XB-ART-46891Cell Biosci April 1, 2013; 3 (1): 18.
Thyroid hormone-induced cell-cell interactions are required for the development of adult intestinal stem cells.
The mammalian intestine has long been used as a model to study organ-specific adult stem cells, which are essential for organ repair and tissue regeneration throughout adult life. The establishment of the intestinal epithelial cell self-renewing system takes place during perinatal development when the villus-crypt axis is established with the adult stem cells localized in the crypt. This developmental period is characterized by high levels of plasma thyroid hormone (T3) and T3 deficiency is known to impair intestinal development. Determining how T3 regulates adult stem cell development in the mammalian intestine can be difficult due to maternal influences. Intestinal remodeling during amphibian metamorphosis resembles perinatal intestinal maturation in mammals and its dependence on T3 is well established. A major advantage of the amphibian model is that it can easily be controlled by altering the availability of T3. The ability to manipulate and examine this relatively rapid and localized formation of adult stem cells has greatly assisted in the elucidation of molecular mechanisms regulating their formation and further revealed evidence that supports conservation in the underlying mechanisms of adult stem cell development in vertebrates. Furthermore, genetic studies in Xenopus laevis indicate that T3 actions in both the epithelium and the rest of the intestine, most likely the underlying connective tissue, are required for the formation of adult stem cells. Molecular analyses suggest that cell-cell interactions involving hedgehog and BMP pathways are critical for the establishment of the stem cell niche that is essential for the formation of the adult intestinal stem cells.
PubMed ID: 23547658
PMC ID: PMC3621685
Article link: Cell Biosci
Species referenced: Xenopus
Genes referenced: shh
Article Images: [+] show captions
|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  for details.|
References [+] :
Amano, Spatio-temporal regulation and cleavage by matrix metalloproteinase stromelysin-3 implicate a role for laminin receptor in intestinal remodeling during Xenopus laevis metamorphosis. 2005, Pubmed, Xenbase