Hasebe T , Fu L , Miller TC , Zhang Y , Shi YB , Ishizuya-Oka A .

Figure 1. Intestinal remodeling during Xenopus metamorphosis as a model to study the formation of adult stem cells during vertebrate development. The illustration (top) depicts the straightening and shortening of the larval intestine during frog metamorphosis. The connective tissue (CT) and muscle (MU) layers increase in size during remodeling while the larval epithelial cells (LE) undergo apoptosis (red cells) or dedifferentiate into adult progenitor/stem cells (dark blue) which rapidly proliferate to form a more folded, mammalian-like epithelial surface with stem cells located at the troughs between epithelial folds. Cross-sections (below) of the intestine at different stages of Xenopus laevis development were stained with pyronin-Y (red staining) and methyl green (blue staining). During the early stage of metamorphosis (prometamorphosis), e.g., stage 57, the intestine is made of mostly a monolayer of larval epithelial cells with little connective tissue (CT) or muscles (MU) except within the single fold, the typhlosole, where CT is abundant. The epithelial cells are moderately stained red. At the climax of metamorphosis (stage 60), most of the larval epithelial cells undergo apoptosis and become stained much weaker. At this stage, strong pyronin-Y signals are strictly localized in the proliferating adult epithelial progenitor/stem cells within the islets (I, arrows). The CT and MU develop extensively during metamorphic climax. By the end of metamorphosis (stage 66), the adult epithelium with multiple folds is formed, with the adult stem cells localized to the trough of the epithelial fold, equivalent to the crypt in the adult mammalian intestine. LE: larval/tadpole epithelium, AE: adult epithelium, CT: connective tissue, MU: muscles, I: islets (clusters of proliferating adult epithelial progenitor/stem cells).

Figure 2. A model for T3 actions for the metamorphic transformation of Xenopus laevis intestine. During metamorphosis, T3 acts directly (1) on the larval epithelium as well as (2) on the rest of the intestine (the non-epithelium), mostly the connective tissue. Most of the larval epithelial cells are induced to undergo programmed cell death by either one of the two T3 actions: T3-induced cell autonomous apoptosis vs. apoptosis induced by ECM remodeling and cell-cell interaction due to T3 action in the non-epithelium. On the other hand, a small number of cells within the larval epithelium undergo dedifferentiation upon receiving the T3 signal. However, T3 action in these cells alone cannot induce the formation of adult stem cells, unless T3 action in the non-epithelium is also present. This suggests that T3-induced tissue interactions are required for the establishment of the stem cell niche, via ECM remodeling and cell-cell interaction, to enable the dedifferentiated epithelial cells to become stem cells. See [100] for details.

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