The quest for tissue stem cells in the pancreas and other organs, and their application in beta-cell replacement

Abstract

Adult stem cell research has drawn a lot of attention by many researchers, due to its medical hope of cell replacement or regenerative therapy for diabetes patients. Despite the many research efforts to date, there is no consensus on the existence of stem cells in adult pancreas. Genetic lineage tracing experiments have put into serious doubt whether β-cell neogenesis from stem/progenitor cells takes place postnatally. Different in vitro experiments have suggested centroacinar, ductal, acinar, stellate, or yet unidentified clonigenic cells as candidate β-cell progenitors. As in the rest of the adult stem cell field, sound and promising observations have been made. However, these observations still need to be replicated. As an alternative to committed stem/progenitor cells in the pancreas, transdifferentiation or lineage reprogramming of exocrine acinar and endocrine α-cells may be used to generate new β-cells. At present, it is unclear which approach is most medically promising. This article highlights the progress being made in knowledge about tissue stem cells, their existence and availability for therapy in diabetes. Particular attention is given to the assessment of methods to verify the existence of tissue stem cells.

Figure 1. Approaches to identify progenitor cells in the adult pancreas

Two major approaches have been applied to find evidence for adult β-cell neogenesis in the adult pancreas (i.e. formation of new β-cells from progenitor cells). One approach consisted of isolating progenitor cells, and stimulating their neogenic activity in vitro. This gave rise to c-Met- [32] or aldehyde dehydrogenase [33] expressing cells, for example. The other approach was based on causing tissue injury to stimulate progenitor cells in vivo, for example, cells that express Ngn3 following duct ligation [25]. In both cases, genetic lineage tracing still needs to be done to identify the stem/progenitor cell source.

Figure 2. Transdifferentiation in the pancreas

Transdifferentiation, or reprogramming, is the conversion of one differentiated cell type into another. For example, in the presence of LIF and EGF, acinar cells have been shown to transdifferentiate into mature β-cells in vitro. This was significantly increased by inhibiting Notch1-Hes1 signaling [28, 53]. α-cells have been shown to transdifferentiate into β-cells in vivo, after genetic ablation of the majority of β-cells [67]. In the latter case, it is not known which factors stimulated this phenomenon. Non-genetic and genetic lineage tracing methods, respectively, have been used in these studies to identify the origin cells.