Diverse mechanisms regulate stem cell self-renewal
Introduction
Self-renewal is the process by which a stem cell divides to generate one (asymmetric division) or two (symmetric division) daughter stem cells with developmental potentials that are indistinguishable from those of the mother cell (Figure 1). The ability of stem cells to self-renew extensively is central to development, as well as to the maintenance of adult tissues. Despite the importance of stem cell self-renewal, we are only beginning to understand how it is regulated.
Self-renewal allows stem cells to replicate themselves with apparently high fidelity while preserving their broad developmental potential and their massive replicative potential. Studies over the past few years have dramatically expanded our understanding of how self-renewal is regulated at a genetic level, yielding several insights. First, the coordinate activities of multiple pathways are required for a stem cell to self-renew. These include pathways whose function is conserved between diverse types of stem cells as well as pathways that are restricted to certain types of stem cells. Second, one reason that multiple pathways are required is that self-renewal involves both proliferation and the maintenance of an undifferentiated state (Figure 1). Some pathways that are necessary for self-renewal appear to regulate only proliferation, while other pathways regulate developmental potential and/or differentiation, and some pathways regulate both (Figure 2). Third, stem cells from different tissues or at different stages of development also differ in the mechanisms they use to regulate their self-renewal (Figure 3) because of differences in developmental potential (e.g. pluripotentiality versus multipotentiality), fate, and constraints on their proliferation. We will review these similarities and differences among stem cells in an effort to discern the principles underpinning the mechanisms that regulate self-renewal.
Section snippets
Embryonic stem cells: unique cells that depend on unique pathways to self-renew
Embryonic stem (ES) cells are pluripotent cells that self-renew in culture and can be propagated indefinitely. ES cell self-renewal requires the coordinate action of multiple pathways, some of which are unique to pluripotent cells (Figure 2). Oct4, a POU domain transcription factor, and the divergent homeodomain protein Nanog are necessary for the maintenance of pluripotentiality in inner-cell-mass cells (the cells in the blastocyst that give rise to ES cell lines in culture). In the absence of
Temporal changes in the self-renewal of germline stem cells
Germline stem cells, the precursors of gametes, bridge the transition from embryonic to adult stem cells. Gametogenesis begins with embryonic precursors known as primordial germ cells, which are detected by E7.5 in the mouse. Primordial germ cells differentiate into spermatogonial stem cells in males and oocyte stem cells in females after migrating into the genital ridges at about E12.5. Spermatogonial stem cells self-renew throughout adulthood to generate sperm continuously, and a recent study
The Notch, Wnt and Hedgehog pathways regulate the self-renewal of diverse stem cells
Given the broad dependence of many embryonic and adult tissues on signaling through the Notch, Wnt and Hedgehog pathways, it is perhaps not surprising that these pathways regulate the self-renewal of many stem cells (Figure 2). Notch activation is critical to maintaining the self-renewal of stem cells in diverse stem cell niches from the worm germline [22] to mammalian hematopoietic stem cells [31]. The ability of Notch to promote self-renewal is probably due to its ability to inhibit
Polycomb family members: regulating self-renewal through chromatin structure
Polycomb family members assemble into large protein complexes that repress transcription by regulating chromatin structure [52]. Mel-18, Rae-28 and Bmi-1 are components of the polycomb maintenance complex. These genes play important roles in the regulation of stem cells, but there are profound differences in their effects on self-renewal. Mel-18-deficient mice exhibit increased fetal hematopoietic stem cell self-renewal, perhaps as a result of increased HoxB4 expression [53], which strongly
Regulating self-renewal by regulating developmental potential
Additional genes that are required for the self-renewal of adult neural stem cells are thought to negatively regulate differentiation. The orphan nuclear receptor Tlx is required for the maintenance of stem cells in the central nervous system postnatally but not during fetal development [62•]. Tlx appears to promote neural stem cell self-renewal by repressing the expression of genes involved in astrocytic differentiation. In this regard, Tlx is similar to N-CoR, a co-repressor that interacts
Cell cycle regulation as a determinant of developmental changes in self-renewal
Cyclin dependent kinase (Cdk) inhibitors regulate progression through G1 phase of the cell cycle and have been shown to regulate multiple kinds of stem cells. The early G1-phase regulator p18Ink4c impairs hematopoietic stem cell self-renewal such that p18Ink4c-deficient mice exhibit increased stem cell self-renewal and increased hematopoietic stem cell frequency [69]. The late G1 phase regulator p21cip1 also impairs hematopoietic stem cell proliferation, but the increased proliferation of p21
Conclusions
Recent insights into the regulation of stem cell self-renewal raise several fundamental questions. What are the mechanisms that confer the competence to undergo multilineage differentiation and to what extent are these mechanisms regulated at the level of chromatin structure? What is the relationship between the mechanisms that confer competence to undergo multilineage differentiation and the mechanisms that regulate differentiation itself? Is pluripotentiality maintained by several factors,
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We apologize to colleagues whose work could not be cited due to space constraints, particularly to the authors of important studies published before 2001. We thank AB Molofsky for helpful comments on the manuscript. AVM is the recipient of a training grant from the National Institutes of Neurological Disorders and Stroke. SJM is an Assistant Investigator of the Howard Hughes Medical Institute.
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