, 2011 Kenneth R. Chien MD, PhD MGH Cardiovascular Research Center Department of Stem Cell and Regenerative Biology Harvard University - PowerPoint PPT PresentationTRANSCRIPT
How to Make a Heart:Towards Pluripotent Cell-Based Heart Stem Cell Therapeutics
ACI 2011 BCIS Meeting
London Hilton MetropoleLondon, UK
January 28, 2011
Kenneth R. Chien MD, PhD
MGH Cardiovascular Research Center Department of Stem Cell and Regenerative
BiologyHarvard University
Harvard Stem Cell Institute
• Islet-1 heart progenitor story
• Heart Parts: Engineering patch of mature heart muscle tissue from ES cells
• Human master Islet-1 progenitors: Human cardiogenesis, congenital heart disease , and regenerative therapeutics
• Laser technology devices for cell based therapy
2
The Unmet Clinical Need: Growing Heart Muscle
22 57
719
2,107 2,1632,199
2,363
0
500
1,000
1,500
2,000
2,500
75 80 85 90 95 00 08
Years
Num
ber o
f Tra
nspl
ants
Hansson, Lindsay, and Chien, Cell Stem Cell, In Press, September, 2009
Regeneration Next: Towards Heart Progenitor Derived Heart Parts
The Meltonian Stem Cell Era: Directed Differentiation of Pluripotent Stem Cells
J Embryol Exp Morphol. 1985
The in vitro development of blastocyst-derived embryonic stem cell lines: formation of visceral yolk sac, blood islands and myocardium.Doetschman TC, Eistetter H, Katz M, Schmidt W, Kemler R.
• Diversification• Scalability• Maturation• Coordination• Durability
5
How to Make a Heart
ES/iPS Pluripotent Stem Cells
Committed Ventricular Progenitor
Differentiated Ventricular Cell
Mature Ventriuclar Cell
Durable VentricularMuscle Tissue
Multipotent Iwlet Heart Progenitor
Ventricular Cardiac Muscle Cell Fate Map:Towards Human Heart Stem Cell Models and Therapeutics
Laugwitz et al, Nature, 2005 Moretti et al Cell, 2006 Qyang et al Cell Stem Cell, 2007 Martin-Puig et al, Cell Stem Cell, 2008 Chien, Nature, 2008 Chien, et al, Science, 2008 Bu et al, Nature, 2009 Domian et al, Science, 2009 Hansson et al, Cell Stem Cell, 2009
Mesodermal Precursor
Multipotent Isl1 Cardiovascular Progenitor
BipotentProgenitor
Differentiated Progeny
Endothelial Cell
Smooth Muscle Cell
Right Ventricular
Cardiomyocyte
AtrialCardiomyocyte
Smooth Muscle Cell
Isl-1Flk-1Nkx2.5
Isl-1Nkx2.5
BryFlk-1
Cardiac Mesodermal Precursor
Primary Heart FieldCardiovascular Progenitor
Nkx2.5Others ?
Left Ventricular Cardiomyocyte
Mlc2-vNkx2.5MHC
Mlc2-vMHC
SLNMHC
CD31vWf
SM-MHC
SM-MHC
Bry
Wnt/-cat
Wnt/-cat
Common PrimordialCardiovascular Progenitor
?
Atrioventricular Nodal Cell
Sinoatrial Nodal Cell
§
Towards defining the heart cell lineage map
?
Coordinated Contractility of a Syncitium of Murine ES cell
derived Islet-1 Progenitors Driven into the Cardiac Lineage
Cardiac Progenitor Cells Form a Thin Film of Beating Cardiac Muscle
Making a Ventricular Heart Muscle Patch:Towards Regenerative Cardiovascular Medicine
Domian et al, Science, 2009
10
Islet Heart Progenitors in the Human Heart
Hansson, Lindsay, and Chien, Cell Stem Cell, October, 2009 Bu et al, Nature, 2009
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Master Human Islet Heart Progenitors from ES Cells Can Make Any Cardiovascular Heart Cell Type
Master ISL1 heart progenitors
A Stem Cell Paradigm for Human Cardiogenesis & Congenital Heart Disease
Hansson, Lindsay, and Chien, Cell Stem Cell, October, 2009
• TBX1• NKX2.5• TBX20
Malformation of several organs, including the cardiovascular system
- arterial tortuosity - diffuse aneurysms - rupture / death young age - congenital heart disease
(PDA, BAV, ASD)
Caused by mutations in TGFRB1 (ALK5) or TGFRB2
Loeys et al., Nature Genetics, 2005
Loeys-Dietz syndrome
iPS derivation EB differentiation
+ / - Alk5 inhibitorPlate & culture underISL1+ promoting conditions
LD syndrome iPS cells display a >4 fold increase in the induction of ISL+ progenitors
+/- Alk5 inhibitor vs control
Analysis of SHF progenitor cells carryingTGFBR mutations causing Loeys-Dietz syndrome
Mesodermal precursors
Multipotent Isl1+ cardiovascular
progenitors
Intermediates committed
to CV lineages
Cardiac mesenchymal cells
prespecification
Islet/Wnt3a
Wnt3a
differentiation
Endothelial cells
Cardiomyocytes
Smooth muscle
TGF-beta
• Diversification (Islet)• Scalability (Wnt)• Maturation (TGF beta Pathway)• Coordination (?)
A Islet Progenitor Fate Map for Regenerative Cardiovascular Medicine
-
CM Progenitors
?
Heart Muscle Tissue Engineering
In vivo delivery
Vascularization
Grafting/Rejection
Side effects/arrhythmogenesis
Efficacy endpoints
The “Apollo” Mission of Cardiac Regenerative Medicine
General Pathway for Cell-based Regenerative Medicine
Lasers in MedicineOphthalmology
Plastic Surgery
Dermatology
Cardiology
Oncology
Radiology
Vascular Medicine
Advantages of Lasers in Medicine
Finely focused laser beams offer precision over scalpels
Hemostasis Miniaturization of laser Adaptability to different needs
Many types of lasers with properties tunable to specific needs
Liver
Day 0 Day 1
Liver
Day 4Day 7
Skeletal muscle regeneration
• Lasers can create finely focused areas of injury
• Skeletal muscle regenerates quickly with a minimum of fibrosis
CD-1 Mice
Human, Human, and Human: Towards Human Heart Parts and Heart Models
• The checkpoints that control the expansion of ventricular progenitors?
• Promoting the in vivo survival and grafting of CVP derived heart patches and in the in vivo context
• In vivo delivery of CVPs—miniaturized endoscopic delivery systems
• Engineering other “Heart Parts”---Coronary Arteriogenesis
• Drug discovery/safety in human models systems
•CHD and adult monogenic CV human disease models