Never-before-seen 3D reconstructions of human liver tissue have been created at a cellular level. The details obtained by a team of UW Medicine and University of Washington engineers and physicians capture the spatial microstructure of multiple lobes of this multitasking organ.
A healthy human liver can perform more than 500 functions essential to keeping our bodies healthy. These include detoxifying harmful substances, helping regulate metabolism, aiding digestion, storing nutrients, producing blood clotting proteins, and assisting in resisting infections.
The reconstructions also reveal how cirrhosis — extensive scarring of the liver — rearranges its intricate architecture and thereby alters biological activities inside the organ.
The project researchers refer to their method as the Liver Map pipeline, which they describe in a paper in the Feb. 18 issue of Science Advances . Additional implementations of their approach might suggest better ways to treat cirrhosis to protect or restore the liver.
The research team also has a vision of using such reconstructions to guide their vision of engineering replacement organs. The future of bioprinting artificial organs depends on understanding their cellular-level structure, according to Kelly Stevens , professor of bioengineering at the UW School of Medicine and the UW College of Engineering. A senior author of the paper, Stevens is a leader in efforts to develop artificial organs to perform physiological functions of living organs.
Organ bioprinting is a fledgling effort to use 3D printers to build living tissues layer upon layer to create a functional organ, or engineer a partial replacement, for transplantation. It uses living cells, biomaterials, and other biological factors. It also relies on techniques to establish blood flow through the organ and to encourage cell maintenance and renewal.
"Our field has skimmed over a fact that could prevent this dream from becoming reality: We don't know what complex organs look like at a cellular level," Stevens said. "We don't yet have the 'blueprints' of human organs to feed into bioprinters. This oversight is important because decades of studies have shown that the structure of human organs, particularly the organ-specific topology of its vasculature [arrangement of blood vessels] is intimately connected to organ function."
She added, "If the maps aren't right, the organs produced will not be functional."
Her team's 3D liver reconstruction relies in part on recent innovations in optics, imaging technologies, computational analysis and chemistry that are moving beyond picturing a flat 2D microscopic world.
"Scientists are now equipped with an enhanced imaging toolkit that is better at elucidating tissue structure and its disease-associated alterations," their Science Advances paper noted.
The lead scientists on the project were Wesley B. Fabyan, Chelsea L. Fortin, and Dorice L. Goune, all of the Department of Bioengineering and the UW Medicine Institute for Stem Cell and Regenerative Medicine. The senior authors, in addition to Stevens, were liver disease physician Rotonya M. Carr , professor of medicine and head of the Division of Gastroenterology, and Raymond S. W. Yeung , a UW Medicine and Fred Hutch cancer surgeon and a professor of surgery at the UW School of Medicine.
The samples for their 3D reconstruction study came from patients who had parts of their livers removed during cancer surgery or who underwent liver transplants. Both groups agreed to have these tissues used in scientific research. Some of the specimens were from cirrhotic livers.
Liver cirrhosis usually stems from persistent damage from viral infections, metabolic disorders, certain medications or alcohol abuse. It can progress to liver failure and other complications that shorten people's lives. The cause of cirrhosis varied in the samples in this study.
Through their 3D reconstructions, the researchers observed several ways that cirrhosis affected liver architecture. Among these were dysregulation of metabolite transport in the sinusoidal zone of the lobes, a reduction in a certain highly specialized liver cells that help lower toxic levels of ammonia, regression of central vein networks, disruption of artery networks, and fragmentation of the network that transports the bile, or fat digesting fluid, produced in the liver.
Taken together, these changes point to a shift in the cirrhotic liver's vascular network, the researchers suggested.
Their research efforts "unveiled never-before-seen 3D human liver structures across multiple size scales and visualized how cirrhosis dysregulates the vascular and biliary architectures," their paper said.
There is a significant limitation that the scientists hope will be addressed as the Liver Map pipeline technology advances. The present imaging tool cannot yet capture the entire depth of a human liver lobule, the hexagonal units that make up the organ.
This research was funded by the National Institutes of Health's National Institute of Diabetes and Digestive and Kidney Diseases (R01DK128551), NIH Environmental Pathology and Toxicology Training Grant (T32 ES007032 ), NCATS Translational Research Training Program (TL1 TR002318), National Institute of General Medical Sciences Molecular Medicine Training Grant (T32 GM095421), National Science Foundation Graduate Research Fellowship Program (DGE-2140004), Howard Hughes Medical Institute Gilliam Fellows Program (GT16560), NIH National Institute on Alcohol Abuse and Addiction (R01AA026302), and Advanced Research Projects Agency for Health (ARPA-H D25AC00460-00).
