At the surface of body organs, epithelial tissues must withstand harsh external environments. To do so, they rely heavily upon stem cells to replenish and repair wounds and replace the many cells that die from this wear and tear. To maintain tissue size, the number of cells lost must be compensated by cell divisions. Tissue homeostasis and wound-repair are ensured by stem cells, located within specialized microenvironments, referred to as niches. Each niche is tailored to accommodate the regenerative needs of its tissue. Some tissues—for instance, skin epithelium—harbor multiple stem cell niches, each with their own responsibility for maintaining cellular balance within their particular domain. Governance of discrete tissue units has ancient origins and is also seen in Drosophila gut epithelium.

Identifying stem cells and tracking their progeny is accelerated by lineage tracing, a technique in which a stem cell is genetically marked in its niche and in a way such that their subsequent progeny retain marker expression. Although interpretation of these experiments has been complicated by the lack of specificity of most stem cell markers, this method can be helpful in evaluating the contribution of stem cells to tissue homeostasis and wound-repair. Additional tools include live imaging of marked stem cells and ablating stem cells in situ either by laser or by targeted expression of diphtheria toxin/receptor in stem cells.

Coordinating stem cell activity to match tissue output. Stem cells (purple) often exist in two states, one more quiescent than the other. Primed stem cells are closer to activating niche signals (green). They typically respond faster and generate shorter-lived progenitors (orange), which also signal, fueling tissue production. Each stem cell niche must be responsive to the regenerative demands of tissue homeostasis and wound-repair and adjust niche activating and inhibitory signals as necessary.

Accumulating evidence on bone marrow, intestinal stem cell crypts, and hair follicles suggests that stem cells often exist in two distinct states based upon their relative activity and/or their ease of activation during homeostasis and/or wound-induced regeneration. Recent studies on the hair follicle reveal that signals emanating from both heterologous niche cells and from lineage progeny influence the timing and length of stem cell activity. This in turn can profoundly affect the amount of tissue regenerated. Stem cell ablation studies on both intestinal and hair follicle stem cell niches further show that the two states are interconvertible, perhaps best exemplified by the ability of a single intestinal stem cell to eventually outcompete its siblings during rounds of turnover within an intestinal villus.

Additional new findings suggest that fates and multilineage potentials of epithelial stem cells can change, depending upon whether a stem cell exists within its resident niche and responds to normal tissue homeostasis, whether it is mobilized to repair a wound, or whether it is taken from its niche and challenged to de novo tissue morphogenesis after transplantation. In this Review, we discuss how naturally lineage-restricted populations of stem cells and committed progenitors can display such remarkable plasticity under these different conditions.

Although the molecular mechanisms underlying cellular plasticity, fate conversion, and reacquisition of stem cell properties in committed and/or differentiated cells still remain poorly understood, this cellular plasticity and lineage reversibility may represent adaptive mechanisms for the self-preservation of epithelia to repair body surfaces and linings in whatever ways possible following injuries. When gone …