Special Morphological Features at the Interface of the Renal Stem/Progenitor Cell Niche Force to Reinvestigate Transport of Morphogens During Nephron Induction

Abstract

Formation of a nephron depends on reciprocal signaling of different morphogens between epithelial and mesenchymal cells within the renal stem/progenitor cell niche. Previously, it has been surmised that a close proximity exists between both involved cell types and that morphogens are transported between them by diffusion. However, actual morphological data illustrate that mesenchymal and epithelial stem/progenitor cell bodies are separated by a striking interface. Special fixation of specimens by glutaraldehyde (GA) solution including cupromeronic blue, ruthenium red, or tannic acid for electron microscopy depicts that the interface is not void but filled in extended areas by textured extracellular matrix. Surprisingly, projections of mesenchymal cells cross the interface to contact epithelial cells. At those sites the plasma membranes of a mesenchymal and an epithelial cell are connected via tunneling nanotubes. Regarding detected morphological features in combination with involved morphogens, their transport cannot longer be explained solely by diffusion. Instead, it has to be sorted according to biophysical properties of morphogens and to detected environment. Thus, the new working hypothesis is that morphogens with good solubility such as glial cell line-derived neurotrophic factor (GDNF) or fibroblast growth factors (FGFs) are transported by diffusion. Morphogens with minor solubility such as bone morphogenetic proteins (BMPs) are secreted and stored for delivery on demand in illustrated extracellular matrix. In contrast, morphogens with poor solubility such as Wnts are transported in mesenchymal cell projections along the plasma membrane or via illustrated tunneling nanotubes. However, the presence of an intercellular route between mesenchymal and epithelial stem/progenitor cells by tunneling nanotubes also makes it possible that all morphogens are transported this way.

Reading First Coordinates from the Nephrogenic Zone in Human Fetal Kidney

“…Consequently, it is necessary to first find a suitable path for drug application via infusion or local stem cell implantation. In this connection, it is obligatory to observe not only the necessary morphogenetic impulses, but also to have a close look at the local microenvironment and the morphogen actions, in which a stem or progenitor cell, respectively a niche, is biologically active [69, 70]. While it is obvious that the creation of the schema introduced here cannot answer the questions raised, it gives the first detailed information about the complex microanatomy of the nephrogenic zone and contained stem cell niches.…”

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“…7). Since concrete data for the human renal stem cell niche is not available, the here introduced concept is founded on neonatal rabbit kidney [74,75] and cell biological data raised in other developmental systems [76].…”

“…Special fixation of specimens with glutaraldehyde (GA) solution including cupromeronic blue, ruthenium red respectively tannic acid for transmission electron microscopy demonstrates that extended areas of the interface within the renal stem cell niche contain filigree extracellular matrix [74,75]. In contrast, a complementary but much minor space does not show any label, appears to be filled only by interstitial fluid and is consequently best suited for diffusion of a readily soluble morphogen (Fig.…”

“…Actual literature demonstrates that projections of mesenchymal stem cells cross the interface and the adjacent basal lamina to establish a contact with epithelia stem cells at the tip of a CD ampulla (▶ Fig. 4) [74,75]. Astonishingly, between the end of a projection and the basal plasma membrane of an epithelial cell tunneling nanotubes occur to establish a cell to cell communication (▶ Fig.…”

“…Instead they were investigated by in vitro experiments with renal cells in different context [47,99]. In sum, due to mentioned arguments and many unanswered questions the transport of morphogens within the renal niche via tunneling nanotubes waits to be investigated, when prolongation of nephrogenesis in preterm or low birth weight babies is therapeutically intended [5,75,100].…”