Purpose and regulation of stem cells: a systems-biology view from the Caenorhabditis elegans germ line

Abstract

Stem cells are expected to play a key role in the development and maintenance of organisms, and hold great therapeutic promises. However, a number of questions must be answered to achieve an understanding of stem cells and put them to use. Here I review some of these questions, and how they relate to the model system provided by the Caenorhabditis elegans germ line, which is exceptional in its thorough genetic characterization and experimental accessibility under in vivo conditions. A fundamental question is how to define a stem cell; different definitions can be adopted that capture different features of interest. In the C. elegans germ line, stem cells can be defined by cell lineage or by cell commitment ('commitment' must itself be carefully defined). These definitions are associated with two other important questions about stem cells: their functions (which must be addressed following a systems approach, based on an evolutionary perspective) and their regulation. I review possible functions and their evolutionary groundings, including genome maintenance and powerful regulation of cell proliferation and differentiation, and possible regulatory mechanisms, including asymmetrical division and control of transit amplification by a developmental timer. I draw parallels between Drosophila and C. elegans germline stem cells; such parallels raise intriguing questions about Drosophila stem cells. I conclude by showing that the C. elegans germ line bears similarities with a number of other stem cell systems, which underscores its relevance to the understanding of stem cells.

Figure 1

Distal end of a C. elegans gonadal arm. (a) Ray tracing rendering of germ cells (blue, Hoechst staining) and of the distal tip cell (green, lag-2::gfp), which acts as a niche for distal germ cells. Cells in the mitotic region, located distally, are all actively cycling [8] but the mitotic index varies on the distal–proximal axis ( [50]; see the sections ‘Stem cells: Drosophila versus C. elegans’ and ‘Why have stem cells: prevention of mutation accumulation?’ in the Supporting information). Proximal to the mitotic region, the vast majority of cells are in the meiotic cycle. The arrowhead shows a long process extended by the distal tip cell. (b) Section through (a), showing that the distal tip cell (green) embraces distal-most germ cells more intimately than more proximal cells, suggesting decreasing contact of germ cells with the distal tip cell as they are displaced proximally. The solid arrow shows the distal–proximal direction in which germ cells are displaced. (c, d) Symmetrical and asymmetrical divisions of cells in row 1, which are likely actual stem cells of the germ line (as discussed in the section ‘Stem cells as defined by lineage: actual stem cells’). Numbers show how cell rows are scored on the distal–proximal axis. Cells in row 1 are highlighted in red. (c) The purple cell in row 1 divides symmetrically and displaces the orange cell. Note that because of the three-dimensional structure of the gonad, the orange cell could have stayed in place while a cell from a different plane in row 1 was displaced to row 2; the division of the purple cell would still have been symmetrical. (d) The purple cell in row 1 divides asymmetrically. (e) Subdivision of the mitotic region between a distal stem cell zone (defined by absence of differentiation upon blocking the cell cycle, assay 3 of commitment in the section ‘Stem cells as defined by commitment’), and a proximal transit-amplifying compartment. (f) Simple model for regulation of differentiation in the mitotic region. Cells trigger a differentiation timer upon leaving the stem cell zone, and differentiate when the timer runs out

Figure 2

Dramatically simplified outline of the regulatory networks controlling stem cell differentiation in the C. elegans hermaphrodite germ line (a) and in the Drosophila female germ line (b). Cross-repression between niche signalling promoting stem-cell maintenance and regulators promoting differentiation establishes a positive feedback loop. A drop of niche signalling intensity below a threshold, occurring as cells are displaced from the niche as an effect of proliferation, could lead to an all-or-none switch to a differentiated state of the regulatory network. Cells displaced from the niche would be in a transit-amplifying state while the switch is under way. The rate of the biochemical reactions in the regulatory network would determine the time for the switch to complete and, together with cycling speed, the size of the transit-amplifying compartment