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(Circulation. 2005;111:1175-1183.)
© 2005 American Heart Association, Inc.

Molecular Cardiology

Cytokine Preconditioning Promotes Codifferentiation of Human Fetal Liver CD133⁺ Stem Cells Into Angiomyogenic Tissue

Sergey V. Shmelkov, MD^*; Sarah Meeus, MD^*; Nelson Moussazadeh, BS; Pouneh Kermani, PhD; William K. Rashbaum, MD; Sina Y. Rabbany, PhD; Marilee A. Hanson, MD; William J. Lane, BS; Ryan St. Clair, BS; Kathryn A. Walsh, BS; Sergio Dias, PhD; Jason T. Jacobson, MD; Barbara L. Hempstead, MD, PhD; Jay M. Edelberg, MD, PhD; Shahin Rafii, MD

From Weill Medical College of Cornell University, Division of Hematology-Oncology, New York, NY.

Correspondence to Shahin Rafii, Weill Medical College of Cornell University, 1300 York Ave, Genetic Medicine, C-606, New York, NY 10021. E-mail srafii{at}med.cornell.edu

Received July 28, 2004; revision received October 14, 2004; accepted October 22, 2004.

Background— CD133 (AC133) is a surface antigen that defines a broad population of stem cells, including myogenic and endothelial progenitors. CD133⁺ cells are rare in adult tissues, and the factors that support their differentiation into mature angiomyogenic cells are not known. These hurdles have hampered the use of CD133⁺ cells for therapeutic purposes. Because human fetal liver is a rich source of CD133⁺ cells, we sought to identify the growth factors that promote codifferentiation of these cells into angiogenic and myogenic cells.

Methods and Results— Human fetal liver CD133⁺ and CD133^– cell subpopulations were cultured with 5'-azacytidine or vascular endothelial growth factor (VEGF₁₆₅) and/or brain-derived nerve growth factor (BDNF). CD133⁺ but not CD133^– cells from human fetal liver codifferentiated into spindle-shaped cells, as well as flat adherent multinucleated cells capable of spontaneous contractions in culture. The resulting spindle-shaped cells were confirmed to be endothelial cells by immunohistochemistry analysis for von Willebrand factor and by acetylated LDL uptake. Multinucleated cells were characterized as striated muscles by electron microscopy and immunohistochemistry analysis for myosin heavy chain. Presence of VEGF₁₆₅ and BDNF significantly enhanced angiomyogenesis in vitro. Inoculation of cells derived from CD133⁺ cells, but not CD133^– cells, into the ear pinna of NOD/SCID mice resulted in the formation of cardiomyocytes, as identified by immunostaining with cardiac troponin-T antibody. These cells generated electrical action potentials, detectable by ECG tracing.

Conclusions— CD133 defines a population of human fetal liver cells capable of differentiating into both angiogenic and myogenic cells. Preconditioning of these CD133⁺ cells with VEGF₁₆₅ and BDNF enhances the angiomyogenesis. CD133⁺ fetal liver cells ultimately may be used for therapeutic angiomyogenesis.

Key Words: angiogenesis • endothelium • growth substances • muscle development

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