Keratinocyte growth factor regulates proliferation and differentiation of hematopoietic cells expressing the receptor gene K-sam

Objective. The aim of this study was to establish a new method to overcome the problems of gene therapy targeting hematopoietic cells, namely low transduction efficiency and induction of differentiation during cytokine treatment. M Materials and Methods. The K-sam gene encoding the receptor for keratinocyte growth factor (KGF) was transduced to three factor-dependent hematopoietic cell lines (Ba/F3, 32Dcl3, and UT-7/GM) using retroviral vector, and their proliferation, differentiation, and intracellular signaling were studied. This gene also was transduced to murine bone marrow cells, and proliferation of colony-forming cells (CFCs) by KGF stimulation was examined. Results. Although KGF is known to target only epithelial cells, all of the three cell lines transduced with K-sam proliferated due to KGF stimulation. Morphologic observation showed that KGF induced proliferation but did not cause significant differentiation of 32D/K-sam cells. KGF treatment increased phosphorylation of ERK1/2 but did not activate STAT molecules. Granulocyte colony-stimutating factor transduced the differentiation signal with the phosphorylation of STAT3 without significant ERK1/2 activation. Proliferation by KGF of murine primary bone marrow cells transduced with K-sam then was examined in liquid culture. KGF treatment significantly increased production of CFCs derived from K-sam-transduced bone marrow cells without causing the exhaustion of immature CFCs. Conclusions. KGF could efficiently induce proliferation of hematopoietic cells expressing the K-sam gene without obvious induction of differentiation or exhaustion of immature progenitor cells. The in vitro data are important for further preclinical in vivo study. (C) 2002 International Society for Experimental Hematology. Published by Elsevier Science Inc.