Facultative stem cells in liver and pancreas: fact and fancy

Abstract

Tissue turnover is a regular feature of higher eukaryotes, either as part of normal wear and tear (homeostasis) or in response to injury (regeneration). Cell replacement is achieved either through replication of existing cells or differentiation from a self-renewing pool of stem cells. The major distinction regards cellular potential, because stem cells by definition have a capacity to differentiate, while replication implies that cells adopt a single fate under physiologic conditions. A hybrid model, the facultative stem cell (FSC) model, posits that tissues contain cells that normally exhibit unipotency but have the capacity to function as stem cells upon injury. The FSC paradigm is well established in urodele amphibians, but the nature and role of FSCs in mammals is less defined. Here, we review the evidence for FSCs in two mammalian organs, the liver and the pancreas, and discuss alternative models that could account for regeneration in these organs.

Fig. 1

Schematic depiction of mechanisms used for maintaining homeostasis and regeneration in various adult mammalian tissues. A: Two classical mechanisms for tissue homeostasis/regeneration involve differentiation of a stem/progenitor population (red box) or proliferation of differentiated cells (blue box). Hematopoietic stem cells have an apparently unlimited self renewal capacity that enables them to continuously supply new blood cells, while cellular maintenance of the cartilage anlagen occurs by means of chondrocyte proliferation within the columnar region. B: Following partial hepatectomy (PHx; top panel), differentiated liver cells undergo replication to make-up for the surgical loss of mass. In a toxin injury (bottom panel), a new cell type known as an “oval cell” is proposed to arise from BECs and function as a bipotent facultative stem cell (FSC). C: The β-cell loss by surgery or targeted genetic ablation is replaced by replication of remaining β-cells (top panel). Following partial duct ligation (PDL), duct cells are proposed to adopt an Ngn3+ progenitor identity and give rise to new β-cells (bottom panel).

Fig. 2

Schematic view of the location of putative locations of FSCs in the liver and pancreas. A: Schematic depiction of a portal tract in the liver. Bile made by hepatocytes drains into the canalicular space and subsequently through the Canals of Hering into the bile duct. The precursors of oval cells in the liver have been proposed to reside within the Canals of Hering, the transitional zone between hepatocytes and biliary cells. HA, hepatic artery; PV, portal vein. B: Schematic depiction of two acinar units in the pancreas. Pancreatic cells of the ductal lineage (which include pancreatic centroacinar cells) have been proposed to adopt progenitor-like properties and give rise to β-cells.

Fig. 3

Schematic of alternative cellular mechanisms of regeneration. As opposed to a unidirectional hierarchy resulting in mature cells through stem-cell differentiation or replication (black arrows), other mechanisms could account for tissue restoration (blue box expanded). These putative mechanisms include both the FSC model and other alternatives. A: A mature, differentiated cell (green square) could dedifferentiate and acquire a progenitor identity (orange triangle), thus functioning as a FSC. B: Mature cells could undergo reprogramming, which would allow them to interchange/transdifferentiate into other differentiated cells. Such a mechanism could be difficult to distinguish from the dedifferentiation–redifferentiation model in A unless the fate of the differentiated cells were followed with precision. C: Finally, simple replication of existing differentiated cells could account for restoration of tissue mass. In this scenario, putative FSCs could simply be “bystanders” and not formally contribute to the regenerated tissue.