Embryonic Kidney Development, Stem Cells and the Origin of Wilms Tumor

Abstract

The adult mammalian kidney is a poorly regenerating organ that lacks the stem cells that could replenish functional homeostasis similarly to, e.g., skin or the hematopoietic system. Unlike a mature kidney, the embryonic kidney hosts at least three types of lineage-specific stem cells that give rise to (a) a ureter and collecting duct system, (b) nephrons, and (c) mesangial cells together with connective tissue of the stroma. Extensive interest has been raised towards these embryonic progenitor cells, which are normally lost before birth in humans but remain part of the undifferentiated nephrogenic rests in the pediatric renal cancer Wilms tumor. Here, we discuss the current understanding of kidney-specific embryonic progenitor regulation in the innate environment of the developing kidney and the types of disruptions in their balanced regulation that lead to the formation of Wilms tumor.

FGF8 induces chemokinesis and regulates condensation of mouse nephron progenitor cells

“…At the same time, nephron progenitor cells (NPCs) from the CM migrate in a stochastic fashion between the top (or tip region) of the epithelial ureteric bud (UB) and the bottom (or trunk region) (Figure 1) [9][10][11]. NPC fate is region-specific and requires reciprocal signals between the UB and the surrounding mesenchymal and stromal cells (Figure 1) [1,2,[11][12][13][14][15][16]. NPCs that are located in the tip region of the UB maintain their progenitor state and are thus called true Fibroblast growth factors (FGFs) are a family of signaling proteins that govern different aspects of kidney development, including UB branching and maintenance of NPCs [24].…”

Clear Cell Renal Cancer, a Tumour with Neuroendocrine Features Originating from the Erythropoietin-Producing Cell

“…ccRCC and papillary renal cell cancers (pRCCs) have been presumed to originate from proximal tubular cells. However, most cells in the adult kidney do not have the ability to divide and thus replace damaged or dead specialised cells [5]. Therefore, replacement of damaged nephrons does not occur after birth [6].…”

Omics profiling identifies MAPK/ERK pathway as a gatekeeper of nephron progenitor metabolism

“…Production of pyruvate is regulated by the embryonic kidney expressed glycolytic enzyme pyruvate kinase isozyme M2 (PKM2), which function is controlled by the mitogenactivated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) (19). We have recently demonstrated the importance of MAPK/ERK activity in mediating extracellular signals to NP regulation, where it on one hand maintains NP identity and on the other hand propels differentiation in nephron precursors (11,20,21). Interestingly, MAPK/ERK target p53 is shown to ensure metabolic fitness in propagating nephron progenitors (22).…”

“…The total NP lifespan is limited to the fetal period in humans and to the first postnatal days of life in mouse (7)(8)(9). The molecular regulation of NP maintenance and differentiation has been extensively studied (10,11), but the factors contributing to the cessation of the nephrogenic program are only evolving and suggest involvement of changes in signal transduction activities (12)(13)(14). Moreover, information is only emerging about metabolic events and especially mitochondrial metabolism, underlying the cell type-specific behaviors of NPs during their propagation and differentiation switches (15,16).…”

“…We have recently demonstrated the importance of MAPK/ERK activity to the transmission of extracellular signals for NP regulation, where it on one hand maintains NP identity and on the other hand propels differentiation in nephron precursors (4,11,29). Interestingly, MAPK/ERK target p53 contributes to metabolic fitness in propagating NPs (30).…”