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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

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slide1

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

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
slide3

Regeneration Next: Towards Heart Progenitor Derived Heart Parts

Hansson, Lindsay, and Chien,

Cell Stem Cell, In Press, September, 2009

slide4

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
how to make a heart
How to Make a Heart

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

ES/iPS Pluripotent Stem Cells

Multipotent Iwlet Heart Progenitor

Committed Ventricular Progenitor

Differentiated Ventricular Cell

Mature Ventriuclar Cell

Durable Ventricular

Muscle Tissue

slide6

Towards defining the

heart cell lineage map

Bipotent

Progenitor

Differentiated

Progeny

Smooth

Muscle Cell

Multipotent

Isl1

Cardiovascular

Progenitor

?

SM-MHC

Wnt/b-cat

Right *

Ventricular

Cardiomyocyte

Wnt/b-cat

Mlc2-v

MHC

Isl-1

Nkx2.5

Atrioventricular

Nodal Cell

Atrial

Cardiomyocyte

Isl-1

Flk-1

Nkx2.5

Common

Primordial

Cardiovascular

Progenitor

Cardiac

Mesodermal

Precursor

Mesodermal

Precursor

SLN

MHC

?

Sinoatrial

Nodal Cell

Endothelial

Cell

CD31

vWf

Bry

Bry

Flk-1

Smooth

Muscle Cell

SM-MHC

Primary Heart Field

Cardiovascular

Progenitor

Left * Ventricular

Cardiomyocyte

Nkx2.5

Others ?

Mlc2-v

Nkx2.5

MHC

slide7

Coordinated Contractility of a Syncitium of Murine ES cell

derived Islet-1 Progenitors Driven into the Cardiac Lineage

slide9

Making a Ventricular Heart Muscle Patch:

Towards Regenerative Cardiovascular Medicine

Domian et al, Science, 2009

islet heart progenitors in the human heart
Islet Heart Progenitors in the Human Heart
  • Hansson, Lindsay, and Chien,
  • Cell Stem Cell, October, 2009

Bu et al, Nature, 2009

master human islet heart progenitors from es cells can make any cardiovascular heart cell type
Master Human Islet Heart Progenitors from ES Cells Can Make Any Cardiovascular Heart Cell Type

Master ISL1 heart progenitors

slide12

A Stem Cell Paradigm for Human Cardiogenesis & Congenital Heart Disease

  • TBX1
  • NKX2.5
  • TBX20

Hansson, Lindsay, and Chien,

Cell Stem Cell, October, 2009

slide13

Loeys-Dietz syndrome

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

slide14

Analysis of SHF progenitor cells carrying

TGFBR mutations causing Loeys-Dietz syndrome

iPS derivation

EB differentiation

Plate & culture under

ISL1+ promoting conditions

+ / - Alk5 inhibitor

LD syndrome iPS cells display a

>4 fold increase in the induction of ISL+ progenitors

+/- Alk5 inhibitor vs control

slide15

A Islet Progenitor Fate Map for Regenerative Cardiovascular Medicine

TGF-beta

-

Intermediates

committed

to CV lineages

Multipotent Isl1+

cardiovascular

progenitors

Mesodermal precursors

Cardiomyocytes

CM Progenitors

differentiation

prespecification

Smooth muscle

Wnt3a

Islet/

Wnt3a

?

Endothelial cells

Cardiac mesenchymal

cells

  • Diversification (Islet)
  • Scalability (Wnt)
  • Maturation (TGF beta Pathway)
  • Coordination (?)
slide16

The “Apollo” Mission of Cardiac Regenerative Medicine

Heart Muscle Tissue Engineering

In vivo delivery

Vascularization

Grafting/Rejection

Side effects/

arrhythmogenesis

Efficacy endpoints

lasers in medicine
Lasers in Medicine

Ophthalmology

Dermatology

Plastic Surgery

Cardiology

Oncology

Vascular Medicine

Radiology

advantages of lasers in 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
Liver

Day 0

Day 1

liver1
Liver

Day 7

Day 4

skeletal muscle regeneration
Skeletal muscle regeneration

CD-1 Mice

  • Lasers can create finely focused areas of injury
  • Skeletal muscle regenerates quickly with a minimum of fibrosis
human human and human towards human heart parts and heart models
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
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