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TRANSLATIONAL AND CLINICAL RESEARCH

Trafficking of Multipotent Mesenchymal Stromal Cells from Maternal Circulation Through the Placenta Involves Vascular Endothelial Growth Factor Receptor-1 and Integrins

^aDivision of High Risk Pregnancy and
^bDepartment of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan;
^cMackay Medicine, Nursing and Management College, Taipei, Taiwan;
^dDivision of Human Development, Medical School, University of Manchester, Manchester, United Kingdom;
^eInstitute of Molecular Biology, Academia Sinica, Taipei, Taiwan;
^fBioresource Collection and Research Center, Food Industry Research and Development Institute, Hsinchu, Taiwan

Key Words. Integrins • Multipotent mesenchymal stromal cell • Microchimerism • Placenta Vascular endothelial growth factor receptor

Correspondence: Chie-Pein Chen, M.D., Ph.D., Division of High Risk Pregnancy, Mackay Memorial Hospital, 92 Sec. 2 Chung San North Road, Taipei 104, Taiwan Telephone: 011-886-2-2543-3535; Fax: 011-886-2-2754-3769; e-mail: cpchen{at}ms2.mmh.org.tw

Received May 24, 2007; accepted for publication October 23, 2007.
First published online in STEM CELLS EXPRESS   November 1, 2007.



Maternal cells can become engrafted in various fetal organs during pregnancy. The nature of the cells and the mechanisms of maternofetal cell trafficking are not clear. We demonstrate that human lineage-negative, CD34-negative (Lin^–CD34^–) multipotent mesenchymal stromal cells express ₂, ₄, ₅, and β₁ integrins, which mediate their adhesion to endothelium, and vascular endothelial growth factor receptor-1 (VEGFR-1), which mediates their response to vascular endothelial growth factor A (VEGF-A). A maternal-fetal VEGF-A concentration gradient exists across the placental barrier, and cord blood plasma induces transendothelial and trans-Matrigel migration of stem cells in vitro. Migration is inhibited by a VEGF-A-neutralizing antibody or antibodies against VEGFR-1 or integrin ₂, ₄, ₅, or β₁. When Lin^–CD34^– multipotent mesenchymal stromal cells are transferred to rat maternal venous blood, they traffic through the placenta, engraft in various fetal organs, and persist in offspring for at least 12 weeks. Cell proliferation ability is retained in the xenogeneic placenta. Maternofetal trafficking is significantly reduced by blocking antibodies against integrins ₂, ₄, ₅, and β₁ or VEGFR-1. These results suggest that maternal microchimerism arises by the trafficking of multipotent mesenchymal stromal cells via VEGF-A- and integrin-dependent pathways across the hemochorial placenta to fetal tissues.

Disclosure of potential conflicts of interest is found at the end of this article.