The field of regenerative medicine seeks to replace, engineer or regenerate human and animal cells, tissues or organs with the goal of establishing or restoring normal function. Researchers hope that stem cells — the body's master cells, from which all cells with specialized functions are generated — may one day be used to treat and cure many severe human diseases.

Now, a recent study published in Nature may have moved the field significantly closer to reaching that goal.

Mimicking Nature

A research team at Pohang University of Science and Technology (POSTECH) led by Professor Kunyoo Shin in Pohang, South Korea, was able to create multi-layered miniature organs called assembloids that precisely mimic human tissues, SciTechDaily reports. The breakthrough represents a first for regenerative medicine.

"These assembloids are the world's first in-vitro reconstituted organoids," Eunjee Kim, the first author of the paper, told SciTechDaily. "We can precisely model a variety of complex intractable diseases such as cancer, degenerative diseases, and various neurological diseases including schizophrenia and autism, and understand the pathogenesis of such diseases to ultimately develop better therapeutic options."

Organoids — often called miniature organs — are organ-like tissues derived from stem cells that imitate the structure and function of human organs. Unfortunately, they're not able to mimic the mature structure of organs because they lack critical interactions between various types of cells within the tissue microenvironment. Hence, the POSTECH team's decision to take a different approach to their regenerative medicine research.

Taking a New Approach

Shin's team focused on creating multi-cellular bladder tissues and tumor tissues as a way to study various bladder diseases, including bladder cancer.

"We generated three-layered bladder assembloids by creating the epithelial (surface) layer with stem cell-derived organoids, the stromal layer (cell layer just below the epithelia layer) with stromal fibroblasts and endothelial cells, and the muscle layer with smooth muscle cells and endothelial cells," Shin said in a recent interview for Now.

The POSTECH team also created patient-specific tumor assembloids by reconstituting tumor-cell-derived bladder tumor organoids with various types of cells found in tissue stroma and the tissue microenvironment, he added.

Endothelial cells form the barrier between vessels and tissue and control the flow of substances and fluid into and out of a tissue.

To create the bladder assembloids, Shin's team first isolated urothelial stem cells from primary tissues and embedded them in matrix gel to generate 3D bladder organoids. They also isolated other cells such as stromal fibroblasts and smooth muscle cells from the bladder, then cultured and expanded them in vitro (outside of the human body). For the tumor assembloids, they isolated tumor cells from human bladder tumor tissues, then embedded them in matrix gel to generate bladder tumor organoids.

They also isolated cancer-associated fibroblasts from bladder tumor tissues from several patients, then cultured and expanded the fibroblasts in vitro.

The various types of tissues and cells were then reconstituted to generate the bladder and tumor assembloids — a process that takes less than 10 minutes per assembloid, Shin said. Each assembloid is about 1 to 2 millimeters wide.

Following the Signals

Through testing, Shin's team discovered that the patient-specific tumor assembloids they produced perfectly mimicked the behavior of in vivo (within the human body) tumors. They used these assembloids to study the pathological characteristics of tumors.

"Previous studies in our laboratory have suggested that signaling feedback between epithelial tumor cells and stromal cells play an important role in tumor plasticity and tumor subtype determination," commented Shin.

He added that the team used the tumor assembloids and genetic engineering technologies to discover mechanisms by which signals from the tumor microenvironment determine the plasticity of tumor cells.

"We think we can pharmacologically inhibit or activate the signaling between tumor and stromal cells with certain drugs," Shin enthused based on his team's findings. "By modulating these signals, it's possible to change the course of illness by inhibiting the growth of the tumor […] or changing an aggressive type of tumor to a less aggressive type."

According to Shin, other scientists have tried creating human organs by fusing multiple organoids, but the results of those other studies have not been released.

Assembloids, he emphasized, are not fusions of organoids but rather miniature organs created by reconstituting organoid tissue and various types of cells found in tissue stroma and the tissue microenvironment. The reconstitution process creates complex interactions among various types of cells, which can induce tissue maturation and generate mature organs.

Regenerating the Future

Shin is cautiously optimistic about what his team's work in assembloids will mean for the future of regenerative medicine.

"Reconstitution of assembloids using cells from patients with intractable diseases such as cancer, degenerative disease or neurological diseases will enable patient-specific disease modeling," he suggested. "By using high-throughput drug screening on those patient-derived assembloids, we'll be able to develop patient-specific treatments for those diseases."

However, to get there, Shin says his team will need to optimize the methods they use to obtain enough cells of the appropriate type from each patient to generate patient-specific assembloids.

"Ultimately," he promised, "we will make our technology applicable to all human organs including the brain to develop better therapeutic options for precise and personalized therapy for many human diseases."

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