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CLINICAL RESEARCH: MYOCARDIAL INFARCTION

Mobilization of Bone Marrow-Derived Oct-4⁺ SSEA-4⁺ Very Small Embryonic-Like Stem Cells in Patients With Acute Myocardial Infarction

Wojciech Wojakowski, MD, PhD^_*, Micha Tendera, MD, PhD, FACC^_*, Magda Kucia, PhD, Ewa Zuba-Surma, PhD, Edyta Paczkowska, MD, PhD, Joanna Ciosek, MD^_*, Maciej Haasa, MD, PhD, Marek Król, MD, PhD, Maciej Kazmierski, MD, PhD^_*, Pawe Buszman, MD, PhD, FACC^_*,, Andrzej Ochaa, MD, PhD^_*, Janina Ratajczak, MD, PhD, Bogusaw Machaliski, MD, PhD and Mariusz Z. Ratajczak, MD, PhD^,,_*

^_* Third Division of Cardiology, Medical University of Silesia, Katowice, Poland
Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky
Department of Pathology and Pathophysiology, Pomeranian Medical University, Szczecin, Poland
American Heart of Poland, Ustron, Poland

Manuscript received April 18, 2008; revised manuscript received September 2, 2008, accepted September 8, 2008.

^_* Reprint requests and correspondence: Dr. Mariusz Z. Ratajczak, University of Louisville, 500 South Floyd Street, Louisville, Kentucky 40202 or Department of Pathology and Pathophysiology, Pomeranian Medical University, 72 Powstancow Wlkp. Str., 70-111 Szczecin, Poland (Email: mzrata01{at}louisville.edu).

Objectives: This study sought to assess of the mobilization of nonhematopoietic very small embryonic-like stem cells (VSELs) in acute myocardial infarction (MI).

Background: Acute MI induces mobilization of bone marrow stem cells. Recently, a rare population of VSELs, expressing markers of embryonic pluripotent stem cells (PSCs), was identified in adult murine bone marrow and human umbilical cord blood.

Methods: Thirty-one patients with acute MI and 30 healthy subjects were enrolled. Blood was sampled on admission, after 24 h, and 5 days later. Erythrocytes were lysed and lin^–CD45^– VSELs were isolated using a live cell sorting system (FACSAria, Beckton Dickinson, San Jose, California).

Results: In healthy subjects the median number of circulating VSELs was very low (median 0.8 [range 0 to 1.3]) cells/µl. In acute MI, VSELs were mobilized early (median 2.7 [range 0.2 to 3.9] cells/µl; p < 0.001) and remained elevated after 24 h and 5 days (median 4.7 [range 0.2 to 6.4] cells/µl; p < 0.003, and median 2.6 [range 0.3 to 3.6] cells/µl; p < 0.03, respectively). The mobilization of VSEL was significantly reduced in patients older than 50 years and with diabetes in comparison with younger and nondiabetic patients. Circulating VSELs were small (7 to 8 µm) and enriched in the messenger ribonucleic acid of PSC markers (Oct-4, Nanog), cardiac lineage (GATA-4, Nkx2.5/Csx, MEF2C), and endothelial (VE-cadherin) markers. The presence of PSC markers (Oct-4, SSEA-4) and the chemokine receptor CXCR4 in circulating VSELs was confirmed at the protein level by immunofluorescent staining and ImageStream system (Amnis Corporation, Seattle, Washington) analysis.

Conclusions: Acute MI induced mobilization of VSELs expressing pluripotent markers, early cardiac and endothelial markers, and chemokine receptor CXCR4.

Key Words: very small embryonic-like stem cells • pluripotent stem cells • acute myocardial infarction • mobilization

Abbreviations and Acronyms   BM = bone marrow   EPC = endothelial progenitor cell   HSC = hematopoietic stem cell   LVEF = left ventricular ejection fraction   MI = myocardial infarction   MNC = mononuclear cell   PB = peripheral blood   PSC = pluripotent stem cell   RT-PCR = (real-time) reverse transcriptase-polymerase chain reaction   SDF = stromal-derived factor   VSEL = very small embryonic-like stem cell

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