Human hepatocyte growth factor gene and secondary lymphedema

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Human hepatocyte growth factor gene and secondary lymphedema

Postby patoco » Wed Sep 20, 2006 12:59 pm

Transfection of human hepatocyte growth factor gene ameliorates secondary lymphedema via promotion of lymphangiogenesis.

Circulation. 2006 Sep 12;114(11):1177-84. Epub 2006 Sep 4.

Yukihiro Saito, MD; Hironori Nakagami, MD, PhD; Ryuichi Morishita, MD,
PhD; Yoichi Takami, MD; Yasushi Kikuchi, MD, PhD; Hiroki Hayashi, BS;
Tomoyuki Nishikawa, PhD; Katsuto Tamai, MD, PhD; Nobuyoshi Azuma, MD, PhD; Tadahiro Sasajima, MD, PhD; Yasufumi Kaneda, MD, PhD

>From the Divisions of Gene Therapy Science (Y.S., H.N., Y.T., Y.K.,

H.H., T.N., K.T., Y.K.) and Clinical Gene Therapy (R.M.), Graduate
School of Medicine, Osaka University, Osaka, and Department of Surgery,
Asahikawa Medical University, Hokkaido (Y.S., N.A., T.S.), Japan.

Correspondence to Hironori Nakagami, MD, PhD, Assistant Professor,
Division of Gene Therapy Science, Graduate School of Medicine, Osaka
University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. E-mail

Received November 22, 2005; revision received June 19, 2006; accepted
July 14, 2006.


Lymphedema is a disorder of the lymphatic vascular system characterized
by impaired lymphatic return and swelling of the extremities. Treatment
for this disabling condition remains limited and largely ineffective.
The goal of the present study was to investigate the therapeutic
efficacy of hepatocyte growth factor (HGF) in animal models of

Methods and Results-

Immunofluorescent analysis demonstrated that canine primary lymphatic
endothelial cells (cLECs) were positive for lymphatic-specific markers
(vascular endothelial growth factor receptor-3, LYVE-1, podoplanin, and
Prox1) and the HGF receptor c-Met. Treating cLECs with human
recombinant HGF resulted in a dose-dependent increase in cell growth
and migration and increased activity of extracellular signal-regulated
kinase and Akt. In human LECs, c-Met also was expressed, and treatment
with HGF increased cell growth and migration in a dose-dependent
manner. Transfection of human HGF plasmid DNA in cLECs also increased
the c-fos promoter activity. Furthermore, weekly HGF gene transfer in a
rat tail lymphedema model by disruption of lymphatic vessels resulted
in a decrease in lymphedema thickness. Although expression of the
endothelial cell marker PECAM-1 was increased in both HGF- and vascular
endothelial growth factor 165-injected groups, expression of LEC
markers (LYVE-1 and Prox1) was increased only in the HGF-injected


These data demonstrate that expression of HGF via plasmid transfer
improves lymphedema via promotion of lymphangiogenesis. Further studies to determine the clinical utility of this approach would be of benefit
to patients with lymphedema. ... 14/11/1177


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