Hyaluronan Synthase Isoforms Direct Distinct Patterns of Fibroblast Activation Linked to Fibrosis Progression Versus Resolution Following Renal Ischaemia
6 affiliations
- 1Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XW, UK
- 2Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Sciences, Nankai University, Tianjin 300071, China
- 3Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Zaloska 4, 1000 Ljubljana, Slovenia
- 4Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907, USA
- 5Department of Internal Medicine, Division of Rheumatology, Rush Medical College, Rush University, Chicago, IL 60612, USA
- 6Cardiff Transplant Unit, Cardiff and Vale University Hospital of Wales, Cardiff CF14 4XW, UK
Abstract
The stroma plays key roles in development and tissue regeneration after injury, but its expansion following injury can drive fibrosis and chronic disease. In the kidney, hyaluronan (HA) is largely absent from the healthy stroma but becomes abundant during disease. To investigate HA regulation in stromal responses, we compared HA and hyaluronan synthase (HAS) expression during kidney development, homeostasis, injury, and recovery. A rat model of ischaemia–reperfusion injury (IRI) with or without ischaemic pre-conditioning (IPC) was studied alongside embryonic and Has1/3−/− mouse kidneys, with mechanistic studies performed in primary human fibroblasts. In healthy kidneys, stromal HA was absent, HAS1 showed limited epithelial expression, and HAS2 was undetectable. Following IRI, stromal HA accumulation and increased HAS2 expression were associated with chronic fibrosis. In contrast, during development, prominent stromal HA matrices were evident in areas of tubular generation, with strong HAS1 (not HAS2) expression. During recovery, stromal HA and HAS2 were attenuated, whereas HAS1+ stromal cells expanded but were distinct from α-SMA+ myofibroblasts. Functionally, HAS1+ fibroblasts displayed enhanced migration, fibroblast activation protein (FAP) expression and reduced profibrotic marker expression, whereas HAS2+ fibroblasts exhibited a contractile myofibroblast phenotype with high extra domain A fibronectin (EDA-FN) and type I collagen, alpha-1 subunit (COL1A1). Together, these findings identify HA as a regulator of stromal fibroblast phenotype and associate HAS1 and HAS2 in divergent fibrotic outcomes following kidney injury.
Related
- Nrf2 Activation Induces Fibroblast Senescence and Promotes Melanosome Accumulation in a Fibroblast-Keratinocyte Co-Culture Model
- Dynamic hybrid-hydrogel lung models decouple matrix composition, stiffness, and fibroblast conditioning to define distinct drivers of fibrotic progression
- Mapping fibroblast plasticity across non-cancer lung diseases at single-cell resolution.
- Fibroblast-Derived PLA2G12A Amplifies Mast Cell Activation Through Extracellular Phospholipid Remodeling
- Modulating the synovial ROS–NO–RNS network attenuates fibroblast-like synoviocyte pyroptosis and osteoarthritis progression
BibTeX
@article{grigorieva2026hyaluronan,
title = {{Hyaluronan Synthase Isoforms Direct Distinct Patterns of Fibroblast Activation Linked to Fibrosis Progression Versus Resolution Following Renal Ischaemia}},
author = {Irina V. Grigorieva and Adam C. Midgley and Charlotte V. M. Brown and Gilda Pino Chavez and Barbara Szomolay and Aled Williams and Rachel DePaul and Richard J. Stanton and John M. Hancock and Timothy Bowen and Deva Chan and Anna Plaas and Rafael Chavez and Robert Steadman and Usman Khalid and Soma Meran},
journal = {Biomolecules},
year = {2026},
month = oct,
doi = {10.3390/biom16101442},
url = {https://www.mdpi.com/2218-273X/16/10/1442},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Hyaluronan Synthase Isoforms Direct Distinct Patterns of Fibroblast Activation Linked to Fibrosis Progression Versus Resolution Following Renal Ischaemia
AU - Irina V. Grigorieva
AU - Adam C. Midgley
AU - Charlotte V. M. Brown
AU - Gilda Pino Chavez
AU - Barbara Szomolay
AU - Aled Williams
AU - Rachel DePaul
AU - Richard J. Stanton
AU - John M. Hancock
AU - Timothy Bowen
AU - Deva Chan
AU - Anna Plaas
AU - Rafael Chavez
AU - Robert Steadman
AU - Usman Khalid
AU - Soma Meran
PY - 2026
DA - 2026/10/01
JO - Biomolecules
DO - 10.3390/biom16101442
UR - https://www.mdpi.com/2218-273X/16/10/1442
AB - The stroma plays key roles in development and tissue regeneration after injury, but its expansion following injury can drive fibrosis and chronic disease. In the kidney, hyaluronan (HA) is largely absent from the healthy stroma but becomes abundant during disease. To investigate HA regulation in stromal responses, we compared HA and hyaluronan synthase (HAS) expression during kidney development, homeostasis, injury, and recovery. A rat model of ischaemia–reperfusion injury (IRI) with or without ischaemic pre-conditioning (IPC) was studied alongside embryonic and Has1/3−/− mouse kidneys, with mechanistic studies performed in primary human fibroblasts. In healthy kidneys, stromal HA was absent, HAS1 showed limited epithelial expression, and HAS2 was undetectable. Following IRI, stromal HA accumulation and increased HAS2 expression were associated with chronic fibrosis. In contrast, during development, prominent stromal HA matrices were evident in areas of tubular generation, with strong HAS1 (not HAS2) expression. During recovery, stromal HA and HAS2 were attenuated, whereas HAS1+ stromal cells expanded but were distinct from α-SMA+ myofibroblasts. Functionally, HAS1+ fibroblasts displayed enhanced migration, fibroblast activation protein (FAP) expression and reduced profibrotic marker expression, whereas HAS2+ fibroblasts exhibited a contractile myofibroblast phenotype with high extra domain A fibronectin (EDA-FN) and type I collagen, alpha-1 subunit (COL1A1). Together, these findings identify HA as a regulator of stromal fibroblast phenotype and associate HAS1 and HAS2 in divergent fibrotic outcomes following kidney injury.
SN - 2218-273X
ER -