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Lab-grown liver grows veins, stops bleeding in mice with engineered clotting proteins
In a breakthrough that brings bioengineered organs one step closer to reality, scientists have created lab-grown liver tissue capable of forming its own blood vessels.
A team from Cincinnati Children's Hospital, in collaboration with Japanese researchers, successfully engineered liver organoids that developed spontaneous vascular systems, overcoming a long-standing challenge in tissue engineering.
This self-vascularizing liver tissue could pave the way for future transplantable grafts and offer new treatment possibilities for people with hemophilia and other coagulation disorders.
Until now, most lab-grown organoids have lacked internal blood vessels, limiting their size, function, and medical potential.
By enabling more effective circulation and tissue maturation, the new technique opens the door to growing complex, functional human organs entirely outside the body.
"Our research represents a significant step forward in understanding and replicating the complex cellular interactions that occur in liver development,' said Takanori Takebe, director for commercial innovation at the Cincinnati Children's Center for Stem Cell and Organoid Research and Medicine (CuSTOM) and lead author of the study.
'The ability to generate functional sinusoidal vessels opens up new possibilities for modeling a wide range of human biology and disease, and treating coagulation disorders and beyond."
At the heart of the process is the use of induced pluripotent stem cells (iPSCs), which are placed in specially formulated gels that guide their development into specific tissue types.
These cells can be sourced from healthy donors or patients with particular medical conditions and may be gene-edited to model or correct diseases.
To overcome the vascularization barrier, a key obstacle in scaling up organoids, the team spent nearly ten years refining their approach.
They began by coaxing iPSCs to differentiate into CD32b+ liver sinusoidal endothelial progenitors (iLSEPs), a type of precursor cell specific to liver blood vessels.
These were then introduced into an inverted multilayered air-liquid interface (IMALI) culture system, a setup that encouraged them to self-organize alongside other liver-supportive cells into more complex, layered tissue.
The result was a quadruple progenitor mix, including hepatic endoderm, septum mesenchyme, arterial, and sinusoidal cells, that naturally developed into functioning sinusoid-like vessels.
Unlike earlier efforts that used fully formed arterial cells, the team's use of liver-specific progenitors allowed for more integrated, lifelike vessel development.
Crucially, spatial arrangement and developmental timing also played a role; the proximity of different cell types in the culture system allowed them to interact and mature just as they would in a developing human liver.
"The success occurred in part because the different cell types were grown as neighbors that naturally communicated with each other to take their next development steps," says the study's first author, Norikazu Saiki, PhD, of the Institute of Science Tokyo.
The vascularized organoids didn't just look more like real liver tissue—they also began to behave like it. The engineered structures produced perfused, sinusoid-like blood vessels that allowed fluid to move through, mimicking the natural rhythm of liver circulation.
More remarkably, the organoids also developed the ability to secrete blood-clotting proteins critical for patients with coagulation disorders.
Among the factors produced was Factor VIII, a protein missing in people with hemophilia A.
When tested in mice engineered to mimic the disease, the organoid-derived Factor VIII was able to correct severe bleeding, offering a proof-of-concept for therapeutic use.
The organoids also generated other coagulation-related proteins, suggesting the potential for broader applications in treating patients with rare clotting disorders or acute liver failure.
In the U.S. alone, an estimated 33,000 males live with hemophilia, the majority of whom have hemophilia A, caused by a deficiency in Factor VIII.
The condition can lead to frequent internal bleeding, especially in joints, resulting in chronic pain, restricted mobility, and long-term damage. More severe cases can pose life-threatening risks, with bleeding episodes in the brain potentially causing seizures or paralysis.
If scaled successfully, these self-vascularizing liver organoids could serve as biological factories, producing essential proteins for people who don't respond to standard treatments or who lack access to gene therapy.
For those with liver damage, they could someday offer a regenerative option, replacing lost function without requiring a full organ transplant.
The full study has been published in Nature Biomedical Engineering.
