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

Alissa C. Greenwald, Tamar Licht, Saran Kumar, Sunday S. Oladipupo, Seema Iyer, Myriam Grunewald*, Eli Keshet

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

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.

Original languageAmerican English
Pages (from-to)215-230
Number of pages16
JournalJournal of Experimental Medicine
Volume216
Issue number1
DOIs
StatePublished - 1 Jan 2019

Bibliographical note

Publisher Copyright:
© 2018 Greenwald et al.

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