TY - JOUR
T1 - Blood outgrowth endothelial cell migration and trapping in vivo
T2 - a window into gene therapy
AU - Milbauer, Liming C.
AU - Enenstein, Judy A.
AU - Roney, Mark
AU - Solovey, Anna
AU - Bodempudi, Vidya
AU - Nichols, Timothy C.
AU - Hebbel, Robert P.
N1 - Funding Information:
The FVIII work was partially supported by Octagen Corporation.
Funding Information:
Supported by National Institutes of Health Grant HL71269, a National Hemophilia Foundation laboratory grant, and Resource Grant HL63098.
PY - 2009/4
Y1 - 2009/4
N2 - Human blood outgrowth endothelial cells (hBOECs) may be useful delivery cells for gene therapy. hBOECs have high expansion capacity and a stable phenotype. If incorporated into blood vessels, hBOECs could release therapeutic agents directly into the bloodstream. However, little is known about the lodging and homing of hBOECs in vivo. We examined the homing patterns of hBOECs in mice and explored extending cell-based factor VIII (FVIII) gene therapy from mice to larger animals. hBOECs were injected into NOD/SCID mice to determine where they localize, how localization changes over time, and if there were toxic effects on host organs. The presence of hBOECs in mouse organs was determined by quantitative polymerase chain reaction (qPCR) and immunofluorescence microscopy. hBOECs lodged most notably in mouse lungs at 3 h, but by 24 h, no differences were observed among 9 organs. The longevity of hBOECs was assessed up to 7 months in vivo. hBOECs expanded well and then reached a plateau in vivo. hBOECs from older cultures expanded equally well in vivo as younger hBOECs. hBOECs caused no noticeable organ toxicity up to 3 days after injection. When mice were pretreated with antibodies to E-selectin, P-selectin, or anti-α4 integrin prior to hBOEC injection, the number of hBOECs in lungs at 3 h was decreased. Preliminary studies that infused hemophilic dogs with autologous canine BOECs that overexpressed FVIII (B-domain deleted) showed improvement in whole blood clotting times (WBCTs). In conclusion, the survivability, expandability, and lack of toxicity of BOECs in vivo indicate that they may be valuable host cells for gene therapy.
AB - Human blood outgrowth endothelial cells (hBOECs) may be useful delivery cells for gene therapy. hBOECs have high expansion capacity and a stable phenotype. If incorporated into blood vessels, hBOECs could release therapeutic agents directly into the bloodstream. However, little is known about the lodging and homing of hBOECs in vivo. We examined the homing patterns of hBOECs in mice and explored extending cell-based factor VIII (FVIII) gene therapy from mice to larger animals. hBOECs were injected into NOD/SCID mice to determine where they localize, how localization changes over time, and if there were toxic effects on host organs. The presence of hBOECs in mouse organs was determined by quantitative polymerase chain reaction (qPCR) and immunofluorescence microscopy. hBOECs lodged most notably in mouse lungs at 3 h, but by 24 h, no differences were observed among 9 organs. The longevity of hBOECs was assessed up to 7 months in vivo. hBOECs expanded well and then reached a plateau in vivo. hBOECs from older cultures expanded equally well in vivo as younger hBOECs. hBOECs caused no noticeable organ toxicity up to 3 days after injection. When mice were pretreated with antibodies to E-selectin, P-selectin, or anti-α4 integrin prior to hBOEC injection, the number of hBOECs in lungs at 3 h was decreased. Preliminary studies that infused hemophilic dogs with autologous canine BOECs that overexpressed FVIII (B-domain deleted) showed improvement in whole blood clotting times (WBCTs). In conclusion, the survivability, expandability, and lack of toxicity of BOECs in vivo indicate that they may be valuable host cells for gene therapy.
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U2 - 10.1016/j.trsl.2008.12.009
DO - 10.1016/j.trsl.2008.12.009
M3 - Article
C2 - 19304277
AN - SCOPUS:62349090097
SN - 1931-5244
VL - 153
SP - 179
EP - 189
JO - Translational Research
JF - Translational Research
IS - 4
ER -