Transforming growth factor-[beta] selectively inhibits branching
morphogenesis but not tubulogenesis..
Sakurai, Hiroyuki, and Sanjay K. Nigam.
Renal Division, Department of Medicine, Brigham and Women's
Hospital and Harvard Medical School, Boston, MA
APStracts 3:0190F, 1996.
When cultured in Type I collagen gels, two kidney derived cell lines,
Madin-Darby canine kidney (MDCK) cells and murine inner medullary
collecting duct (mIMCD3) cells, form branching tubular structures in
the presence of Swiss 3T3 conditioned medium, in which hepatocyte
growth factor (HGF) is the major branching tubule inducing factor.
However, upon incubation with transforming growth factor-[beta] (TGF
-[beta]) in the presence of 3T3 conditioned medium, MDCK tubulogenesis
and branching was markedly inhibited. In contrast, mIMCD3 cells,
which are much less susceptible to growth and tubulogenesis
inhibition by TGF-[beta], formed long straight tubule-like structures
in the presence of TGF-[beta], suggesting a dissociation between
tubulogenesis and branching morphogenesis. Interestingly, those long
tubules which did branch often resembled the early branching ureteric
bud in embryonic kidneys. Quantitation of branching events revealed a
selective branch-inhibiting effect of TGF-[beta] on mIMCD3 cells at
concentrations between 0.02-2 ng/ml. There was no qualitative or
quantitative difference among TGF-[beta]1, [beta]2 and [beta]3 on
inhibition of branching events, suggesting the existence of
potentially redundant mechanisms for modulating branching
morphogenesis. Concentrations of TGF-[beta] that resulted in long
non-branching tubules also altered the profile of extracellular
matrix-degrading proteases and their inhibitors expressed by the
developing tubules. The ratios of u-PA/PAI-1 and MMP-1/TIMP-1 were
both markedly decreased. In addition, apart from a direct effect on
epithelial cell branching morphogenesis, TGF-[beta] down-regulated
the expression of HGF mRNA in Swiss 3T3 cells. Thus, TGF-[beta]
exerts at least three distinct effects relevant to tubulogenesis and
branching morphogenesis: inhibition of branching morphogenesis alone,
inhibition of both tubulogenesis and branching morphogenesis, and
inhibition of the growth factor expression which induces
tubulogenesis and branching morphogenesis. In the context of
epithelial tissue development, which requires tightly regulated
branching tubulogenesis of epithelial cells, the data suggest a model
where branching patterns are regulated by a precise temporal and
spatial balance between branching morphogens such as HGF and
inhibitory morphogens such as members of the TGF-[beta] superfamily
(TGF-[beta] isoforms, certain BMPs, etc.).
Received 30 July 1996; accepted in final form 2 October 1996.
APS Manuscript Number F225-6.
Article publication pending Am. J. Physiol. (Renal Fluid Electrolyte
Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 5 November 1996