Trafficking of Multipotent Mesenchymal Stromal Cells From Maternal Circulation Through the Placenta Involves VEGFR-1 and Integrins

¹ Division of High Risk Pregnancy and Department of Medical Research, Mackay Memorial Hospital, Taipei 104, Taiwan. Mackay Medicine, Nursing and Management College, Taipei 112, Taiwan
² Department of Medical Research, Mackay Memorial Hospital, Taipei 104, Taiwan
³ Division of High Risk Pregnancy, Mackay Memorial Hospital, Taipei 104, Taiwan
⁴ Division of Human Development, Medical School, University of Manchester, Manchester M13 0JH, United Kingdom
⁵ Institute of Molecular Biology, Academia Sinica, Taipei 115, Taiwan
⁶ Bioresource Collection and Research Center, Food Industry Research and Development Institute, Hsinchu, Taiwan

^* To whom correspondence should be addressed. E-mail: cpchen{at}ms2.mmh.org.tw.

	Abstract

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 ₁ integrins, which mediate their adhesion to endothelium, and vascular endothelial cell growth factor receptor-1 (VEGFR-1), which mediates their response to vascular endothelial cell 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, integrin ₂, ₄, ₅ or ₁. 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 ₁, 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.

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