The mutual patterning between the developing nephron and its covering tissues—valid reasons to rethink the search for traces left by impaired nephrogenesis

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The interstitium at the developing nephron in the fetal kidney during advanced pregnancy — a microanatomical inventory

Background A series of noxae can evoke the termination of nephron formation in preterm and low birth weight babies. This results in oligonephropathy with severe consequences for health in the later life. Although the clinical parameters have been extensively investigated, little is known about the initial damage. Previous pathological findings indicate the reduction in width of the nephrogenic zone and the lack of S-shaped bodies. Current morphological investigations suggest that due to the mutual patterning beside the forming nephron, also its structural neighbors, particularly the interjacent interstitium, must be affected. However, beside the findings on integrative and mastering functions, systematic microanatomical data explaining the configuration of the interstitium at the developing nephron in the fetal kidney during advanced pregnancy is not available. Therefore, this work explains the typical features. Results The generated data depicts that the progenitor cells, nephrogenic niche, pretubular aggregate, and mesenchymal-to-epithelial transition are restricted to the subcapsular interstitium. During the proceeding development, only the distal pole of the renal vesicles and comma- and S-shaped bodies stays in further contact with it. The respective proximal pole is positioned opposite the peritubular interstitium at the connecting tubule of an underlying but previously formed nephron. The related medial aspect faces the narrow peritubular interstitium of a collecting duct (CD) ampulla first only at its tip, then at its head, conus, and neck, and finally at the differentiating CD tubule. The lateral aspect starts at the subcapsular interstitium, but then it is positioned along the wide perivascular interstitium of the neighboring ascending perforating radiate artery. When the nephron matures, the interstitial configuration changes again. Conclusions The present investigation illustrates that the interstitium at the forming nephron in the fetal kidney consists of existing, transient, stage-specific, and differently far matured compartments. According to the developmental needs, it changes its shape by formation, degradation, fusion, and rebuilding

PCDAmpl, a new antigen at the interface of the embryonic collecting duct epithelium and the nephrogenic mesenchyme

P CDAmpl, a new antigen at the interface of the embryonic collecting duct epithelium and the nephrogenic mesenchyme. In the neonatal rabbit kidney nephrogenesis is not yet terminated. The ampullar collecting duct epithelium acts as an inducer that generates the nephron anlagen, however, to date the morphogenic mechanisms involved are unknown. A presupposition for successful nephron induction is the close tissue interaction between the basal aspect of the ampullar collecting duct epithelium and the surrounding mesenchyme. To gain new insights in this area we raised monoclonal antibodies (mabs), to identify specific structures localized at the tissue interface. With the generated mab CDAmpl we found an intensive immunohistochemical reaction between the basal aspect of the ampullar collecting duct epithelium and the mesenchyme. The label was most concentrated at the ampullar tip and continuously decreased in the shaft region. In the maturing collecting duct of the neonatal kidney and in the adult renal collecting duct no immunohistochemical reaction was found. The binding pattern of mab CDAmpl is different from that of all known collecting duct cell markers and from antibodies against known basement membrane compounds such as laminin or collagen type IV. Under in vitro conditions immunoreactivity with mab CDAmpl was obtained using embryonic collecting duct epithelia and perfusion culture. The antigen was present in specimens treated with Iscove's modified Dulbecco's Medium (IMDM) containing 10% fetal bovine serum. Omittance of serum or hormonal treatment with aldosterone, insulin or vitamin D3 led to the disappearance of the newly detected antigen, while characteristics of the differentiated collecting duct cells were up-regulated. We conclude that the expression of P CDAmpl is a characteristic feature of the embryonic parts of the collecting duct epithelium. It may play a pivotal role during nephron induction

The rabbit nephrogenic zone in culture: past, present and future as a model to investigate causes of impaired nephrogenesis

In preterm infants, intrauterine as well as extrauterine influences are held responsible for causing prematurity of renal parenchyma and impaired nephrogenesis, leading to a high incidence of severe kidney diseases later in life. Although involved noxae and resulting molecular effects are quite different, all of them converge to the nephrogenic zone which is restricted to the outer cortex of a developing kidney. Covered by the organ capsule, it consists of aligned ureteric bud-derived collecting duct (CD) ampullae containing epithelial stem cells, nephrogenic mesenchymal stem cells, renal vesicles and S-shaped bodies. Owing to the complex composition of the nephrogenic zone and the different noxae, it is appropriate to investigate impaired nephrogenesis with an adequate in vitro system. In this case, isolation and culture of the nephrogenic zone from neonatal rabbit kidney is particularly well-suited. As compared to human specimens, it exhibits to a large extend a comparable microarchitecture. However, a decisive advantage is that it can be easily and quickly isolated in original composition with microsurgical techniques. Thus, pieces of the explant are available to a variety of advanced culture experiments. Formation of renal spheroids can be used for drug toxicity testing. Mounting in a tissue carrier makes it possible to register functional differentiation of the CD epithelium. Perfusion culture within an artificial interstitium enables investigation of spatial development of tubules. The present article has been written to inform about past and present results, recognized risks and future challenges

What is the functional background of filigree extracellular matrix and cell-cell connections at the interface of the renal stem/progenitor cell niche?

Development of a nephron is induced by a reciprocal exchange of morphogenetic proteins between epithelial and mesenchymal cells within the renal stem/progenitor cell niche. For sustaining concentration of diffusing proteins high, it is believed that an intimate contact exists between involved cells. However, actual morphological data show that both types of stem/progenitor cell bodies are separated by an interface. To analyze details of this arrangement, neonatal rabbit kidneys were fixed in traditional glutaraldehyde (GA) solution for transmission electron microscopy. For an enhanced contrast fixation of samples was performed in GA solution including either cupromeronic blue, ruthenium red or tannic acid. To record always the same perspective, embedded blocks of parenchyma were cut in orientated vertical and transverse planes to the lumen of lining collecting duct tubules. Screening of samples fixed by GA solution demonstrates a constant separation of stem/progenitor cell bodies by an unobstrusively looking interface. In contrast, improved fixation of specimens in GA solution including cupromeronic blue, ruthenium red or tannic acid unveils between them earlier not visible filigree extracellular matrix. Further projections of mesenchymal cells covered by this matrix cross the interface to contact epithelial cells. The end of a projection does not dangle but is mounted by a special plug connection. At this site the plasma membranes of mesenchymal and epithelial cells are connected via tunneling nanotubes. Regarding this unique arrangement the principal question is to what extent illustrated extracellular matrix and cell-cell connections are involved in the exchange of morphogenetic proteins during induction of a nephron.   Proceedings of the 2nd International Course on Perinatal Pathology (part of the 11th International Workshop on Neonatology · October 26th-31st, 2015) · Cagliari (Italy) · October 31st, 2015 · Stem cells: present and future Guest Editors: Gavino Faa, Vassilios Fanos, Antonio Giordan