Role of cell division in branching morphogenesis and differentiation of the embryonic pancreas

A new culture system for the embryonic pancreas enables the formation of a branched organ in vitro. In such cultures, each terminal branch originates as a small bud and the number of buds and of terminal branches increases pr ogressively with the expansion of the culture. However buds can also be res orbed during growth. The normal labelling index of cells in incipient buds ("tips") is greater than between buds ("dips") suggesting that budding may be driven by a local increase of cell division. Consistent with this, treat ments that reduce cell division repress the formation of buds and branches. It is not possible to initiate budding in isolated endodermal epithelium b y treatment with fibroblast growth factor, although this does increase the degree of differentiation of exocrine cells. Cultures in which cell divisio n is completely inhibited by aphidicolin treatment will produce more endocr ine cells than usual and inhibit the differentiation of exocrine cells. Con sistent with this it is found that in untreated cultures the division of en docrine precursors cannot be detected by BrdU labelling whereas the divisio n of exocrine precursors is frequent. It is concluded that cell division is necessary for bud formation in the embryonic pancreas and that the growth factors required for this normally come from the mesenchyme. Cell division is also necessary for exocrine differentiation. Endocrine cells, however, c an arise from undifferentiated progenitors without cell division.