Human stem cells for cardiac repair

Applications of human stem cells for cardiac repair

Prof Pieter A. Doevendans (UMCU) Prof Translational Cardiology 2004

Prof Hans Clevers (KNAW, Hubrecht lab)

Consortium

Christine Mummery LUMC

Eric Duckers Erasmus MC

Vincent Christoffels AMC

Jeroen Bakkers KNAW, (Hubrecht)

Joost Sluijter UMCU

ICIN (KNAW, Dir. Wiek van Gilst)

Wanted: immunology

Consortium

Health Care problem

Aim: reduce the number of pts with symptomatic cardiac failure

Unravelling the mechanisms behind the beneficial effects of stem cell therapy will allow us to improve the cardiac regenerative capacity of the human heart.

Research questions

What roles do neovascularization, paracrine factors, microRNAs play in cardiac regeneration and repair?

Why do patients post-MI or with chronic angina respond positively tostem cell transplantation and others do not?

Do cardiovascular risk factors (Gender, smoking, diabetes, high bloodpressure, high cholesterol DM) have an impact on stem cell behaviour or host response?

Do endogenous progenitors contribute to cardiac repair in response tostem cell transplantation?

Can we boost endogenous regenerative capacity of the heart?

Loffredo et al. Cell stem cell 2011

Intramyocardial Delivery of Bone Marrow-Derived c-kit+ Cells after MI Stimulates Endogenous CM Regeneration.

Cardiogenesis and

Regeneration

Large animal

models

Variations in

individual response

Clinical trialsCVON

Cardiogenesis and regeneration (Bakkers, Christoffels, Clevers, Mummery,

Sluijter)

ESC: cardiogenesis, compound screening

Zebrafish: regeneration, genetic screening

Lineage tracing (mouse) : cardiogenesis and regeneration

Alternative stem cell sources and products

WP 1

• Todd Heallen,1 Min Zhang,1 Jun Wang,1 Margarita Bonilla-Claudio,1 Ela Klysik,1 Randy L. Johnson,2 James F. Martin1*

Hippo Pathway Inhibits Wnt Signaling

to Restrain CardiomyocyteProliferation and Heart Size

Science April 2011

WP 2

• Individual variation (Mummery, Sluijter, Bakkers)

– GENDER differences

– Role of risk factors (age, metabolism)

WP 3

• Preclinical trials (Doevendans, Duckers)

– Delivery

– Function

– Imaging

WP 4

Clinical trials (Doevendans, Duckers)

– MSC

– ATMNC

– CSC

– Delivery

Translation

Basic Science: Cardiogenesis

(Pre) clinical trials

Focus areas Netherlands Heart Foundation

Individual variation:

G,A,M

Hartfalen, Hartstilstand, GENDER, Aangeboren Hartafwijkingen

Females respond differently to heart attacks than males. In addition, the electrophysiological responses of freshly isolated human primary cardiomyocytes differ in males and females. We will investigate the responses of human stem cell derived cardiomyocytes in culture to male and female hormones. Inclusion females preclinical and clinical.

Perspective

Central in the Field in the Netherlands. See also Scheme

- Roots in private – pubic programmes

• Europa

•FP6 Eugene

•FP6,7 Cardiac Repair CHeart (Moorman)

•FP7 Bioscent

•In preparation: FP 7 with Australia

•Healthy aging

Valorisatie

Company Employees Patents

PD LeadpharmaDutchCardio

306

4

HC U-BiSysAgamyxis

? 14001

?5

CM Pluriomics 6 2

ED BioTxs 3 4

JS 1

VC

JB