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

Installation of the developing nephron in the fetal human kidney during advanced pregnancy

Background The kidneys of preterm and low birth weight babies reflect vulnerability, since several noxae can evoke the termination of nephron formation. This again leads to oligonephropathy with severe consequences for health in the later life. While the clinical parameters have been intensely investigated, only little is known about the initial traces left by the noxae. For the fetal human kidney, solely the lack of basophilic S-shaped bodies and the reduction in width of the nephrogenic zone were registered. It is not known in how far also the involved progenitor cells, the earlier nephron stages, the collecting duct (CD) ampullae, and the local interstitium are collaterally harmed. Aim The interstitium at the forming nephron is heterogeneously structured. Thereby, it fulfills quite different mastering and integrative tasks. Since data dealing with the installation of a nephron is not available, the microanatomical features were recorded. Results The microscopic specimens show that the installation of the transient stages of nephron anlage is not synchronized. Instead, it is controlled within a nephrogenic compartment of the nephrogenic zone. It starts near the renal capsule by positioning the nephrogenic niche so that the nephrogenic progenitor cells face the epithelial progenitor cell at the tip of a CD ampulla. Then, the induced nephrogenic progenitor cells assimilate in the pretubular aggregate. While its medial part remains opposite the head of the CD ampulla, at its proximal end, the primitive renal vesicle is formed. Only a part of it separates to stick to the section border between the head and conus of the CD ampulla. This marks the link with the future connecting tubule at the distal pole of the extending renal vesicle. Meanwhile, the proximal pole is mounted next to the connecting tubule of an earlier developed nephron. The resulting two-point mounting serves a common elongation of the conus at the CD ampulla and the medial aspect of the comma-shaped body. In the S-shaped body, it supports to defoliate the arising glomerulus and to link it with the perforating radiate artery at its deep lateral aspect. Conclusions The investigation depicts that the installation is an interactive process between the stages of nephron anlage and its structural neighbors. A special meaning has the interjacent interstitium. It is vital for the positioning, shaping, and physiological integration. Due to its special location, this is mainly exposed to noxae

Radial Expansion of the Nephrogenic Zone in the Fetal Human Kidney During Advanced Pregnancy: A Microanatomical Look at a Little Noticed Process

Introduction: The experiences with preterm and low birth weight babies indicate a special vulnerability of their kidneys, since different kinds of noxae can evoke the termination of nephron formation. This leads to oligonephropathy, which is associated with serious consequences for health in the later stages of life. While the clinical aspects have been intensely investigated, only few pathological data point to the initial traces left by the noxae. Up to this date, only the reduction in the width of the nephrogenic zone (NZ) and the lack of here occurring basophilic S-shaped bodies were reported. Methods and Materials: The relationship between the arising nephron and its structural neighbors changes throughout the developmental progress. Locally, this determines the vertical width of the NZ reflected by the radial expansion of both the parenchyma and the interstitium. Since information about the origin, the site, and the involved structures is not available, the related microanatomical features were recorded. Results: The data reveal that the renal vesicles, comma-shaped bodies, and S-shaped bodies are unequally distributed in the NZ. Due to their progressive sizes, it has an influence on the local vertical width of the NZ. This parameter is registered as the distance between the inner side of the renal capsule and the proximal pole of the respective stage of the nephron anlage. The vertical width can be further subdivided: the constant height of the district of progenitor cell recruitment and the variable height of the area of nephron shaping. Exclusively here, the radial expansion of the shaping nephron stages can be noticed. It starts at the section border between the head and the conus of the related collecting duct ampulla by positioning the primitive renal vesicle. While the respective proximal pole stays mounted next to the connecting tubule of a previously developed nephron, the distal pole sticks between the head and the conus at the CD ampulla for linking the future connecting tubule. This causes that henceforth the medial aspect of the extending renal vesicle, comma-shaped body, or S-shaped body stages radially expands in close proximity to the elongating conus of the CD ampulla. Conclusion: Between the arising nephron stages and the elongating conus of the CD ampulla, a linked radial expansion occurs. This new finding is essential to identify the extent of targeting of noxae that subsequently leads to a reduction in the width of the NZ

Cell Projections and Extracellular Matrix Cross the Interstitial Interface within the Renal Stem/Progenitor Cell Niche: Accidental, Structural or Functional Cues?

Background: During nephron induction, morphogenetic molecules are reciprocally exchanged between epithelial and mesenchymal stem/progenitor cells within the renal stem/progenitor cell niche. That these molecules remain concentrated, it is assumed that both cell populations stand in close contact to each other. However, recently published data illustrate that epithelial and mesenchymal cells are separated by an astonishingly wide interstitial interface. Methods: To gain deeper morphological insights into the spatial distribution of mesenchymal and epithelial stem/progenitor cells, the embryonic zone of neonatal rabbit kidney was fixed either with glutaraldehyde (GA) or in a combination with cupromeronic blue, ruthenium red or tannic acid. Transmission electron microscopy was then performed on exactly orientated sections. Results: Conventional fixation with GA illustrates that epithelial and mesenchymal stem/progenitor cells are separated by a bright but inconspicuously looking interstitial interface. In contrast, fixation of specimens in GA containing cupromeronic blue, ruthenium red or tannic acid elucidates that part of the interstitial interface exhibits a special extracellular matrix extending like woven strands between mesenchymal and epithelial stem/progenitor cells. In parallel, filigree projections from mesenchymal stem/progenitor cells cross the interstitial interface to penetrate the basal lamina of epithelial cells. Fusion of the plasma membranes cannot be observed. Instead, touching mesenchymal cell projections form a cone at the contact site with tunneling nanotubes. Conclusions: The results demonstrate that the contact between mesenchymal and epithelial stem/progenitor cells does not form accidentally but physiologically and appears to belong to a suspected system involved in the exchange of morphogenetic information

Microanatomy of the developing nephron in the fetal human kidney during late gestation

Background: Clinical experiences reveal that the kidneys of preterm and low birth weight infants are highly vulnerable. Noxae of various molecular composition can damage the outer renal cortex, resulting in an early termination of nephron formation. However, in contrast to what is known about the rodent kidney, with reference to the damage on the early stages of nephron anlage such as the comma-shaped body, renal vesicles, pretubular aggregate or nephrogenic niche, this information in the fetal human kidney is not available. The few documented pathological alterations in the fetal human kidney during late gestation are glomeruli with a dilated Bowman's space and a shrunken tuft, the reduction in width of the nephrogenic zone and the lack of here contained S-shaped bodies. The latter points out that the shaping, folding or expansion of the developing nephron must be disrupted. Since these specific aspects have been little investigated, the aim of the present microanatomical contribution is to highlight it. Methods: Firstly, the individual stages of nephron anlage in the fetal human kidney during late gestation were documented by microscopic images. Then, as a stylistic tool for the pointing to specific sites of the running developmental process, a series of true to scale sketches were produced. Results: The generated sketches depict the spatial expansion of the transiently appearing stages of nephron anlage. These are restricted to the nephrogenic zone and are framed by the inner side of the renal capsule, the related collecting duct ampulla and a perforating radiate artery. Practical hints and a consequent nomenclature explain the developmental course and help us to identify the precise location of the proximal - distal poles, medial - lateral profiles, connecting points, adhesion sites or folds at the developing nephron on microscopic specimens. Conclusions: The impairment of nephrogenesis in preterm and low birth weight babies is an unsolved biomedical issue. To contribute, by provided true to scale sketches, numerous practical hints and a consequent nomenclature typical features of nephron formation in the fetal human kidney at late gestation are demonstrated. (C) 2021 Elsevier GmbH. All rights reserved

In Search of Imprints Left by the Impairment of Nephrogenesis

Clinical aspects dealing with the impairment of nephrogenesis in preterm and low birth weight babies were intensely researched. In this context it was shown that quite different noxae can harm nephron formation, and that the morphological damage in the fetal kidney is rather complex. Some pathological findings show that the impairment leads to changes in developing glomeruli that are restricted to the maturation zone of the outer cortex in the fetal human kidney. Other data show also imprints on the stages of nephron anlage including the niche, the pretubular aggregate, the renal vesicle, and comma- and S-shaped bodies located in the overlying nephrogenic zone of the rodent and human kidneys. During our investigations it was noticed that the stages of nephron anlage in the fetal human kidney during the phase of late gestation have not been described in detail. To contribute, these stages were recorded along with corresponding images. The initial nephron formation in the rodent kidney served as a reference. Finally, the known imprints left by the impairment in both specimens were listed and discussed. In sum, the relatively paucity of data on nephron formation in the fetal human kidney during the late phase of gestation is a call to start with intense research so that concepts for a therapeutic prolongation of nephrogenesis can be designed.</jats:p