Biomedical Engineering Reference
In-Depth Information
10.2 Liver Disease States as Targets for Regenerative
Therapies
The acute and self-limiting liver diseases (e.g. due to acute viral disease, toxins,
transient ischemia) normally result in complete regeneration and ''restitutio ad inte-
grum''. More massive injuries may temporarily exhaust the regenerative capacity of
the liver and result in ''acute liver failure'', a clinical syndrome, which is characterized
by progressive loss of hepatic function and multiorgan failure. Persistent injuries to the
liver also induce regenerative responses but eventually result in scarring and excess
deposition of extracellular matrix components including collagen. Fibrosis and cir-
rhosis are the end result of chronic inflammatory reactions induced by a variety of
stimuli including persistent infections, autoimmune reactions, allergic responses,
chemical insults, radiation, and tissue injury. Although current treatments for fibrotic
diseases, such as idiopathic pulmonary fibrosis, systemic sclerosis, and liver fibrosis/
cirrhosis typically target the inflammatory response, there is accumulating evidence
that the mechanisms driving liver fibrogenesis are distinct from those regulating
inflammation. The key cellular mediator of fibrosis is the myofibroblast, which, once
activated, serves as the primary collagen-producing cell. Myofibroblasts are generated
from a variety of sources including resident mesenchymal cells (Ito cells) and circu-
lating fibroblast-like cells called fibrocytes that are derived from bone marrow stem
cells. Myofibroblasts are activated by paracrine signals derived from lymphocytes to
macrophages, autocrine factors secreted by myofibroblasts, and pathogen-associated
molecular patterns (PAMPS) produced by pathogenic organisms that interact with
pattern recognition receptors (i.e. TLRs) on fibroblasts.
The liver is central to many metabolic activities with hundreds of genes
involved in their regulation. In recent years, the genetic basis for more than 100
liver diseases involving malfunction of the organ has been clarified. Hereditary
liver diseases usually result from point mutations, deletions, or other genetic
defects in single or multiple genes, which are normally expressed in the liver and
can cause acute and chronic liver diseases. The liver also secrets many proteins,
which deliver functions for other organ systems, and a state of protein deficiency
may not affect the liver function itself. For most of the hereditary liver diseases
liver organ transplantation cures the disease or the state of protein deficiency and
has become the most important therapeutic approach. Conceptually, many of these
disorders, for which organ transplantation is effective, can be principally cured by
cell- or gene therapies.
10.3 Cells for the Treatment of Liver Diseases
Many of the regenerative technologies generated or envisioned to treat liver dis-
eases are based on cellular substrates, which are either transplanted/injected into
recipients or utilized in extracorporeal devices. The primary adult hepatocyte is
