Bioengineered Systems and Designer Matrices That Recapitulate the Intestinal Stem Cell Niche

Abstract

The relationship between intestinal stem cells (ISCs) and the surrounding niche environment is complex and dynamic. Key factors localized at the base of the crypt are necessary to promote ISC self-renewal and proliferation, to ultimately provide a constant stream of differentiated cells to maintain the epithelial barrier. These factors diminish as epithelial cells divide, migrate away from the crypt base, differentiate into the postmitotic lineages, and end their life span in approximately 7 days when they are sloughed into the intestinal lumen. To facilitate the rapid and complex physiology of ISC-driven epithelial renewal, in vivo gradients of growth factors, extracellular matrix, bacterial products, gases, and stiffness are formed along the crypt-villus axis. New bioengineered tools and platforms are available to recapitulate various gradients and support the stereotypical cellular responses associated with these gradients. Many of these technologies have been paired with primary small intestinal and colonic epithelial cells to re-create select aspects of normal physiology or disease states. These biomimetic platforms are becoming increasingly sophisticated with the rapid discovery of new niche factors and gradients. These advancements are contributing to the development of high-fidelity tissue constructs for basic science applications, drug screening, and personalized medicine applications. Here, we discuss the direct and indirect evidence for many of the important gradients found in vivo and their successful application to date in bioengineered in vitro models, including organ-on-chip and microfluidic culture devices.

Advances in Hydrogels in Organoids and Organs‐on‐a‐Chip

“…Hydrogels acted as 3D matrices or scaffolds have been incorporated into OOC to engineer human tissues with multicellular architecture and organ‐specific functions by spatial control of microenvironment cues . A variety of 3D parenchymal tissues in hydrogel‐based organs‐on‐chips have been reported, such as liver, heart, skeletal muscle, intestine, and nasal mucosa …”

“…In addition, collagen is a common substrate or matrix for the construction of tissue models in OOC systems. For example, a microengineered collagen scaffold was developed to generate human small intestinal epithelium with polarized crypt‐villus architecture driven by the chemical gradients, recapitulating the key features of native small intestine.…”

Gfi1-expressing Paneth cells revert to stem cells following intestinal injury

“…Further studies are needed to more definitively elucidate the interaction between the PI3K/AKT and Wnt pathways in the injury-repair process. Additional studies using the enteroid system to explore the mechanisms and potential mitigators of stem cell injury are needed and will be facilitated by high-throughput screening methodologies as recently described 45, 46 .…”

Developingin vitroassays to transform gastrointestinal safety assessment: potential for microphysiological systems

“…Although less appreciated, non-spherical GI microtissues have been developed by combining stimuli consistent with a microtiter plate format such as transwell culturing, air-liquid interface, and undefined growth factors from a feeder layer of mesenchymal cells. [32][33][34][35] In the future, the growth factor cues may be switched from proteins to small molecules in order to improve consistency, reduce cost, and refine pharmacology. To date, small molecule inhibitors of GSK3 (CHIR-99021) and the BMP type I receptor (LDN-193189) have been shown to maintain intestinal stem cells.…”