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PRE-CLINICAL RESEARCH

Guided Cardiopoiesis Enhances Therapeutic Benefit of Bone Marrow Human Mesenchymal Stem Cells in Chronic Myocardial Infarction

Atta Behfar, MD, PhD^_*, Satsuki Yamada, MD, PhD^_*, Ruben Crespo-Diaz, BS^_*, Jonathan J. Nesbitt, BS^_*, Lois A. Rowe, ASCP^_*, Carmen Perez-Terzic, MD, PhD^_*,, Vinciane Gaussin, PhD, Christian Homsy, MD, Jozef Bartunek, MD, PhD and Andre Terzic, MD, PhD^_*,_*

^_* Department of Medicine, Division of Cardiovascular Diseases, Marriott Heart Disease Research Program, Mayo Clinic, Rochester, Minnesota
Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, Minnesota
Cardio3 BioSciences, Mont-Saint-Guibert, Belgium
Cardiovascular Center, OLV Ziekenhuis, Aalst, Belgium

Manuscript received August 24, 2009; revised manuscript received March 2, 2010, accepted March 9, 2010.

^_* Reprint requests and correspondence: Dr. Andre Terzic, Mayo Clinic, Stabile 5, 200 First Street SW, Rochester, Minnesota 55905 (Email: terzic.andre{at}mayo.edu).

Objectives: The goal of this study was to guide bone marrow-derived human mesenchymal stem cells (hMSCs) into a cardiac progenitor phenotype and assess therapeutic benefit in chronic myocardial infarction.

Background: Adult stem cells, delivered in their naïve state, demonstrate a limited benefit in patients with ischemic heart disease. Pre-emptive lineage pre-specification may optimize therapeutic outcome.

Methods: hMSC were harvested from a coronary artery disease patient cohort. A recombinant cocktail consisting of transforming growth factor-beta₁, bone morphogenetic protein-4, activin A, retinoic acid, insulin-like growth factor-1, fibroblast growth factor-2, alpha-thrombin, and interleukin-6 was formulated to engage hMSC into cardiopoiesis. Derived hMSC were injected into the myocardium of a nude infarcted murine model and followed over 1 year for functional and structural end points.

Results: Although the majority of patient-derived hMSC in their native state demonstrated limited effect on ejection fraction, stem cells from rare individuals harbored a spontaneous capacity to improve contractile performance. This reparative cytotype was characterized by high expression of homeobox transcription factor Nkx-2.5, T-box transcription factor TBX5, helix–loop–helix transcription factor MESP1, and myocyte enhancer factor MEF2C, markers of cardiopoiesis. Recombinant cardiogenic cocktail guidance secured the cardiopoietic phenotype across the patient cohort. Compared with unguided counterparts, cardiopoietic hMSC delivered into infarcted myocardium achieved superior functional and structural benefit without adverse side effects. Engraftment into murine hearts was associated with increased human-specific nuclear, sarcomeric, and gap junction content along with induction of myocardial cell cycle activity.

Conclusions: Guided cardiopoiesis thus enhances the therapeutic benefit of bone marrow-derived hMSC in chronic ischemic cardiomyopathy.

Key Words: cell therapy • ischemic cardiomyopathy • heart failure • patient-derived • transplantation

Abbreviations and Acronyms   BMP = bone morphogenetic protein   DNA = deoxyribonucleic acid   FGF = fibroblast growth factor   GMP = good manufacturing practice   hMSC = human mesenchymal stem cell   IGF = insulin-like growth factor   IL = interleukin   mRNA = messenger ribonucleic acid   PCR = polymerase chain reaction   TGF = transforming growth factor

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