Transferrin as a fetal growth factor: acquisition of responsiveness related to embryonic induction.

Abstract

Differentiation of the metanephric mesenchyme, which is triggered by an inductive tissue interaction, has been shown to proceed in a chemically defined medium containing transferrin. Here, we report that neither transferrin-depleted serum nor a chemically defined medium devoid of transferrin promote differentiation and that activity can be restored by the addition of transferrin. It thus appears that we have identified the serum factor required for kidney differentiation. Transferrin seems to affect differentiation by stimulating cell proliferation. We show by using an organ-culture model system that only mesenchymes induced to differentiate by the 24-hr tissue interaction respond to transferrin by proliferation and differentiation, whereas uninduced mesenchymes remain unresponsive. The inductor tissue used is not responsive to transferrin. Thus, the data suggest that the short-range cell-mediated tissue interaction acts by making the nephrogenic mesenchyme responsive to the long-range mediator, which is transferrin. Transferrin is suggested to be an important circulating growth factor required for proliferation during embryogenesis.Transferrin is an iron-binding serum protein that has recently received considerable attention because of its profound effect on cell proliferation in vitro (1, 2). It is required for the longterm survival of most cells in serum-free media (2), and there is evidence that transferrin stimulates growth by binding to specific proliferation-related cell surface receptors (3-5). We have recently demonstrated that exogenous transferrin promotes differentiation of kidney epithelial cells in an organ culture (6). Since serum contains numerous components thought to be required for differentiation, we have now studied whether transferrin-depleted serum promotes differentiation. The evidence suggests that no other serum factors can replace transferrin, and we report on studies designed to clarify the mechanism of the effect of transferrin on kidney differentiation.Differentiation of the metanephric kidney is triggered by an inductive tissue interaction between the ureter bud and the nephrogenic mesenchyme (7,8). In the organ culture model system used here, induction is complete within the first day of culture (9-11). The induced nephrogenic mesenchyme is then converted into an epithelium and, during subsequent days, the polarizing cells express markers for the different segments of the nephron (12)(13)(14).It is known for some other organs that certain serum factors can affect morphogenesis through cell and tissue interactions (15-19). It was therefore considered possible that transferrin could be required for the initial inductive interaction in the kidney model system. The data presented, however, suggest that cells become responsive to transferrin as a result of the initial inductive interaction. Transferrin is then required for proliferation during overt differentiation.MATERIALS AND METHODS Culture System. CBA x C57BL hybrid mouse embryos were used. For transfilter cultures, the u...

Renal Iron Metabolism

“…It is interesting that TfR is expressed on the apical membrane of proximal tubule and collecting duct cells in mice (Figure 1), in distal convoluted tubules in the medulla of rats (20), and in all tubules in humans (21), offering a straightforward mechanism by which Tf can be retrieved from filtrate ( Figure 2). It has been found that Tf is an essential growth factor in the development of kidney and differentiation of tubule (22), and retrieval of Tf from filtrate may be the major mechanism by which proximal tubule cells acquire the iron that they need (19).…”

Ovotransferrin and ovotransferrin receptor expression during chondrogenesis and endochondral bone formation in developing chick embryo

“…A similar situation may occur in brain where the transferrin produced by oligodendrocytes and other cells probably plays atrophic role on developing neurons and astrocytes (Aizenman et al, 1986). Finally a role for transferrin and its receptor in embryonic morphogenesis has been shown by Ekblom et al (1983) in mouse organ cultures of developing kidneys and teeth (Partanen et al, 1984). Transferrin is necessary to cell proliferation and cell differentiation.…”

“…It is widely accepted that the major role of transferrin is iron transport and delivery to cells and tissues, nevertheless it has also been proposed that transferrin is important for growth and differentiation of several cell types. In particular, transferrin seems to play a significant role as a mitogenic factor (Trowbridge and Omary, 1981), as a neuro- (Aizenman et al, 1986) and myotrophic agent (Li et al, 1982) and in embryonic morphogenesis (Ekblom et al, 1983;Partanen et al, 1984).…”

Midkine Promotes Selective Expansion of the Nephrogenic Mesenchyme during Kidney Organogenesis

“…Metanephric kidneys were dissected from LacZ positive embryos and grown for 6 days in the presence or absence of 7nM MK, at 37˚C, 5% CO 2 on 0.4 µm pore size transwells as described above. Kidneys were fixed in 4% paraformaldehyde for 1.5 hours and washed with tissue rinse solution A (0.1 M PO 4 6 ) for 1 hour at 37˚C. The tissues were then processed for paraffin sectioning using Histogel.…”

“…[1][2][3] The identification of the epithelial-mesenchymal signaling pathways responsible for these complex inductive events has been a major objective in the effort to understand kidney organogenesis in molecular terms. The ureteric bud provides essential survival factors for the metanephric mesenchyme [4][5][6] and recent studies employing metanephric organ culture have demonstrated that Tissue Inhibitor of Metalloproteinase II (TIMP2), 7 Fibroblast Growth Factor 2 (FGF2) and Bone Morphogenetic Protein 7 ( BMP7) may play important roles in these processes. 8,9 In turn, retinoid-dependent mesenchymal stromal cell signaling activates ureteric bud branching morphogenesis by maintaining the expression of the c-ret receptor tyrosine kinase in the ureteric bud epithelium 10 which functions as the signal transducer for the mesenchymal cell-secreted factor GDNF.…”