Epithelial tension controls intestinal cell extrusion.

Cell extrusion is essential for homeostatic self-renewal of the intestinal epithelium. Extrusion is thought to be triggered by crowding-induced compression of cells at the intestinal villus tip. In this study, we found instead that a local "tug-of-war" competition between contractile cells regulated extrusion in the intestinal epithelium.

Organoids as models of immune-organ interaction.

Incorporating immune cells into organoids enables exploring previously inaccessible aspects of immune-epithelial interactions in vitro. In this review, we start by detailing how immune-organoid co-cultures can model mucosal immunity at each stage of a functional inflammatory response. We then describe how inflammatory organoid systems have informed our understanding of the features driving chronic stress and remodeling in autoimmune diseases and explore how patient-derived carcinoma organoids can be combined with tumor-relevant immune compartments for oncology research.

An integrated transcriptomic cell atlas of human endoderm-derived organoids.

Human pluripotent stem cells and tissue-resident fetal and adult stem cells can generate epithelial tissues of endodermal origin in vitro that recapitulate aspects of developing and adult human physiology. Here, we integrate single-cell transcriptomes from 218 samples covering organoids and other models of diverse endoderm-derived tissues to establish an initial version of a human endoderm-derived organoid cell atlas. The integration includes nearly one million cells across diverse conditions, data sources and protocols.

Human organoids with an autologous tissue-resident immune compartment.

The intimate relationship between the epithelium and immune system is crucial for maintaining tissue homeostasis, with perturbations therein linked to autoimmune disease and cancer. Whereas stem cell-derived organoids are powerful models of epithelial function, they lack tissue-resident immune cells that are essential for capturing organ-level processes. We describe human intestinal immuno-organoids (IIOs), formed through self-organization of epithelial organoids and autologous tissue-resident memory T (T) cells, a portion of which integrate within the epithelium and continuously survey the barrier.

Analysis of off-tumour toxicities of T-cell-engaging bispecific antibodies via donor-matched intestinal organoids and tumouroids.

Predicting the toxicity of cancer immunotherapies preclinically is challenging because models of tumours and healthy organs do not typically fully recapitulate the expression of relevant human antigens. Here we show that patient-derived intestinal organoids and tumouroids supplemented with immune cells can be used to study the on-target off-tumour toxicities of T-cell-engaging bispecific antibodies (TCBs), and to capture clinical toxicities not predicted by conventional tissue-based models as well as inter-patient variabilities in TCB responses. We analysed the mechanisms of T-cell-mediated damage of neoplastic and donor-matched healthy epithelia at a single-cell resolution using multiplexed immunofluorescence.

Safety Profiling of Tumor-targeted T Cell-Bispecific Antibodies with Alveolus Lung- and Colon-on-Chip.

Traditional drug safety assessments often fail to predict complications in humans, especially when the drug targets the immune system. Rodent-based preclinical animal models are often ill-suited for predicting immunotherapy-mediated adverse events in humans, in part because of the fundamental differences in immunological responses between species and the human relevant expression profile of the target antigen, if it is expected to be present in normal, healthy tissue. While human-relevant cell-based models of tissues and organs promise to bridge this gap, conventional in vitro two-dimensional models fail to provide the complexity required to model the biological mechanisms of immunotherapeutic effects.

An Model of T Cell Infiltration Dynamics Based on an Advanced System to Enhance Preclinical Decision Making in Cancer Immunotherapy.

Cancer immunotherapy often involves the use of engineered molecules to selectively bind and activate T cells located within tumour tissue. Fundamental to the success of such treatments is the presence or recruitment of T cells localised within the tumour microenvironment. Advanced organ-on-a-chip systems provide an setting in which to investigate how novel molecules influence the spatiotemporal dynamics of T cell infiltration into tissue, both in the context of anti-tumour efficacy and off-tumour toxicity.

Patient-derived micro-organospheres enable clinical precision oncology.

Patient-derived xenografts (PDXs) and patient-derived organoids (PDOs) have been shown to model clinical response to cancer therapy. However, it remains challenging to use these models to guide timely clinical decisions for cancer patients. Here, we used droplet emulsion microfluidics with temperature control and dead-volume minimization to rapidly generate thousands of micro-organospheres (MOSs) from low-volume patient tissues, which serve as an ideal patient-derived model for clinical precision oncology.

The Effect of Thiol Structure on Allyl Sulfide Photodegradable Hydrogels and their Application as a Degradable Scaffold for Organoid Passaging.

Intestinal organoids are useful in vitro models for basic and translational studies aimed at understanding and treating disease. However, their routine culture relies on animal-derived matrices that limit translation to clinical applications. In fact, there are few fully defined, synthetic hydrogel systems that allow for the expansion of intestinal organoids.

Biomaterials approaches in stem cell mechanobiology.

Multiple molecular and physical cues engage in complex interplay to afford the fine control over stem cell behavior that is required during tissue development, homeostasis, and repair. As a result of a close collaboration between biologists, engineers, and physicists over the past decade, the types of mechanical parameters which influence stem cells, along with the corresponding cellular outcomes, have started to emerge. Moreover, the field has begun to identify the molecular structures and mechanisms whereby stem cells sense physical signals and transduce them into biological response.

Bioengineering approaches to guide stem cell-based organogenesis.

During organogenesis, various molecular and physical signals are orchestrated in space and time to sculpt multiple cell types into functional tissues and organs. The complex and dynamic nature of the process has hindered studies aimed at delineating morphogenetic mechanisms in vivo, particularly in mammals. Recent demonstrations of stem cell-driven tissue assembly in culture offer a powerful new tool for modeling and dissecting organogenesis.

Drug discovery through stem cell-based organoid models.

The development of new drugs is currently a long and costly process in large part due to the failure of promising drug candidates identified in initial in vitro screens to perform as intended in vivo. New approaches to drug screening are being developed which focus on providing more biomimetic platforms. This review surveys this new generation of drug screening technologies, and provides an overview of recent developments in organoid culture systems which could afford previously unmatched fidelity for testing bioactivity and toxicity.