The instructive role of metanephric mesenchyme in ureteric bud patterning, sculpting, and maturation and its potential ability to buffer ureteric bud branching defects

Abstract

Nigam SK. The instructive role of metanephric mesenchyme in ureteric bud patterning, sculpting, and maturation and its potential ability to buffer ureteric bud branching defects. Am J Physiol Renal Physiol 297: F1330-F1341, 2009. First published September 2, 2009 doi:10.1152/ajprenal.00125.2009.-Kidney organogenesis depends on reciprocal interactions between the ureteric bud (UB) and the metanephric mesenchyme (MM) to form the UB-derived collecting system and MM-derived nephron. With the advent of in vitro systems, it is clear that UB branching can occur independently of MM contact; however, little has been done to detail the role of MM cellular contact in this process. Here, a model system in which the cultured isolated UB is recombined with uninduced MM is used to isolate the effects of the MM progenitor tissue on the development and maturation of the collecting system. By morphometrics, we demonstrate that cellular contact with the MM is required for vectorial elongation of stalks and tapering of luminal caliber of UB-derived tubules. Expression analysis of developmentally significant genes indicates the cocultured tissue is most similar to an embryonic day 19 (E19) kidney. The likely major contributor to this is the functional maturation of the collecting duct and proximal nephron segments in the UB-induced MM, as measured by quantitative PCR, of the collecting duct-specific arginine vasopressin receptor and the nephron tubule segment-specific organic anion transporter OAT1, Na-Pi type 2 cotransporter, and Tamm-Horsfall protein gene expressions. However, expression of aquaporin-2 is upregulated similarly in isolated UB and cocultured tissue, suggesting that some aspects of functional maturation can occur independently of MM cellular contact. In addition to its sculpting effects, the MM normalized a "branchless" UB morphology induced by FGF7 or heregulin in isolated UB culture. The morphological changes induced by the MM were accompanied by a reassignment of GFR␣1 (a receptor for GDNF) to tips. Such "quality control" by the MM of UB morphology may provide resiliency to the branching program. This may help to explain a number of knockout phenotypes in which branching and/or cystic defects are less impressive than expected. A second hit in the MM may thus be necessary to make these defects fully apparent. kidney development; branching morphogenesis; mesenchymal-to-epithelial transformation; polycystic kidney disease; kidney tissue engineering THE MAMMALIAN KIDNEY ARISES from reciprocal inductive interactions of two primordial tissues, the ureteric bud (UB) and the metanephric mesenchyme (MM). Development of the kidney is initiated by the outgrowth of the epithelial UB from the mesonephric or Wolffian duct, presumably in response to inductive signals from the MM (a loose aggregation of cells derived from the intermediate mesoderm). The UB then rapidly invades the MM where it is induced to undergo numerous iterations of branching morphogenesis, leading to the formation of the treelike collecting system of the ki...

Constructing Kidney-like Tissues from Cells Based on Programs for Organ Development: Toward a Method ofIn VitroTissue Engineering of the Kidney

“…4d), reminiscent of the recombination of cultured isolated UB with MM. [11][12][13]43 Thus, cultured cells derived from the UB can, in this system, induce a mesenchymal-to-epithelial transition in the isolated MM. The E-cadherin-positive/DB-negative MM-derived tubule appeared continuous with the DBpositive/E-cadherin-positive UB-cell-derived structure.…”

“…MMs isolated from day 13 embryonic kidneys as previously described [11][12][13] were placed directly onto a cell-culturetreated plate and cultured for 5 days in the growth medium supplemented with 50 ng/mL of FGF2 and 10 ng/mL transforming growth factor-a, which support MM survival. 9 The MM cells were then trypsinized and placed on new plates and used for the experiments.…”

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