Stem cells in the adult pancreas and liver

Abstract

Stem cells are undifferentiated cells that can self-renew and generate specialized (functional) cell types. The remarkable ability of stem cells to differentiate towards functional cells makes them suitable modalities in cellular therapy (which means treating diseases with the body's own cells). Potential targets for cellular therapy include diabetes and liver failure. However, in order for stem cells to be clinically useful, we must learn to identify them and to regulate their differentiation. We will use the intestine as a classical example of a stem cell compartment, and then examine the evidence for the existence of adult stem cells in two endodermally derived organs: pancreas and liver. We will review the characteristics of the putative stem cells in these tissues and the transcription factors controlling their differentiation towards functional cell types.

Figure 1. Scheme of stem cell self-renewal and differentiation

Stem cells are capable of maintaining the stem cell compartment through self-renewal and can also give rise to progenitor cells that may undergo subsequent differentiation along more than one lineage to generate cell-type-specific derivatives. For an animated version of this Figure, see http://www.BiochemJ.org/bj/404/0169/bj4040169add.htm.

Figure 2. Representation of the cellular components of the intestinal crypt and the signalling pathways involved in differentiation and maintenance of the crypt–villus axis

The intestinal crypt–villus axis can be divided into three zones: the lower stem cell and Paneth cell compartment, the cell amplification zone, both located in the crypt; and the cell differentiation zone that constitutes the villus epithelium. Stem cells located at approx. position 5 maintain genomic integrity through chromatid segregation by donating newly synthesized DNA to their offspring while retaining their original genomic content. Progenitors arising in the stem cell compartment may differentiate into Paneth cells that migrate into the bottom of the crypt, directed by interactions between EphB2/3 and ephrin, where they will reside for up to 20 days before being replaced by new Paneth cells. Alternatively, stem cell progenitors enter the amplification zone in the crypt. When the stem cell progenitors reach the base of the villus they will undergo cell-cycle arrest and differentiate along an absorptive enterocyte, goblet or enteroendocrine cell lineage. Cells shed at the tip of the villus are replaced by constant generation of new progenitors in the crypt. Wnt and Notch signalling components are restricted to the base of the crypt where they play an important role in maintaining the stem cell compartment. BMP and hedgehog signalling along the crypt–villus axis have been shown to regulate cell renewal and lineage specification.

Figure 3. Diagram showing the generation of hepatocytes from embryonic and adult cells through normal development, regeneration and transdifferentiation

During normal liver development, hepatocytes and biliary epithelial cells are generated by differentiation of embryonic hepatoblasts. Under conditions of regeneration, both hepatocyte and bile duct lineages arise from oval cells, the progeny of the putative hepatic stem cell. Hepatocytes can also be generated from pancreatic cell types: either through the treatment of rats with a copper-deficient diet in vivo or through the treatment of the pancreatic cell line AR42J-B13 with 1 μM dexamethasone in vitro.