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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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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


The unmet clinical need growing heart muscle
The Unmet Clinical Need: Growing Heart Muscle


Regeneration Next: Towards Heart Progenitor Derived Heart Parts

Hansson, Lindsay, and Chien,

Cell Stem Cell, In Press, September, 2009


The Meltonian Stem Cell Era: Parts

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 Parts

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


Towards defining the Parts

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


Coordinated Contractility of a Syncitium of Murine ES cell Parts

derived Islet-1 Progenitors Driven into the Cardiac Lineage



Making a Ventricular Heart Muscle Patch: Muscle

Towards Regenerative Cardiovascular Medicine

Domian et al, Science, 2009


Islet heart progenitors in the human heart
Islet Heart Progenitors in the Human Heart Muscle

  • 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


A Stem Cell Paradigm for Human Cardiogenesis & Congenital Heart Disease

  • TBX1

  • NKX2.5

  • TBX20

Hansson, Lindsay, and Chien,

Cell Stem Cell, October, 2009


Loeys-Dietz syndrome Heart Disease

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


Analysis of SHF progenitor cells carrying Heart Disease

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


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 (?)


The “Apollo” Mission of Cardiac Regenerative Medicine Medicine

Heart Muscle Tissue Engineering

In vivo delivery

Vascularization

Grafting/Rejection

Side effects/

arrhythmogenesis

Efficacy endpoints



Lasers in medicine
Lasers in Medicine Medicine

Ophthalmology

Dermatology

Plastic Surgery

Cardiology

Oncology

Vascular Medicine

Radiology


Advantages of lasers in medicine
Advantages of Lasers in Medicine 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 Medicine

Day 0

Day 1


Liver1
Liver Medicine

Day 7

Day 4


Skeletal muscle regeneration
Skeletal muscle regeneration Medicine

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: MedicineTowards 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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