Vascularized engineered human liver tissue that has self-organized into a lobule-like microstructure.
Being able to grow your own new organs may be in reach—with some cellular assembly required.
With a carefully constructed clump of cells, mice grew their own functional human liver organoids in a matter of months, researchers report this week in Science Translational Medicine. The cellular organ seeds blossomed in the rodents, expanding 50-fold in that time. They appeared to form complex liver structures, tap into vasculature, and carry out the functions of a normal liver. The critical factor in getting the organoids to take root, the authors report, was having the seed cells arranged just right.
Though the organ seeds are far from any clinical application, researchers are hopeful that they’ll one day be able to engineer larger liver organs to treat patients with liver failure or damage.
As Ars has reported before, researchers have been working hard to generate whole organs from engineered tissue. The problem is always assembly—getting a variety of cell types to neatly arrange into intricate and functional structures while allowing life-sustaining vasculature to permeate the tissue is tough. Researchers have tried everything from printing tissue to stripping the cells off spinach to create beating, leaf-shaped heart tissue.
Researchers created small “SEEDs” of liver tissue (right) composed of aggregates of liver cells and connective tissue (shown under a fluorescence microscope in left and center images).
Researchers mixed together human liver cells (hepatocytes) and human connective tissue cells (fibroblasts) to create small aggregates that grew and expanded.
Researchers 3D printed lattices of carbohydrate glass (shown in left and center images), which they filled with living cells (shown in right).
Assembly of the SEED
Small “SEEDs” of liver tissue that were grafted into mice grew and began producing functional markers (shown in red and green) under the influence of regenerative cues.
To grow a liver, researchers led by MIT engineer Sangeeta Bhatia started by carefully designing a cellular scaffold for the organ to grow on. They first got human liver cells (hepatocytes) and connective tissue cells (fibroblasts) to grow together in clumps. Then they used a micro-tissue molding to create ropes endothelial cells, which make up the lining of blood and lymphatic vessels. Last, they carefully assembled rows of the cell clumps in between strands of endothelial chords and held the structure together with a biodegradable hydrogel.
In all, they called the organ starter kit SEED, for “In Situ Expansion of Engineered Devices.”
To test out the SEEDs, the researchers implanted them into the belly fat of healthy mice and mice with a genetic disorder that causes liver damage. In the healthy mice, the liver seeds didn’t grow very much. But in the rodents with liver damage—which were circulating liver-regenerating growth factors and other molecular signals to repair their damaged liver—the organ SEEDs sprouted.
Eighty days after implantation, there was a 50-fold cellular expansion along the SEED’s scaffold. The liver organoid formed precursor bile ducts and contained clusters of red blood cells, suggesting vasculature formation. The organoid also pumped out standard human liver proteins, including albumin and transferrin.
There’s a lot more work to go before researchers have a human-sized, functional liver, but the team is optimistic. “We believe that this work sets the stage for using SEEDs as an alternative strategy for scale-up of engineered organs, one that uses native developmental, injury, or regenerative signals to expand prefabricated constructs in situ,” they conclude.
Image Credit: Stevens et al., Science Translational Medicine (2017)