Stem cell plasticity. Plasticity of epithelial stem cells in tissue regeneration

Abstract

Tissues rely upon stem cells for homeostasis and repair. Recent studies show that the fate and multilineage potential of epithelial stem cells can change depending on 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 different populations of naturally lineage-restricted stem cells and committed progenitors can display remarkable plasticity and reversibility and reacquire long-term self-renewing capacities and multilineage differentiation potential during physiological and regenerative conditions. We also discuss the implications of cellular plasticity for regenerative medicine and for cancer.

Fig. 1. Skin and intestinal epithelia: paradigms for epithelial stem cell biology

(A) Schematic illustrating the epithelial lineages of hairy skin, color-coded here, which derive from at least four distinct stem cell populations. (B) Schematic illustrating the location of intestinal crypt stem cells (green), giving rise to TA cells and, in turn, four distinct cell types, three in the villus and one in the crypt.

Fig. 2. Epidermal homeostasis is achieved through distinct pools of stem cells

(A) Schematic illustrating the outcome of five separate lineage tracings of Rosa26-floxed-stop-floxed–reporter mice. In each experiment, a different inducible Cre recombinase was expressed in the desired SC or progenitor compartment. Because the Rosa26 promoter is generic, once Cre is activated and the stop codon is excised, the marked cells and all their downstream progeny express the reporter. The results shown here illustrate that each SC compartment is responsible for sustaining tissue homeostasis within a discrete skin domain. (B) We purified fluorescently marked bulge SCs (green) by fluorescence activated cell sorting (FACS) and cultured them as individual colonies of cells before transplanting the cells to a hairless mouse. The experiment illustrated that a clone from a single bulge SC can regenerate the entire skin epithelium, which documents the stemness and multipotency of the cells (9, 69, 70). We now know that when taken out of their native niche and engrafted, epithelial SCs are often less restricted in their fates.

Fig. 3. Interconversion and monoclonal drift of intestinal stem cells

(A) Lineage tracing of Lgr5⁺ cells (green) showing that these crypt cells give rise to all intestinal lineages during homeostasis (38). (B and C) Intravital microscopy showing the colonization of the crypt from Lgr5 cells at bottom center. Bmi1⁺ border (+4) cells either colonize the bottom of the crypt or give rise to TA cells (red) (42). (D) Lineage ablation of Lgr5⁺ (yellow X’s) prompts Bmi1⁺ cells (red) to convert into Lgr5⁺ crypt cells, and thus gut homeostasis is not impaired (43). (E) Multicolor lineage tracing rapidly leads to unicolor crypts, which demonstrate the monoclonal drift of ISCs (49).

Fig. 4. Plasticity of glandular epithelium during regeneration

(A) Lineage tracing reveals that during puberty and pregnancy, MG expansion is sustained largely by unipotent myoepithelial cells (red) and luminal cells (green) (52). (B) After transplantation into mammary mesenchyme, unipotent myoepithelial cells (red) from the MG or the SwG acquire multipotency and reform a new gland replete with basal and luminal cells (52, 53).

Fig. 5. Plasticity of epidermal cells during tissue repair

(A) Lineage tracing of IFE SCs (blue) and progenitors (grey) during wound healing showing that SCs stably contribute to epidermal repair while progenitor contribution is only transient (26). (B and C) Lineage tracing of bulge (B) and infundibulum SCs (C) demonstrate that adult HFSCs are rapidly recruited to IFE during wounding, but very few cells survive and contribute to IFE homeostasis after wound repair (19, 21). (D) After ablation of bulge cells (red X’s), hair germ (HG) cells (green) recolonize the bulge niche and mediate hair regeneration (16).

Fig. 6. Plasticity and interconversion into SCs during intestinal regeneration

(A and B) Dll1 lineage tracing showing that, although Dll1⁺ cells (red) are transient and typically only differentiate into secretory cells (black; interspersed in villus) during homeostasis (A), upon γ-radiation–induced cell death (blue X’s), Dll1⁺ TA cells revert and colonize the crypt (B) (82). (C) When intestine is depleted of Lgr5⁺ cells (yellow X’s) and then exposed to γ-radiation, regeneration is impaired, revealing a critical role for Lgr5⁺ cells in repairing extensive tissue damage (83).

Fig. 7. Plasticity and interconversion into SCs during tracheal regeneration

During tracheal homeostasis, basal cells (green) give rise to TA Clara cells (pink) and terminally differentiated ciliated cells (white). Lineage ablation of basal cells (red X’s) induces the interconversion of Clara and/or ciliated cells into basal SCs (85).