Keratinocyte growth factor and beta-cell differentiation in human fetal pancreatic endocrine precursor cells

Abstract

Aims and hypothesis. Keratinocyte growth factor (KGF) is a member of the heparin-binding fibroblast growth factor family with a high degree of specificity for epithelial cells in vitro and in vivo. Our aim was to study the effect of KGF on beta-cell growth and differentiation on islet-like cell clusters derived from human fetal pancreas. Methods. We investigated the effects of KGF, in vitro, on beta-cell differentiation from undifferentiated pancreatic precursor cells and in vivo after transplantating human fetal pancreatic cells into athymic rats treated with KGF. Results. Treatment of islet-like cell clusters with KGF in vitro did not change the number of insulin producing cells, as measured by the measurement of insulin content or DNA. The in vivo treatment of recipient rats with KGF increased the number of beta cells within the grafts 8 weeks after transplantation. At this time, glucose-stimulated insulin secretion was evaluated by glucose stimulation tests in rats bearing the transplants. Measurements of human C-peptide concentrations after glucose challenge showed that the newly differentiated beta cells in the KGF-treated group were functionally competent as opposed to the control group, where the graft failed to release insulin appropriately. Conclusion/interpretation. These findings suggest that in vivo, KGF is capable of inducing human fetal beta-cell expansion. The growth promoting effect of KGF on beta cells occurred mainly through the activation of ductal cell proliferation and their subsequent differentiation into beta cells. [Diabetologia (2003) 46:822-829]

Fibroblast growth factors 7 and 10 are expressed in the human embryonic pancreatic mesenchyme and promote the proliferation of embryonic pancreatic epithelial cells

“…Another group has recently shown that FGF7 treatment activated beta cell development from human fetal pancreatic cell preparations grafted to athymic rats. No ef- fect of FGF7 was seen in vitro, suggesting that the growth effect of FGF7 was indirect [10]. Here, we show that FGF7 and FGF10 also have a direct effect on embryonic pancreatic cells.…”

Early administration of keratinocyte growth factor improves β-cell regeneration in rat with streptozotocin-induced diabetes

“…A possible explanation for the greater effect of KGF on b-cell differentiation in diabetic rats is the context of restricted b-cell mass in those rats, which implies the activation of several interconnected compensatory mechanisms in the pancreas in order to regulate cell homeostasis. In keeping with this idea, we have previously shown that KGF administration to nude rats bearing transplant composed of fetal endocrine pancreatic precursor cells led to the increase in the total number of b-cells in the graft without increasing the b-cell number within the pancreas of adult non-diabetic rats (Movassat et al 2003). In order to elucidate whether KGF is able to stimulate b-cell growth in neonatal rats with spontaneous b-cell deficiency, we are currently investigating the effect of an early postnatal treatment of Goto-Kakizaki rats with KGF on the b-cell growth.…”

“…In the pancreas, KGF and its receptor are upregulated in pancreatic carcinomas (Ishiwata et al 1998) and ectopic expression of KGF in b-cells resulted in intra-islet duct cell proliferation (Krakowski et al 1999). Moreover, KGF stimulates differentiation of endocrine precursor cells isolated from human fetal pancreas into b-cells (Movassat et al 2003). Here, we investigated the impact of an early treatment of non-diabetic and diabetic rat neonates with KGF (palifermin) on the regulation of b-cell growth and regeneration.…”

Increased islet beta cell replication adjacent to intrapancreatic gastrinomas in humans

“…Many of these factors are well known to stimulate beta cell growth in vitro [11,[23][24][25][26][27][28]. Further support for a possible gastrin-independent mechanism for the increased beta Fig.…”