Hyaluronan/CD44 axis regulates S100A4-mediated mesenchymal progenitor cell fibrogenicity in idiopathic pulmonary fibrosis.

Abstract

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.

• Authors: Hong Xia, Jeremy Herrera, Karen Smith, Libang Yang, Adam Gilbertsen, Alexy Benyumov, Emilian Racila, Peter B Bitterman, Craig A Henke
• Journal: American journal of physiology. Lung cellular and molecular physiology (Am J Physiol Lung Cell Mol Physiol) Vol. 320 Issue 5 Pg. L926-L941 (05 01 2021) ISSN: 1522-1504 [Electronic] United States
• PMID: 33719561 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• CD44 protein, human
• Hyaluronan Receptors
• Multiprotein Complexes
• S100 Calcium-Binding Protein A4
• TNPO1 protein, human
• beta Karyopherins
• S100A4 protein, human
• Hyaluronic Acid

Topics

• Animals
• Cell Nucleus (genetics, metabolism, pathology)
• Disease Models, Animal
• Gene Knockdown Techniques
• Humans
• Hyaluronan Receptors (genetics, metabolism)
• Hyaluronic Acid (genetics, metabolism)
• Idiopathic Pulmonary Fibrosis (genetics, metabolism, pathology)
• Mesenchymal Stem Cells (metabolism, pathology)
• Mice
• Multiprotein Complexes (genetics, metabolism)
• S100 Calcium-Binding Protein A4 (genetics, metabolism)
• Signal Transduction
• beta Karyopherins (genetics, metabolism)