Regenerative hepatology has emerged as a novel field with great potential to overcome the limitations of liver transplantation—the only curative treatment currently available for end-stage liver disease.

The liver has a natural capacity for regeneration. “Because of the liver’s astounding ability to tolerate long periods of injury and to regenerate after major parenchymal loss, the liver has always been a paradigm for human organ regeneration,” Jalan-Sakrikar and colleagues wrote in a recent review article published in Hepatology.

Decades of investigation in liver regeneration constitute the pillars of modern liver regenerative medicine approaches. As explained by Jalan-Sakrikar et al, regenerative hepatology encompasses 2 complementary approaches:


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  1. Promote endogenous tissue repair and regeneration to reverse liver disease before irreversible damage occurs.
  2. Replace the damaged cells or tissues with healthy ones, in an autologous or allogeneic manner, when the liver no longer has endogenous regenerative capacity or the damage is irreversible.

When compared with conventional liver transplantation, these approaches have several advantages. They are not conditioned by the availability of a healthy organ donor; they avoid the use of immunosuppression, as they can use autologous cells; and they can surpass the need for surgery, and, consequently, postoperative complications since cells can be administered as an infusion.

Types of Liver Organoids

Regenerative medicine involves replacement using a cell-based approach such as liver organoids, regeneration, and rejuvenation.

The concept of organoids has evolved since their first use. “Organoids, in the modern context, can be defined
as 3D structures, grown in vitro from stem/progenitor cells or primary tissue, that self-organize in an organotypic manner through spatio-temporal patterning that may recapitulate developmental stages (eg, stem cell-derived
organoids) and/or resembles counterpart tissues in vivo (eg, primary organoids),” Jalan-Sakrikar et al wrote.

Liver Organoids Present New Opportunities in Medical Research

Different types of liver organoids have been used for research and clinical purposes. Several studies used organoids derived from induced pluripotent stem cells (iPSCs), adult stem cells, or primary tissue to regenerate hepatocellular parenchyma (hepatocellular organoids) and bile ducts (cholangiocyte organoids). As discussed by Jalan-Sakrikar and colleagues, each system has advantages and limitations that should be carefully weighed against its final application:

  • Hepatocyte- and adult stem cell-derived organoids are less prone to genetic instability and might have higher differentiation efficiency than iPSC-derived organoids, but are more difficult to obtain due to restricted access to primary tissue.
  • Adult stem cell-derived organoids are more suitable for diseases that affect hepatic and biliary compartments as they theoretically can regenerate both.
  • Primary hepatocytes are more suitable for diseases that affect primarily hepatocytes as they remain committed to the hepatic lineage.
  • iPSC- and adult stem cell-derived cholangiocyte organoids engraft but do not rescue animal models of biliary injury.

Ectopic transplantation of multicellular liver organoids, the so-called “mini-livers,” might be essential in cases of end-stage organ damage, when hepatocyte transplantation fails to fully restore the liver function due to a hostile microenvironment. So far, only iPSC-derived hepatocyte organoids have been developed.

Liver Organoids in Rare Diseases

Patient-derived hepatocyte organoids have been used to create disease models for Alagille syndrome (ALGS) and alpha-1 antitrypsin deficiency (AATD), among other diseases.

It is essential that cells meet high-quality standards to be successfully used in liver regenerative medicine. For example, in the case of AATD, transplanted cells must engraft, survive long-term, and integrate with the host vasculature to support the secretion of alpha-1 antitrypsin (AAT) into the bloodstream.

Could Organoid Cultures Help Better Understand Alagille Syndrome?

Cholangiocyte organoids have also been used to study biliary abnormalities in several diseases, including ALGS, cystic fibrosis (CF), and cholangiocarcinoma (CC). Some studies have successfully applied iPSC-derived cholangiocyte organoid platforms to screen and repurpose drugs in CF. However, new evidence suggests that cholangiocytes may alter their phenotype when removed from their native niche, thereby compromising the integrity of cholangiocyte organoids.

Lapatinib Inhibits Tumor Growth in Cholangiocarcinoma Organoid

Additionally, organoids derived from nonparenchymal cells (eg, cells) have been particularly useful to study inflammation and fibrosis, as well as to evaluate the potential of antifibrotic therapies.

Challenges in Liver Regenerative Medicine

Organoids provide several advantages over 2D cultures and have allowed for great advances in the field of regenerative medicine. However, several limitations remain to be addressed. This explains, at least in part, the still limited use of organoids in clinical trial settings.

Directing Cholangiocyte Branching Shows Potential for ALGS Liver Tissue

The method for obtaining organoids is laborious and time-consuming, and the 3D conditions needed to culture cells are not always compatible with automated, large-scale manufacturing platforms. However, a research team from the Cincinnati Children’s Hospital Medical Center in Ohio recently developed a method that allows for precursor cells to be frozen and thawed and still produce high-quality organoids.

“Using this approach will make it possible for many research labs to use organoids in their experiments without the time and expense of learning how to grow iPSCs,” Chris Mayhew, PhD, director of the Pluripotent Stem Cell Facility at Cincinannati Children’s said. “The ability to freeze the precursor cells also will allow labs to easily make organoids without having to start each new experiment with complicated and highly variable iPSC differentiation.”

The efficacy and safety of primary or iPSC-based organoids are of utmost importance for regenerative medicine. Therefore, long-term longitudinal large animal studies are essential to evaluate such aspects, including their tumorigenic potential.

Reference

Jalan-Sakrikar N, Brevini T, Huebert RC, Sampaziotis F. Organoids and regenerative hepatologyHepatology. Published online May 21, 2022. doi:10.1002/hep.32583

Organoid production breakthrough to help accelerate disease and drug development research. News release. Cincinnati Children’s Hospital Medical Center; July 28, 2022.