Abstract
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.
Highlights
The intestinal epithelium is responsible for the principle physiological function of this organ: digestion and absorption of nutrients
The Extracellular matrix (ECM) that separates the epithelium and the connective tissue, is made of proteins secreted by both the epithelium and connective tissue, these findings suggest that ECM remodeling and changes in the connective tissue during intestinal metamorphosis can influence epithelial cell response to T3
We recently showed that expression of the dominant positive T3 receptors (TRs) in the epithelium alone led to the formation of epithelial cells expressing Sonic hedgehog (Shh), which is highly expressed in the developing adult progenitor/ stem cells during intestinal metamorphosis, as well as larval epithelial apoptosis, mimicking natural development [100]
Summary
The intestinal epithelium is responsible for the principle physiological function of this organ: digestion and absorption of nutrients. It can be manipulated by controlling the availability of T3 to the tadpoles via either inhibiting endogenous T3 synthesis or adding exogenous, physiological levels of T3 to the tadpole rearing water This makes amphibian metamorphosis a superior model to study the developmental mechanisms in vivo when compared to mammalian postembryonic development, where maternal influences complicate the studies on the embryos/neonates. The formation of the adult intestine takes place during amphibian metamorphosis when circulating T3 level peaks, just like the maturation of the mammalian intestine during the perinatal period In amphibians such as Xenopus laevis and tropicalis, the premetamorphic tadpole intestine is a simple tubular structure made of mostly a single layer of larval epithelial cells with little connective tissue or muscles except in the single fold, the typhlosole, where the connective tissue is abundant (Figure 1) [25,27,28]. Some larval epithelial cells escape cell death and instead undergo dedifferentiation to become the adult progenitor/stem cells (Figure 1), which eventually form an adult epithelium comprised of multiple folds surrounded by much thicker layers of connective tissue and muscles, resembling the adult mammalian
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