Despite modest improvement in patient outcomes from recent advances in pharmacotherapy targeting fibrogenic signaling pathways, idiopathic pulmonary fibrosis (IPF) remains a major unsolved clinical problem. One reason for this is that available antifibrotic agents slow down but do not arrest fibrotic progression. To arrest fibrotic progression, its obligatory drivers need to be identified. We previously discovered that fibrogenic mesenchymal progenitor cells (MPCs) are key drivers of fibrotic progression in IPF, serving as cells of origin for disease-mediating myofibroblasts. IPF MPCs have high levels of nuclear S100A4, which interacts with the proteasome to promote p53 degradation and self-renewal. However, the mechanism underlying S100A4 accumulation in the nucleus of IPF MPCs remains unknown. Here we show that hyaluronan (HA) is present in the fibroblastic focus together with CD44-expressing MPCs and that ligation of CD44 by HA triggers S100A4 nuclear translocation to support IPF MPC self-renewal. The mechanism involves HA-mediated formation of a CD44/S100A4/transportin 1 complex, which promotes S100A4 nuclear import. In a humanized mouse model of pulmonary fibrosis, IPF MPC fibrogenicity was significantly attenuated by 1) knockdown of CD44 or 2) introduction of an S100A4 mutant construct that prevents S100A4 nuclear import. These data indicate that signaling through the HA/CD44/S100A4 axis is an integral component of IPF MPC fibrogenicity.
|American Journal of Physiology - Lung Cellular and Molecular Physiology
|Published - May 18 2021
Bibliographical noteFunding Information:
This work was supported by National Heart, Lung, and Blood Institute (NHLBI) Grants R01 HL125227 to C. A. Henke and R01 HL125236 to P. B. Bitterman and by funds provided by the O’Brien and Witowski families.
We acknowledge the assistance of the Flow Cytometry Core Facility of the Masonic Cancer Center, a comprehensive cancer center designated by the National Cancer Institute, supported in part by P30 CA77598 and the University of Minnesota Imaging Center. We also acknowledge the Center for Mass Spectrometry and Proteomics.
Copyright © 2021 the American Physiological Society
- Idiopathic pulmonary fibrosis
- Mesenchymal progenitor cells