Klinikum der

Johann Wolfgang Goethe Universität

Frankfurt am Main

Overview of the field of cell-

based therapies for myocardial

regeneration

Stefanie Dimmeler

Conflict of interest: T2cure GmbH

Cells for cardiac regeneration

(modified Dimmeler et al, JCI 2005)

Induced

pluripotent

stem cells

Somatic

Cells

4 genes: Oct4, Klf4, Sox2,

myc

Direct

Reprogramming Cardiospheres

Cardiac

Stem Cells

2001/ 2002

2008 2012

Enhancement •Shock waves for enhancing

cell engraftment •Factors to enhance cardiac

differentiation

Cardiac stem cells •c-kit+

•Cardiospheres

Embryonic stem cells?

iPS cells ?

Bone marrow-

derived cells

2006 2009

New types of adult stem cells

New enhance- ment strategies

Cell therapy of cardiovascular diseases: start of clinical trials

Adipose-tissue

derived cells

Cardiac Stem

cells

Skeletal muscle

cells

Bone marrow-

derived cells

SEPAX

Bone marrow

mononuclear cells (BMC)

Mesenchymal stromal

cells (MSC)

CD133+ or CD34+ cells

Bone marrow-derived cell for cardiovascular repair

Selected subpopulations

Manual cell isolation

Mol Vis. 2008 4; 14:431-442

Rare population

Expansion required

CD34

CD133

Cell therapy of cardiovascular diseases with bone marrow cells

Meta-

Analysis

(N = 2625)

(Jeevanantham et al, Circulation 2012)

• Modest improvement in LVEF and ESV

BMC therapy in patients with acute myocardial infarction:

Enhancement •Shock waves for enhancing

cell engraftment •Factors to enhance cardiac

differentiation

Cardiac stem cells •c-kit+

•Cardiospheres

Embryonic stem cells?

iPS cells ?

New types of adult stem cells

New enhance- ment strategies

Open questions

• Clinical benefit of bone marrow-derived

mononuclear cells?

• Effect of timing?

• Autologous versus allogeneic (MSC)?

Phase III clinical trials aiming for approval of cell therapy

3000 Patients with acute

myocardial infarction

(LVEF < 45 %)

1:1 randomised, controlled

i.c. BMC vs standard care

Primary endpoint: mortality

Aim: to reduce 2-year mortality

by 25%

400 Patients with refractory

angina

1:1:1 randomised, controlled

i.m. CD34+ vs. active control vs.

standard care

Primary endpoint: Total exercise

time on ETT (modified Bruce

protocol) at 12M

Enhancement •Shock waves for enhancing

cell engraftment •Factors to enhance cardiac

differentiation

Cardiac stem cells •c-kit+

•Cardiospheres

Embryonic stem cells?

iPS cells ?

New types of adult stem cells

New enhance- ment strategies

Open questions

• Clinical benefit of bone marrow-derived

mononuclear cells?

• Effect of timing?

• Autologous versus allogeneic (MSC)?

Cells

Target

tissue

Timing of cell delivery after AMI

Time after acute myocardial infarction

ROS Chemokines

Cell

death

Cell

homing

Inflammation Fibrosis Scar

Influence of time after AMI

on cell homing Early versus delayed?

Time after acute myocardial infarction (days)

Bone marrow is activated after AMI

Metabolic activation

(FDG-PET) CD34+ Invasion

Assmus et al, EHJ 2012

Enhancement •Shock waves for enhancing

cell engraftment •Factors to enhance cardiac

differentiation

Cardiac stem cells •c-kit+

•Cardiospheres

Embryonic stem cells?

iPS cells ?

New types of adult stem cells

New enhance- ment strategies

Open questions

• Clinical benefit of bone marrow-derived

mononuclear cells?

• Effect of timing?

• Autologous versus allogeneic (MSC)?

Autologous Allogeneic

- Individualized expansion

of cells is expensive and

time consuming (limits use of expanded

autologous cells for treatment

of patients with AMI)

- Impaired function of

autologous cells in

patients

- Immune response:

may interfere with

survival of long term

incorporating cells

- precludes repetitive

treatment?

Open questions: autologous versus allogeneic

Mesenchymal stromal cells/Cardiac stem cells:

Time required for cell expansion (>1 month) excludes

early treatment of patients with acute myocardial infarction

Limitations of autologous and allogeneic cell therapy

AHA 2012:

Side-by-side comparison of

autologous versus allogeneic MSC

2001/ 2002

2008 2012

Enhancement •Shock waves for enhancing

cell engraftment •Factors to enhance cardiac

differentiation

Cardiac stem cells •c-kit+

•Cardiospheres

Embryonic stem cells?

iPS cells ?

Bone marrow-

derived cells

2006 2009

New types of adult stem cells

New enhance- ment strategies

Cell therapy of cardiovascular diseases: start of clinical trials

Adipose-tissue

derived cells

Cardiac Stem

cells

Skeletal mucle

cells

Beltrami et al, Cell 114(6):763-76, 2003

•c-kit (mouse, dog, human)

•Sca-1 (mouse)

Sca-1-like (dog, human)

•Cardiospheres (murine, human)

•Islet (postnatal mouse, human)

(Beltrami, Cell 2003)

(Oh et al, PNAS 2003)

(Laugwitz et al, Nature 2005)

(Messina et al, Circ Res 2004)

Cardiac stem cells: the heart´s little helper

2009

Enhancement •Shock waves for enhancing

cell engraftment •Factors to enhance cardiac

differentiation

Cardiac stem cells •c-kit+

•Cardiospheres

Embryonic stem cells?

iPS cells ?

New types of adult stem cells

New enhance- ment strategies

Cell therapy with cardiac stem cells

2011

Cardiospheres (Caduceus trial)

Ejection Fraction at 4 Months After CSCs

N=17 N=17 N=8

• No difference in EF or volumes

First patient

treated Phase I data: presented AHA 2011

c-kit+ CSC (Scipio trial) (Makkar et al Lancet 2012) (Bolli et al Lancet 2011)

AHA 2012: Up-date: 2 year follow up AHA 2012: Combination with FGF

Infarct size reduction at 6 and 12 months after Cardiospheres