VEGF expands erythropoiesis via hypoxia-independent induction of erythropoietin in noncanonical perivascular stromal cells

Abstract

Insufficient erythropoiesis due to increased demand is usually met by hypoxia-driven up-regulation of erythropoietin (Epo). Here, we uncovered vascular endothelial growth factor (VEGF) as a novel inducer of Epo capable of increasing circulating Epo under normoxic, nonanemic conditions in a previously unrecognized reservoir of Epo-producing cells (EPCs), leading to expansion of the erythroid progenitor pool and robust splenic erythropoiesis. Epo induction by VEGF occurs in kidney, liver, and spleen in a population of Gli1+SMA+PDGFRβ+ cells, a signature shared with vascular smooth muscle cells (VSMCs) derived from mesenchymal stem cell–like progenitors. Surprisingly, inhibition of PDGFRβ signaling, but not VEGF signaling, abrogated VEGF-induced Epo synthesis. We thus introduce VEGF as a new player in Epo induction and perivascular Gli1+SMA+PDGFRβ+ cells as a previously unrecognized EPC reservoir that could be harnessed for augmenting Epo synthesis in circumstances such as chronic kidney disease where production by canonical EPCs is compromised.

Different subpopulations of kidney interstitial cells produce erythropoietin and factors supporting tissue oxygenation in response to hypoxia in vivo

“…These results are in good accordance with previous findings. 1,8,28 Interestingly, the TNC þ RICs identified in this study seem to play a role during experimental kidney fibrosis. During UUO this subpopulation of potential EPO-producing cells sustained a de novo expression of EPO mRNA in the IM whereas EPO production in the kidney cortex declined (Figure 5c).…”

“…These results are supported by a recent study suggesting Gli1 þ cells as possible production sites for EPO. 28 EPO-expressing cells showed the characteristic stellate appearance described for EPO-expressing cells of anemic kidneys 10,14 or of PDGFR-b CreERT2/þ Vhl fl/fl mice 13 (Supplementary Figure S3). Gli1 þ cells are considered closely related to pericytes, which transform into myofibroblasts in states of interstitial kidney fibrosis.…”

Angiotensin-Converting Enzyme Inhibitors Have Adverse Effects in Anti-Angiogenesis Therapy for Hepatocellular Carcinoma

“…The whole operation process of real-time PCR (RT-PCR) reactions was carried out as described by Alissa C. et al [27]. The EPO primers were synthesized by Biotechnology Engineering (Shanghai, China) Co., Ltd., and the sequences were EPO-s: 5′-AATGGAGGTGGAAGAACAGGCCAT-3′, EPO-as: 5′-CGAAGCAGT GAAGTGAGGCTACGTA-3′.…”

“…The liver, kidney, spleen and tumor are potential organs or tissues for EPO synthesis [21,27]. Therefore, EPO mRNA was measured in these tissues, and no signi cant change was observed in the liver, spleen or tumor tissues.…”

Kidney‐in‐a‐lymph node: A novel organogenesis assay to model human renal development and test nephron progenitor cell fates

“…Moreover, EPO can also be produced under normoxia by intercalated cells of the collecting ducts and proximal and distal tubules (Nagai et al, ). Finally, very recent evidence shows the existence of an additional EPO‐producing cell population of perivascular stromal cells, which driven by vascular endothelial growth factor A, is capable of increasing EPO production independently from hypoxia (Greenwald et al, ). We have never observed interstitial cell production of EPO in our kidney grafts.…”