Cellular Mechanisms of Liver Regeneration and Cell-Based Therapies of Liver Diseases

Abstract

The emerging field of regenerative medicine offers innovative methods of cell therapy and tissue/organ engineering as a novel approach to liver disease treatment. The ultimate scientific foundation of both cell therapy of liver diseases and liver tissue and organ engineering is delivered by the in-depth studies of the cellular and molecular mechanisms of liver regeneration. The cellular mechanisms of the homeostatic and injury-induced liver regeneration are unique. Restoration of the mass of liver parenchyma is achieved by compensatory hypertrophy and hyperplasia of the differentiated parenchymal cells, hepatocytes, while expansion and differentiation of the resident stem/progenitor cells play a minor or negligible role. Participation of blood-borne cells of the bone marrow origin in liver parenchyma regeneration has been proven but does not exceed 1-2% of newly formed hepatocytes. Liver regeneration is activated spontaneously after injury and can be further stimulated by cell therapy with hepatocytes, hematopoietic stem cells, or mesenchymal stem cells. Further studies aimed at improving the outcomes of cell therapy of liver diseases are underway. In case of liver failure, transplantation of engineered liver can become the best option in the foreseeable future. Engineering of a transplantable liver or its major part is an enormous challenge, but rapid progress in induced pluripotency, tissue engineering, and bioprinting research shows that it may be doable.

Figure 1

Schematic histological structure of liver tissue. Functional units of liver tissue are formed by trabeculae and accompanying blood sinusoids. Liver tissue gets its afferent blood supply from two sources: hepatic artery and portal vein. Hepatic arterioles (HAs) and the terminal branches of portal vein (PV) merge to form blood sinusoids (BSs) lined with endotheliocytes and drained into the central veins (CVs). In the sinusoids, close to endothelium reside liver macrophages named Kupffer cells. Bile produced by hepatocytes flows in the opposite direction and is discharged into the bile ducts (BDs). Hepatic arterioles, terminal branches of portal vein, and the smallest bile ducts are drawn together forming compact structures called portal tracts shown at the right side of the figure. Liver trabeculae are built of hepatocytes. The inner cavities of trabeculae form canaliculi which are closed at the central ends of the lobules (left side of figure) and while on their way to BD they convert into bile ductules (BDLs) via a transitory zone called the canals of Hering (CH). Bile ductules drained into the bile ducts are lined with cholangiocytes, and the canals of Hering contain LSPCs. Tiny spaces between trabeculae and the endothelium of blood sinusoids are called the spaces of Disse (SD). They participate in the bidirectional traffic of different substances between blood and hepatocytes and contain stellate (Ito) cells.

Figure 2

Methods of regenerative medicine for the therapy of liver diseases. Hepatocytes, hematopoietic stem cells (HSCs), and mesenchymal stromal cells (MSCs) are the three cell types commonly used as starting material for the design of cell-based therapies of liver diseases and for liver tissue/organ engineering. Primary hepatocytes isolated from liver biopsies and HSCs isolated from bone marrow or blood, are used for cell therapy after minimum in vitro processing. HSCs can be also expanded in culture (not shown) before transplantation or induced to pluripotency and utilized in cell therapy and tissue/organ engineering applications after hepatogenic differentiation. Chances are that HSCs can be directly transdifferentiated into hepatocytes. MSCs after isolation are in most cases extensively expanded. MSC cultures are then either used for transplantation or transformed into hepatocytes or other liver cells via iPSCs or by direct transdifferentiation. MSC-derived differentiated liver cells are used in cell therapy and tissue/organ engineering applications.