Regulation of Nephron Progenitor Cell Self-Renewal by Intermediary Metabolism

Abstract

Nephron progenitor cells (NPCs) show an age-dependent capacity to balance self-renewal with differentiation. Older NPCs (postnatal day 0) exit the progenitor niche at a higher rate than younger (embryonic day 13.5) NPCs do. This behavior is reflected in the transcript profiles of young and old NPCs. Bioenergetic pathways have emerged as important regulators of stem cell fate. Here, we investigated the mechanisms underlying this regulation in murine NPCs. Upon isolation and culture in NPC renewal medium, younger NPCs displayed a higher glycolysis rate than older NPCs. Inhibition of glycolysis enhanced nephrogenesis in cultured embryonic kidneys, without increasing ureteric tree branching, and promoted mesenchymal-to-epithelial transition in cultured isolated metanephric mesenchyme. Cotreatment with a canonical Wnt signaling inhibitor attenuated but did not entirely block the increase in nephrogenesis observed after glycolysis inhibition. Furthermore, inhibition of the phosphatidylinositol 3-kinase/Akt self-renewal signaling pathway or stimulation of differentiation pathways in the NPC decreased glycolytic flux. Our findings suggest that glycolysis is a pivotal, cell-intrinsic determinant of NPC fate, with a high glycolytic flux supporting self-renewal and inhibition of glycolysis stimulating differentiation.

Canagliflozin Prevents Intrarenal Angiotensinogen Augmentation and Mitigates Kidney Injury and Hypertension in Mouse Model of Type 2 Diabetes Mellitus

“…Droplet Digital PCR ddPCR was performed to determine AGT mRNA copies in the liver, adipose tissue, and renal cortex of mice as previously described [16]. Moreover, copy numbers of renin, ACE, AT1a, and SGLT2 mRNA in renal cortex were evaluated by ddPCR.…”

Age-Dependent Changes in the Progenitor Translatome Coordinated in part byTsc1Increase Perception of Signaling Inputs to End Nephrogenesis

“…Thus, there is no need to change the niche signaling milieu -a key component in the tipping point appears to be increased "awareness" in older NPCs to their existing signaling environment. These translational changes may work synergistically or independently from the Lin28/Let7 axis (Yermalovich et al, 2019) or metabolism (Liu et al, 2017). Third, whereas "young" NPC in the Six2 TGC strain are indeed either naïve (Six2 + , Cited1 + , Wnt4 -) or "primed" (Six2 + , Cited1 -, Wnt4 + ) (Mugford et al, 2009), ~3% older NPC in the same strain are reverting from a "primed" to naïve state , identified by a triple positive (Six2 + , Cited1 + , Wnt4 + ) state due to the presence of unspliced, new Cited1 transcripts.…”

“…The entire cap mesenchyme (CM) group was also enriched for ribosomal proteins, BMP and Notch signaling, whereas the non-CM NPCs were enriched for ontologies related to Hedgehog signaling, DNA replication, and one carbon metabolism ( Figure 2M, Supplemental Figure S2). Electron transport and oxidative phosphorylation pathways where enriched in non-CM E14 Six2 TGC clusters and P0 Six2 TGC;Tsc1 CM, inconsistent with reduced respiration driving increased nephron endowment in the latter population (Liu et al, 2017). Given the high levels of Cited1 at E14 in Six2 KI (Figure 2F), distinct clustering of E14 Six2 KI cells away from age-matched cells, we surmise that the increased nephron endowment in Six2 KI might be driven by a mechanism acting earlier in nephrogenesis, before P0.…”

“…First, increased nephron endowment may reflect either an expanded or distinct, novel population of NPCs. Second, age-dependent change in the transcriptome (Chen et al, 2015) and/or metabolome (Liu et al, 2017) in these two models may unfold more slowly, enabling NPC to retain their "youthful" character relative to chronologically matched NPCs from the control strain, Six2 TGC . Third, a molecular mechanism(s) unrelated to the relative age of the progenitors is involved.…”

Orphan nuclear receptor COUP-TFII drives the myofibroblast metabolic shift leading to fibrosis

“…The phenotypic resemblance between COUP-TFII overexpressed alone cells and WT cells treated with TGFβ1 suggests that COUP-TFII is essential to establish the myofibroblast phenotype through augmented glycolysis. High glycolytic flux is important for the self-renewal of progenitor cells (Liu, Edgington-Giordano et al, 2017). Interestingly, COUP-TFII expression is abundant in the mesenchymal compartment of the developing organs during embryonic organogenesis but declines significantly right after birth (Pereira, Qiu et al, 1995).…”