Abstract
Background and Aims Glisson’s capsule is the interstitial connective tissue that surrounds the liver. As part of its normal physiology, it withstands significant daily changes in liver size. The pathophysiology of the capsule in disease is not well understood. The aim of this study was to characterize the changes in capsule matrix, cellular composition, and mechanical properties that occur in liver disease and to determine whether these correlate with disease severity or etiology.
Methods 10 control, 6 steatotic, 7 moderately fibrotic and 37 cirrhotic patient samples were collected from autopsies, intraoperative biopsies and liver explants. Matrix proteins and cell markers were assessed by staining and second harmonic generation imaging. Mechanical tensile testing was performed on a test frame.
Results Capsule thickness was significantly increased in cirrhotic samples compared to normal controls irrespective of disease etiology (69.62 ± 9.99 and 171.269 ± 16.65 µm respectively), whereas steatosis and moderate fibrosis had no effect on thickness (62.15 ± 4.97 µm). Changes in cirrhosis included an increase in cell number (fibroblasts, vascular cells, infiltrating immune cells and biliary epithelial cells). Key matrix components (collagens 1 and 3, hyaluronan, versican and elastin) were all deposited in the lower capsule although only the relative amounts per area of hyaluronan and versican were increased. Organizational features including crimping and alignment of collagen fibers were also altered in cirrhosis. Unexpectedly, capsules from cirrhotic livers had decreased resistance to loading in comparison to controls.
Conclusions The liver capsule, like the parenchyma, is an active site of disease, demonstrating changes in matrix and cell composition as well as mechanical properties.
Lay summary We assessed the changes in composition and response to stretching of the liver outer sheath, the capsule, in human liver disease. We find an increase in key structural components and numbers of cells as well as a change in matrix organization of the capsule in the later stages of disease. This allows the diseased capsule to stretch more under any given force, suggesting it is less stiff than healthy tissue.
Highlights
The capsule is an active site of disease: thickness and cellularity increase markedly in cirrhosis
Extracellular matrix composition and organization change in cirrhosis
The cirrhotic capsule stretches more and is less stiff
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Conflict of interest statement: The authors declare no conflicts of interest that pertain to this work.
Financial support statement: This work was supported by the Center for Engineering MechanoBiology (CEMB), an NSF Science and Technology Center, under grant agreement CMMI: 15-48571, and by NIH/NIBIB R01 EB017753 (to RGW).
Abbreviations
- EHBD
- extrahepatic bile duct
- SMA
- smooth muscle actin
- DAPI
- 4’,6-diamidino-2-phenylindole
- SHG
- second harmonic generation
- HA
- hyaluronic acid/hyaluronan