The pathophysiology caused by nonlytic viral infections is complex, often driven by macrophage-mediated immune responses that lead to hyperinflammation and collateral tissue damage. To conceptualize this complexity, we propose a pathogenic circuit comprising three interconnected nodes: nonlytic infection, inflammation, and immune-mediated cell death. To investigate this circuit, we combined hepatitis E virus (HEV), a prototypical nonlytic RNA virus, and macrophage-augmented organoids (MaugOs) as an innovative model. Here, we report successful recapitulation of the pathogenic circuit induced by HEV infection in MaugOs. Nonlytic HEV infection triggered robust inflammatory responses and subsequent cell death involving pyroptosis, apoptosis, and necroptosis pathways. By pharmacologically targeting individual circuit nodes as well as individual cell death pathways, we have dissected their interactions and identified potential therapeutic targets. Finally, we developed multitarget strategies by simultaneously targeting two or three nodes through rational drug combinations to effectively disrupt the pathogenic loop. Collectively, these findings elucidate the architecture of the pathogenic circuit underlying nonlytic HEV infection in MaugOs and inform the development of innovative multitarget therapies for improved disease treatment.

The development of techniques to culture and differentiate adult and pluripotent stem cells into diverse cell types over the past decades has sparked an increasing interest in the use of cells for organ regeneration. Such therapies aim to replace lost or damaged cells with functional ones. This can be achieved either through tissue engraftment of therapeutic cells or via their paracrine effects on resident cells, thereby offering a potential cure for debilitating degenerative diseases. The development of regenerative cell therapies, however, is ultimately complex. Effective cell therapy requires the delivery and successful engraftment of therapeutic cells to the correct location or sufficient paracrine activity, while ensuring safety is key to gaining support from funders, caregivers, and patients. A wide variety of cell sources has been used for the development of regenerative cell therapies, ranging from mesenchymal stromal cells (MSC) that act to stimulate local progenitor cells through their secretome to tissue-specific cell types differentiated from adult or pluripotent stem cells and organoids that engraft in tissues. While cell administration to patients is challenging based on both practical and ethical perspectives, the development of techniques to preserve transplant organs ex situ on machine perfusion devices offers a unique opportunity for studying regenerative cell therapy for organ repair in a safe and controllable environment. The present review addresses the current progress of cell therapy for organ regeneration of the intestine, kidney, liver, lung, and heart and discusses the challenges and opportunities of this potentially curing therapeutic approach.

Organoids are innovative three-dimensional and self-organizing cell cultures of various lineages that can be used to study diverse tissues and organs. Human organoids have dramatically increased our understanding of developmental and disease biology. They provide a patient-specific model to study known diseases, with advantages over animal models, and can also provide insights into emerging and future health threats related to climate change, zoonotic infections, environmental pollutants or even microgravity during space exploration. Furthermore, organoids show potential for regenerative cell therapies and organ transplantation. Still, several challenges for broad clinical application remain, including inefficiencies in initiation and expansion, increasing model complexity and difficulties with upscaling clinical-grade cultures and developing more organ-specific human tissue microenvironments. To achieve the full potential of organoid technology, interdisciplinary efforts are needed, integrating advances from biology, bioengineering, computational science, ethics and clinical research. In this Review, we showcase pivotal achievements in epithelial organoid research and technologies and provide an outlook for the future of organoids in advancing human health and medicine.

The extracellular matrix (ECM) is essential for cell support during homeostasis and plays a critical role in cancer. Although research often concentrates on the tumor's cellular aspect, attention is growing for the importance of the cancer-associated ECM. Biochemical and physical ECM signals affect tumor formation, invasion, metastasis, and therapy resistance. Examining the tumor microenvironment uncovers intricate ECM dysregulation and interactions with cancer and stromal cells. Anticancer therapies targeting ECM sensors and remodelers, including integrins and matrix metalloproteinases, and ECM-remodeling cells, have seen limited success. This review explores the ECM's role in cancer and discusses potential therapeutic strategies for cell-ECM interactions.