Transplanted human intestinal organoids: a resource for modeling human intestinal development.

The in vitro differentiation of pluripotent stem cells into human intestinal organoids (HIOs) has served as a powerful means for creating complex three-dimensional intestinal structures. Owing to their diverse cell populations, transplantation into an animal host is supported with this system and allows the temporal formation of fully laminated structures, including crypt-villus architecture and smooth muscle layers that resemble native human intestine. Although the endpoint of HIO engraftment has been well described, here we aim to elucidate the developmental stages of HIO engraftment and establish whether it parallels fetal human intestinal development. We analyzed a time course of transplanted HIOs histologically at 2, 4, 6 and 8 weeks post-transplantation, and demonstrated that HIO maturation closely resembles key stages of fetal human intestinal development. We also utilized single-nuclear RNA sequencing to determine and track the emergence of distinct cell populations over time, and validated our transcriptomic data through in situ protein expression. These observations suggest that transplanted HIOs do indeed recapitulate early intestinal development, solidifying their value as a human intestinal model system.

Rosacea pathogenesis and therapeutics: current treatments and a look at future targets.

Rosacea is a chronic inflammatory skin condition associated with a significant health and economic burden from costs and loss of productivity due to seeking medical treatment. The disease encompasses multiple phenotypic manifestations involving a complex and multi-variate pathogenesis. Although the pathophysiology of rosacea is not completely understood, ongoing research is continually elucidating its mechanisms. In this review, current concepts of rosacea pathogenesis will be addressed which involve skin barrier and permeability dysfunction, the innate and adaptive immune systems, and the neurovascular system. More specifically, the cathelicidin pathway, transient potential receptor channels, mast cells, and the NLRP3 inflammasome pathway are various targets of current pharmacologic regimens. Future therapies may seek different mechanisms to act on current treatment targets, like the potential use of JAK/STAT inhibitors in ameliorating skin barrier dysfunction or TLR antagonists in alleviating cathelicidin mediated inflammation. Other potential treatments aim for entirely different molecular targets such as microvesicle particle mediated local and systemic inflammation. Ultimately rosacea is associated with a significant health and economic burden which warrants deeper research into its pathogenesis and resultant new treatment discovery.

In vivo development of immune tissue in human intestinal organoids transplanted into humanized mice.

Human intestinal organoids (HIOs) derived from pluripotent stem cells provide a valuable model for investigating human intestinal organogenesis and physiology, but they lack the immune components required to fully recapitulate the complexity of human intestinal biology and diseases. To address this issue and to begin to decipher human intestinal-immune crosstalk during development, we generated HIOs containing immune cells by transplanting HIOs under the kidney capsule of mice with a humanized immune system. We found that human immune cells temporally migrate to the mucosa and form cellular aggregates that resemble human intestinal lymphoid follicles. Moreover, after microbial exposure, epithelial microfold cells are increased in number, leading to immune cell activation determined by the secretion of IgA antibodies in the HIO lumen. This in vivo HIO system with human immune cells provides a framework for future studies on infection- or allergen-driven intestinal diseases.