Trafficking of multipotent mesenchymal stromal cells from maternal circulation through the placenta involves vascular endothelial growth factor receptor-1 and integrins.
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 alpha(2), alpha(4), alpha(5), and beta(1) 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 alpha(2), alpha(4), alpha(5), or beta(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 alpha(2), alpha(4), alpha(5), and beta(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.
Chen
Chie-Pein
CP
Division of High Risk Pregnancy, Mackay Memorial Hospital, 92 Sec. 2 Chung San North Road, Taipei 104, Taiwan. cpchen@ms2.mmh.org.tw
Lee
Ming-Yi
MY
Huang
Jian-Pei
JP
Aplin
John D
JD
Wu
Yi-Hsin
YH
Hu
Cing-Siang
CS
Chen
Pei-Chun
PC
Li
Hung
H
Hwang
Shiaw-Min
SM
Liu
Shu-Hsiang
SH
Yang
Yuh-Cheng
YC
D000818:Animals; D001483:Base Sequence; D002465:Cell Movement; D017931:DNA Primers / Q000235:genetics; D005260:Female; D006801:Humans; D016023:Integrins / Q000037:antagonists & inhibitors / Q000502:physiology*; D008431:Maternal-Fetal Exchange; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000502:physiology*; D039902:Multipotent Stem Cells / Q000166:cytology* / Q000502:physiology*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000502:physiology
D017931:DNA Primers; D016023:Integrins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2