Research ArticleCELL BIOLOGY

Monocyte-derived multipotent cell delivered programmed therapeutics to reverse idiopathic pulmonary fibrosis

See allHide authors and affiliations

Science Advances  27 May 2020:
Vol. 6, no. 22, eaba3167
DOI: 10.1126/sciadv.aba3167
  • Fig. 1 Schematic illustration of lung-targeted programmed MOMC/PER therapeutic designed to reverse IPF.

    (A) Bioconjugated MOMC/PER was prepared by incubating PER NPs with MOMC. (B) MOMC/PER has multifunctional moieties including a homing moiety, responsive release moiety, and retargeting moiety to reverse IPF. Then, a weeding and uprooting strategy contributes to IPF reversion. (C) Schematic illustration of MOMC/PER for improved drugs accumulation and antifibrotic effect in IPF lung microenvironment.

  • Fig. 2 The PER NPs can adhere to MOMC and pathology responsively release and then be internalized by A549 in vitro.

    (A) The proliferation of Nanog+ cells in serum and lung tissues by ELISA assay. (B) The MOMC phenotypes. The level of TGF-β (C) and hydroxyproline (D) in IPF lung tissues, respectively. (E) The level of TGF-β/Smad in vitro. (F) Schematic showing the preparation of MOMC/PER. (G) Schematic showing the adhesion of PER NPs to MOMC. (H) SEM images of MOMC and MOMC/PER-DiI. (I) Fluorescent signals of MOMC and PER-DiI NPs by CLSM. (J) The adhesion between MOMC and PER-DiI NPs by flow cytometry. (K) In vitro migration model. The migration ability of MOMC and MOMC/PER in CXCL 12 (L) and CCL 19 (M), respectively. (N) Schematic showing sensitive release of MOMC/PER-DiI triggered by MMP-2. (O) Characterizations by TEM. MOMC is the triangle, and PER-DiI NPs are the arrows. (P) Fluorescent images of MOMC and released PER-DiI NPs by CLSM. (Q) The flow cytometry showed responsive release. (R) Schematic showing the retarget ability of released PER NPs. (S) Characterization of retargeting ability by TEM. (T) The fluorescent images by CLSM. (U) Cellular uptake in A549 by flow cytometry (n = 3). Statistical significance was calculated via one-way analysis of variance (ANOVA).

  • Fig. 3 Homing ability and therapeutic efficacy of MOMC/PER in vivo.

    (A) Schematic of the targeting performance of MOMC/PER in the blood circulation to IPF lungs. (B) In vivo fluorescence images of IPF mice intravenous injection with MOMC-DiR, MOMC/PER-DiR, and DiR (n = 3). (C) Quantification of the in vivo retention profile (n = 3). (D) The different stages of MOMC/PER-DiI. (E) The whole lungs were imaged and investigated after 28 days. Lung morphologies (i) [Photo credit (i): Xin Chang, China Pharmaceutical University], H&E staining (ii), and Masson staining (iii). The morphologies of mitochondria by TEM (iv). The levels of TGF-β (F), IL-1β (G), and IL-4 (H) by ELISA assay (n = 5). The levels of lymphocytes (I), white blood cells (J), and neutrophils (K) in whole blood (n = 5). The levels of GSH (L) and SOD (M), respectively (n = 5). (N) The expression of SPC. (O) Survival rate curves (n = 10). Statistical significance was calculated via one-way ANOVA.

  • Fig. 4 Schematic representation of the performance of PER NPs.

    (A) Schematic of PER NPs circulation in vivo, reprogramming of MOMC/PER, and recruitment to IPF tissue. (B) The targeting ability of PER-DiI NPs. (C) The accumulation of PER-DiI NPs in normal and IPF lungs. (D) Fluorescence IVIS imaging (n = 3). (E) Ex vivo fluorescence imaging and quantification of major organs (n = 3). (F) The accumulation PER-DiI NPs in the lungs at different times. Lung function indexes of GSH (G), SOD (H), and MDA (I). TGF-β (J), IL-1β (K), and IL-4 (L) by ELISA assay (n = 5). (M) Proliferation of fibroblasts. (N) Expression of collagen I. Statistical significance was calculated via one-way ANOVA.

  • Fig. 5 Antifibrosis mechanism with dual drugs synergy.

    (A) Expression of the vimentin in vitro. (B) The ROS level in vitro. (C) The changes of mitochondrial membrane potential. (D) Invasion assay. (E) Fibronectin expression. (F) H&E, Masson, and IHC staining. (G) The level of hydroxyproline. (H) The α-SMA and β-actin by Western blotting. The mRNA expression of Acta2 (I) and Ctgf (J) by qPCR (n = 3). Contents of GSH (K), MDA (L), and SOD (M) (n = 5). Statistical significance was calculated via one-way ANOVA.

  • Fig. 6 The whole lungs were investigated after treatment on day 28.

    (A) H&E staining. (B) Masson staining. The levels of TGF-β in the lungs (C) and spleen tissues (D). N.S., not significant. The levels of IL-1β in the lungs (E) and spleen tissues (F). BUN (G), ALT (H), and aspartate aminotransferase (I) in serum (n = 4). Statistical significance was calculated via one-way ANOVA.

Supplementary Materials

  • Supplementary Materials

    Monocyte-derived multipotent cell delivered programmed therapeutics to reverse idiopathic pulmonary fibrosis

    Xin Chang, Lei Xing, Yi Wang, Chen-Xi Yang, Yu-Jing He, Tian-Jiao Zhou, Xiang-Dong Gao, Ling Li, Hai-Ping Hao, Hu-Lin Jiang

    Download Supplement

    This PDF file includes:

    • Figs. S1 to S10

    Files in this Data Supplement:

Stay Connected to Science Advances

Navigate This Article