Pluripotent Stem Cells in Chronic Heart Failure Repair

Wolfram-H. Zimmermann

Department of Pharmacology

Heart Research Center Göttingen Georg-August-University Göttingen

Clinical Scenario and Mechanism of Action of Cells

Acute or Subacute Myocardial Infarction Prevent further damage Cell-Tx in addition to state-of-the-art revascularization Paracrine support Improved biomechanics

Chronic Heart Failure Remusculariziation Cell-Tx in addition to state-of-the-art drug, devices and HTX

Survival Factors

Cardiomyocytes

www.cuhk.edu.hk/med/paf/slides/

http://echoincontext.mc.duke.edu/2002tele/pathologySupp.asp

Soonpaa et al. 1994 Science 294:98-101

Remuscularizing the Failing Heart

Induced pluripotent stem cells

Embryonic stem cells

Nanog Sox2 c-Myc Oct4 Klf4 Lin28

Spermatogonial stem cells

Germline stem cells

Embryo Oocyte

♂

♀

Parthenogenesis

Parthenote

Parthenogenetic stem cells

Christalla et al. 2012 CTO

Pluripotent Stem Cells for Heart Repair

miR302 ….

Soonpaa et al. 1994 Science 294:98-101

Myocardial Infarction à † 1.000.000.000 myocytes

Intramyocardial cell injection à >95% of the cells are lost

Calculated Therapeutic Cell Dose à 20.000.000.000 myocytes

Total myocyte number of the heart à ~4.000.000.000

Myocardial Infarction à † 1.000.000.000 myocytes

Intramyocardial cell injection à >95% of the cells are lost

Calculated Therapeutic Cell Dose à 20.000.000.000 myocytes

Total myocyte number of the heart à ~4.000.000.000

Myocardial Infarction à † 1.000.000.000 myocytes

Intramyocardial cell injection à >95% of the cells are lost

Calculated Therapeutic Cell Dose à 20.000.000.000 myocytes

Total myocyte number of the heart à ~4.000.000.000

Myocardial Infarction à † 1.000.000.000 myocytes

Intramyocardial cell injection à >95% of the cells are lost

Calculated Therapeutic Cell Dose à 20.000.000.000 myocytes

Total myocyte number of the heart à ~4.000.000.000

Remuscularizing the Failing Heart

Tissue Engineering-based Heart Repair

Post MI CHF

DCM

a) Multi-loop engineered heart tissue b) BioVAD™ i.e. biological ventricular assist device

Zimmermann et al. 2006 Nat Med Yildirim et al. 2007 Circulation

Zimmermann et al. 2002 Circulation Naito et al 2006 Circulation Soong et al. 2012 CPCB

Engineered Heart Muscle - Adaptable Design

(1) Force of contraction: >0.3 mN (2) Elastic modulus: >20 kPa (3) Anisotropic spread of excitation: >0.1 m/sec (4) Defined cell composition: 30-60% cardiomyocytes, 40-60% meso. non-myocytes (5) Negative for Oct4 cells

Tiburcy, Soong et al. unpublished

Reducing Immunological Complexity

Nakajima et al. 2007 Stem Cells (modified)

Single Mismatch (biparental origin)

No Mismatch (uniparental origin)

Two Mismatches (biparental origin)

Finding Immunologically Appropriate Cells

No Mismatch (biparental origin)

Embryogenesis and Parthenogenesis

PSC

Germinal vesicle

ESC

MII oocyte

MII oocyte

Roadmap

Karikkineth und Zimmermann 2011 CBP (in press)

- Scalable - Human (ESC/iPSC) - Serum-free - Functional

Department of Pharmacology Heart Research Center Göttingen University Medical Center Göttingen

Brian Golat Claudia Noack Farah Raad Christiane Vettel

Collaborators: R. Al-Daccak/D. Charron (Paris) A. Bernard (Madrid) T. Braun (Bad Nauheim) L. Couture (City of Hope) A. Schwörer/H. Ehmke (Hamburg) T. Eschenhagen (Hamburg) L.J. Field (Indianapolis) I. Kehat/O. Caspi/L. Gepstein (Haifa) J. Gold (San Francisco) G. Keller (Toronto) M. Mayr (London) P. Menasche (Paris) C. Murry (Washington) R. Robbins (San Francisco) M. Rubart (Indianapolis) H. Schöler (Münster) G. Vunjak-Novakovic (New York) J. Wu (San Francisco) M. Zenke (Aachen)

HRCG Göttingen: K. Guan B. Unsöld S. Lehnart L. Maier G. Hasenfuß F. Schöndube R. Dressel S. Luther (MPI-DS) E. Bodenschatz (MPI-DS) R. Behr (DPZ)