The National Center for Advancing Translational Sciences (NCATS) Assay Guidance Manual (AGM) Workshop on 3D Tissue Models for Antiviral Drug Development, held virtually on 7-8 June 2022, provided... Show moreThe National Center for Advancing Translational Sciences (NCATS) Assay Guidance Manual (AGM) Workshop on 3D Tissue Models for Antiviral Drug Development, held virtually on 7-8 June 2022, provided comprehensive coverage of critical concepts intended to help scientists establish robust, reproducible, and scalable 3D tissue models to study viruses with pandemic potential. This workshop was organized by NCATS, the National Institute of Allergy and Infectious Diseases, and the Bill and Melinda Gates Foundation. During the workshop, scientific experts from academia, industry, and government provided an overview of 3D tissue models' utility and limitations, use of existing 3D tissue models for antiviral drug development, practical advice, best practices, and case studies about the application of available 3D tissue models to infectious disease modeling. This report includes a summary of each workshop session as well as a discussion of perspectives and challenges related to the use of 3D tissues in antiviral drug discovery. Show less
Riet, S. van; Schadewijk, A. van; Khedoe, P.P.S.J.; Limpens, R.W.A.L.; Barcena, M.; Stolk, J.; ... ; Does, A.M. van der 2022
Development of effective treatment strategies for lung tissue destruction as seen in emphysema would greatly benefit from representative human in vitro models of the alveolar compartment. Studying... Show moreDevelopment of effective treatment strategies for lung tissue destruction as seen in emphysema would greatly benefit from representative human in vitro models of the alveolar compartment. Studying how cellular cross talk and/or (altered) biomechanical cues affect alveolar epithelial function could provide new insight for tissue repair strategies. Preclinical models of the alveolus ideally combine human primary patient-derived lung cells with advanced cell culture applications such as breathing-related stretch, to reliably represent the alveolar microenvironment. To test the feasibility of such a model, we isolated primary alveolar type 2 cells (AEC2s) from patient-derived lung tissues including those from patients with severe emphysema, using magnetic bead-based selection of cells expressing the AEC2 marker HTII-280. We obtained pure alveolar feeder-free organoid cultures using a minimally modified commercial medium. This was confirmed by known AEC2 markers as well as by detection of lamellar bodies using electron microscopy. Following (organoid-based) expansion, cells were seeded on both cell culture inserts and the Chip-S1 Organ-Chip that has a flexible polydimethylsiloxane (PDMS) membrane enabling the application of dynamic stretch. AEC2s cultured for 7 days on inserts or the chip maintained expression of HTII-280, prosurfactant protein C (SP-C), SP-A and SP-B, and zonula occludens-1 (ZO-1) also in the presence of stretch. AEC2s cultured on the chip showed lower expression levels of epithelial-mesenchymal transition-related vimentin expression compared with static cultures on inserts. The combination of a straightforward culture method of patient-derived AEC2s and their application in microfluidic chip cultures supports successful development of more representative human preclinical models of the (diseased) alveolar compartment. Show less
Aim: To explore the perspectives of patients and laymen with regard to the development, use and storage of cerebral organoids, in order to contribute to the ethical debate about this technology.... Show moreAim: To explore the perspectives of patients and laymen with regard to the development, use and storage of cerebral organoids, in order to contribute to the ethical debate about this technology. Materials & methods: In depth semi-structured interviews with 28 patients and laymen were conducted. A qualitative thematic analysis was undertaken using a constant comparative method. Results: Three interrelated themes emerged from the empirical material: moral value; willingness to donate; and elements of good governance. Conclusion: Patients and laymen are most concerned about cerebral organoids potentially developing consciousness and potential misuse. They support the use of cerebral organoids under the conditions that donors are adequately informed and that there will be good governance. Perspectives of patients and laymen are helpful to enable responsible development and use of cerebral organoids in practice.Lay abstractIn this study, we asked patients and laymen for their perspectives and opinions on the development, use and storage of so-called 'brain organoids'. Brain organoids are 3D cell structures that resemble parts of the human brain. These can be used as a model to study the development of the human brain and brain diseases. It is a promising technology that also raises ethical questions. For example, what kind of entity is a brain organoid and what should (and should not) be done with it? Our interview-study shows that patients and laymen are concerned that brain organoids might develop consciousness. They are also concerned about potential misuse of brain organoids. Overall, patients and laymen support the development of brain organoids if donors are well-informed and if responsible use is guaranteed by good governance. For them, good governance involves safety measures, well-defined boundaries to research and ethical oversight. The perspectives of these patients and laymen contribute to further development of brain organoids in a morally justifiable and socially acceptable way. Show less
Wnt/beta-catenin signaling regulates progenitor cell fate decisions during lung development and in various adult tissues. Ectopic activation of Wnt/beta-catenin signaling promotes tissue repair in... Show moreWnt/beta-catenin signaling regulates progenitor cell fate decisions during lung development and in various adult tissues. Ectopic activation of Wnt/beta-catenin signaling promotes tissue repair in emphysema, a devastating lung disease with progressive loss of parenchymal lung tissue. The identity of Wnt/beta-catenin responsive progenitor cells and the potential impact of Wnt/beta-catenin signaling on adult distal lung epithelial progenitor cell function in emphysema are poorly understood. Here, we used a TCF/Lef:H2B/GFP reporter mice to investigate the role of Wnt/beta-catenin signaling in lung organoid formation. We identified an organoid-forming adult distal lung epithelial progenitor cell population characterized by a low Wnt/beta-catenin activity, which was enriched in club and alveolar epithelial type (AT)II cells. Endogenous Wnt/beta-catenin activity was required for the initiation of multiple subtypes of distal lung organoids derived from the Wnt(low)epithelial progenitors. Further ectopic Wnt/beta-catenin activation specifically led to an increase in alveolar organoid number; however, the subsequent proliferation of alveolar epithelial cells in the organoids did not require constitutive Wnt/beta-catenin signaling. Distal lung epithelial progenitor cells derived from the mouse model of elastase-induced emphysema exhibited reduced organoid forming capacity. This was rescued by Wnt/beta-catenin signal activation, which largely increased the number of alveolar organoids. Together, our study reveals a novel mechanism of lung epithelial progenitor cell activation in homeostasis and emphysema. Show less
Regenerative medicine is emerging as a novel field in organ transplantation. In September 2019, the European Cell Therapy and Organ Regeneration Section (ECTORS) of the European Society for Organ... Show moreRegenerative medicine is emerging as a novel field in organ transplantation. In September 2019, the European Cell Therapy and Organ Regeneration Section (ECTORS) of the European Society for Organ Transplantation (ESOT) held its first meeting to discuss the state-of-the-art of regenerative medicine in organ transplantation. The present article highlights the key areas of interest and major advances in this multidisciplinary field in organ regeneration and discusses its implications for the future of organ transplantation. Show less
