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. Author manuscript; available in PMC: 2020 Nov 1.
Published in final edited form as: Science. 2020 May 1;368(6490):497–505. doi: 10.1126/science.aay0267

Fig. 4. Androgen receptor-mediated induction of neuregulin in mesenchymal cells is a potential driver of luminal regeneration.

Fig. 4.

(A) Changes in expression of key stromal ligands over the C/R time course. Smoothed mean expression relative to intact prostate (T0) (y axis) of ligands in different subsets of stromal and epithelial cells (per color code). (B) In situ validation of growth factor expression by RNA-FISH of prostate tissue isolated on regeneration day 2. Representative growth factors (Egf, Nrg2, Rspo3, Fgf10; green), luminal cells (CD24a; white) and proliferating cells (Mki67; red) are shown. Scale bar: 25μm. (C-E) Nrg promotes luminal regeneration in mouse and human organoids. (C) Relative proliferation of murine L1 cells (CD26/Dpp4+; top) and L2 cells (Sca1/Ly6a+; bottom) in the presence of Egf, Nrg, Fgf10 Igf or no growth factor, in the presence of DHT (1nM) or enzalutamide (10μM). The data are displayed as average growth ± standard deviation (y axis) of 5,000 cells measured by Cell titer glo at 7 days. Base organoid medium contains noggin, R-spondin, A83-001 and Y-27632. N=3. *designates p< 0.05, **designates p< 0.01, t test. (D) Relative proliferation of murine L1 and L2 cells measured as in (C), in the presence of EGF alone or EGR in combination with either Nrg, Ffg10 or Igf, all in the presence of DHT (1nM) (x axis). N=3. *designates p< 0.05, **designates p< 0.01, t test. (E) Relative proliferation of human prostate luminal cells (CD26/DPP4+) measured as in (C), in the presence of EGF, NRG or ERG plus NRG in base human organoid medium (NOGGIN, R-SPONDIN1, FGF2, FGF10, PGE2, A83-001, NICOTINAMID, SB202190, DHT and Y-27632). N=3. *designates p< 0.05, **designates p< 0.01, t test. Human organoids for this panel were derived from normal prostate tissue isolated during cystectomy surgery.