Intestinal Stem Cell Niche Insights Gathered from Both In Vivo and Novel In Vitro Models

Abstract

Intestinal stem cells are located at the base of the crypts and are surrounded by a complex structure called niche. This environment is composed mainly of epithelial cells and stroma which provides signals that govern cell maintenance, proliferation, and differentiation. Understanding how the niche regulates stem cell fate by controlling developmental signaling pathways will help us to define how stem cells choose between self-renewal and differentiation and how they maintain their undifferentiated state. Tractable in vitro assay systems, which reflect the complexity of the in vivo situation but provide higher level of control, would likely be crucial in identifying new players and mechanisms controlling stem cell function. Knowledge of the intestinal stem cell niche gathered from both in vivo and novel in vitro models may help us improve therapies for tumorigenesis and intestinal damage and make autologous intestinal transplants a feasible clinical practice.

Figure 1

The stem cell niche of the small intestine. Epithelial and nonepithelial environments support the signals required for stem cell maintenance. Among them, Wnt and Notch signaling have been defined as major determinants for stem cell self-renewal, for proliferation/differentiation of stem cells in the crypt. Stromal BMP antagonists regulate the crypt-villus axis, and the extracellular cell matrix (ECM) support signals that control stem cell fate. Other cells: neural, immune, and endothelial cells. TA: transit-amplifying progenitors; sPLA2: secreted phospholipases A2.

Figure 2

Engineering the ISC niche in vitro. Bioengineering approaches could further increase the tractability of organoid models and their fidelity to the real intestine. Synthetic matrices simplify the complexity of Matrigel and offer a powerful new toolkit with which to examine the effects of individual or combinations of ECM and mechanical niche signals. Microengineering approaches can be used to introduce spatial and temporal control over the biochemical and biophysical environment of ISCs, thereby mimicking the native niche more closely.