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PubMed2026

Using Organoids to Unlock the Potential of Human Torpor for Spaceflight.

PURPOSE OF REVIEW: This paper reviews the current understanding of the potential for humans to enter a state of torpor/hibernation, and discusses the possibility of inducing torpor in astronauts for long-duration space travel, including some of the physiological, technological, and ethical considerations associated with its implementation. By exploring means to induce torpor in various human organoid systems, we hope such research can provides insights to comprehensive solutions to overcome some of the major hurdles that limit the potential for human to enter a state of torpor during long-duration deep-space missions, and contribute to the ongoing efforts to make such missions more feasible and safer for astronauts. RECENT FINDINGS: On future deep space missions such as NASA's planned missions to the Moon, Mars, and near-Earth asteroids, astronauts will be continuously exposed to environments that are radically different from those on Earth, each presenting multiple logistical and physiological challenges. Beyond the well-documented physiological effects of microgravity, space travelers will encounter a complex radiation environment that may contribute to significant short- and long-term adverse effects on human physiology and increase the risk of cancer and other diseases. Besides these physical challenges, life support systems must also be designed to mitigate psychological impacts of long-term isolation and confinement - all of which collectively pose formidable engineering problems. Hibernation/torpor is a state of prolonged inactivity and metabolic depression used by a wide variety of mammals to survive periods of cold temperatures and food scarcity, including some primates and perhaps even an extinct early line of hominins that lived nearly half a million years ago. Since modern humans share common ancestry with these hominins and hibernating primates, it is likely the human genome encodes the necessary genetic information to hibernate, or at least enter the similar, more transient state of torpor. The reduced body activity, lowered metabolism, and decreased energy requirements that characterize torpor suggest that developing means of inducing such a state in astronauts could address these challenges, including providing a degree of radioprotection. SUMMARY: This review explores the potential application of human torpor as a countermeasure to address the many challenges posed by long-duration spaceflight beyond low-Earth orbit (LEO), discusses various natural hibernating model systems for studying means of inducing a torpor-like state in humans, and highlights the vast potential of using human organoids to test and validate mechanisms that govern induction and maintenance of torpor to identify the means to one day safely induce this state in astronauts to provide additional protection from the myriad stressors of spaceflight.

Astronaut Health↗
PubMed2026

Phytolacca acinosa Roxb. induces intestinal toxicity through the histamine-MLCK-tight junction axis: Integrated evidence from proteomics, metabolomics, intestinal organoids and epithelial barrier validation.

Phytolacca acinosa Roxb. (PR) is a saponin-rich medicinal plant associated with gastrointestinal toxicity, but the mechanisms underlying PR-induced intestinal barrier injury remain unclear. In this study, raw PR extract was analytically characterized by UPLC-ZenoTOF-MS/MS, confirming triterpenoid saponins as the predominant constituents. C57BL/6 J mice were orally exposed to characterized PR extract (1.20 or 12.0 g/kg for 5 h), and Caco-2 cells and mouse intestinal organoids were used to assess epithelial toxicity and barrier disruption. Histopathology, ELISA, FITC-dextran permeability assays, immunofluorescence, CCK-8, LDH release, western blotting, DIA-based proteomics and untargeted metabolomics were integrated to define toxicological mechanisms. PR induced dose-dependent intestinal inflammation and barrier dysfunction, with the ileum as the most sensitive target. PR increased serum DAO and D-lactate and intestinal TNF-α and IL-1β, disrupted organoid morphology, enhanced epithelial permeability, and reduced ZO-1 expression. Proteomics revealed changes in inflammatory, lipid-metabolic, cytoskeletal and tight-junction pathways, including upregulation of MLCK3 and phospholipase-related proteins and downregulation of ZO-1 and ZO-2. Metabolomics identified histidine metabolism disturbance and histamine accumulation. Integrated multi-omics and pharmacological validation indicated that histamine activated the PLC/IP₃/Ca²⁺/CaM/MLCK cascade, promoting MLC phosphorylation, tight-junction disassembly and epithelial leakiness. MLCK inhibition partially restored ZO-1/ZO-2 expression and attenuated PR-induced epithelial injury. These findings identify the histamine-MLCK-tight junction axis as a key mechanism of PR-induced intestinal toxicity and support hazard identification of saponin-rich PR exposure.

Animals↗
PubMed1999

In-vivo delivery of therapeutic proteins by genetically-modified cells: comparison of organoids and human serum albumin alginate-coated beads.

We have designed a self-assembling multimeric soluble CD4 molecule by inserting the C-terminal fragment of the alpha chain of human C4-binding protein (C4bp alpha) at the C-terminal end of human soluble CD4 genes. This CD4-C4bp alpha fusion protein (sMulti-CD4) and two other reference molecules, a fusion protein of human serum albumin (HSA) and the first two domains of CD4 (HSA-CD4) and monomeric soluble CD4 (sMono-CD4), were delivered in vivo by genetically modified 293 cells. These cells were implanted in mice as organoids and also encapsulated in HSA alginate-coated beads. sMulti-CD4 showed an apparent molecular weight of about 300-350 kDa, in accordance with a possible heptamer formula. sMulti-CD4 produced either in cell culture or in vivo in mice appeared to be a better invitro inhibitor of HIV infection than sMono-CD4. Plasma levels of sMulti-CD4, HSA-CD4, and sMono-CD4 reached approximately 2,300, 2,700, and 170 ng/mL, respectively, 13 weeks after in-vivo organoid implantation, which had formed tumours at that time. This suggests that the plasma half-life of sMulti-CD4 is much longer than that of sMono-CD4. The 293 xenogeneic cells encapsulated in HSA alginate-coated beads remained alive and kept secreting sMono-CD4 or HSA-CD4 continuously at significant levels for 18 weeks in nude mice, without tumour formation. When implanted in immunocompetent Balb/c mice, they were rejected two to three weeks after implantation. In contrast, encapsulated BL4 hybridoma cells remained alive and kept secreting BL4 anti-CD4 mAb for at least four weeks in Balb/c mice. These results suggest the clinical potential of the C4bp-multimerizing system, which could improve both the biological activity and the poor in-vivo pharmacokinetic performance of a monomeric functional protein like soluble CD4. These data also show that a systemic delivery of therapeutic proteins, including immunoglobulins, can be obtained by the in-vivo implantation of engineered allogeneic cells encapsulated in HSA alginate-coated beads.

Alginates↗
PubMed1996

Tissue-engineered skeletal muscle organoids for reversible gene therapy.

Genetically modified murine skeletal myoblasts were tissue engineered in vitro into organ-like structures (organoids) containing only postmitotic myofibers secreting pharmacological levels of recombinant human growth hormone (rhGH). Subcutaneous organoid implantation under tension led to the rapid and stable appearance of physiological sera levels of rhGH for up to 12 weeks, whereas surgical removal led to its rapid disappearance. Reversible delivery of bioactive compounds from postmitotic cells in tissue engineered organs has several advantages over other forms of muscle gene therapy.

Animals↗
PubMedDate not supplied

Hepatic organoid formation in collagen sponge of cells isolated from human liver tissues.

We examined whether small hepatocytes (SHs), which are hepatic progenitor cells, could be isolated from a normal human liver and whether human hepatic cells could form hepatic organoids in a collagen sponge. Normal liver tissues were obtained from resected specimens from nine patients who underwent hepatic resection. Isolated hepatic cells were plated on dishes and a collagen sponge. More than 1 month later, SH-like cells appeared and proliferated on the dishes, whereas cell aggregates were formed in the sponge and showed characteristic tissue architecture: columnar and/or cuboidal epithelial cells lined the surface of the sponge. Clusters of epithelial cells with a large cytoplasm and ductular structures were observed under the lining cells. The lining and ductular cells were positive for cytokeratins 7 and 19, which indicated they were biliary epithelial cells (BECs), and the epithelial cells forming clusters were positive for the anti-human hepatocyte antibody, identifying them as hepatocytes. Some lining cells were positive for both the hepatic marker and the BEC markers. The cells in the collagen sponge actively proliferated and the hepatocytes excreted albumin into the medium. Thus, hepatic organoids could be reconstructed in a collagen sponge by normal human liver cells.

Adult↗
PubMed1987

Piloleiomyoma arising in an organoid nevus: a case report and review of the literature.

The case of a 59-year-old woman with a history of an organoid nevus of the scalp is reported. Histologic examination revealed multiple secondary tumors including a tumor of the follicular infundibulum, an apocrine nevus, a syringocystadenoma papilliferum, an apocrine adenoma, and a piloleiomyoma occurring in the absence of sebaceous glands. The types of secondary tumors which may develop within organoid nevi are reviewed. The terminology and pathogenesis of this hamartoma are discussed.

Female↗
PubMed2004

Collagen vitrigel: a novel scaffold that can facilitate a three-dimensional culture for reconstructing organoids.

Three-dimensional reconstructed organoids in vitro are valuable for not only regenerative medicine but also drug development. However, the manipulation of conventional three-dimensional cultures is not simple. We describe a nylon membrane ring-embedded or a pressed silk sheet-embedded scaffold made of collagen "vitrigel" that can facilitate three-dimensional cultures for reconstructing an epithelial-mesenchymal model or a hard connective tissue model, respectively. Here we define vitrigel as a gel in a stable state produced by rehydration after the vitrification of a traditional hydrogel. The collagen vitrigel was successfully prepared in three steps involving a gelation process in which a cold and clear neutral salt solution containing type I collagen formed an opaque and soft gel by incubation at 37 degrees C, a vitrification process in which the gel becomes a rigid material like glass after sufficient drying out, and finally a rehydration process to convert the vitrified material into a thin and transparent gel membrane with enhanced gel strength. The framework-embedded collagen vitrigel scaffold that can be easily reversed by forceps was prepared by inserting a nylon ring or a silk sheet in the collagen solution prior to the gelation. The scaffold enabled culturing anchorage-dependent cells on both surfaces of the collagen vitrigel by the manipulation of two-dimensional cultures and consequently resulted in reconstructing a three-dimensional organoid. An intestinal epithelial-mesenchymal model was reconstructed by coculturing fibroblasts on the opposite side of monolayered Caco-2 cells on the nylon ring-embedded collagen vitrigel. Also, fibroblasts seeded on both surfaces of the silk sheet-embedded collagen vitrigel proliferated well and formed multilayers and some cells invaded into the vitrigel framed by the network of numerous strong silk filaments, suggesting a reconstruction of a hard connective tissue model. These data demonstrate that the collagen vitrigel is a valuable scaffold for tissue engineering.

Caco-2 Cells↗
PubMedDate not supplied

Organoid nevus.

The organoid nevus is a malformation of most of the normal tissue components in a strictly localized, smaller or larger area of skin, most commonly the scalp. It undergoes more or less predictable developmental changes in puberty and then remains stable, but is subject to secondary development of benign or semimalignant adnexal tumors in a significant percentage of cases. It may present clinically and histologically in a variety of forms, the most common ones being nevus sebaceus and nevus verrucosus. It may be associated with neurologic and skeletal abnormalities in the organoid nevus syndrome (Schimmelpenning-Feuerstein-Mims). Total excision before adolescence is the treatment of choice.

Apocrine Glands↗
PubMed1984

[Interaction of rifampicin with hepatocyte organoids in rats and its intracellular distribution].

Interaction of rifampicin with isolated subcellular fractions of the rat liver (binding and dissociation of the complexes) and intracellular distribution of the antibiotic were studied in the presence of the main organoids taken in the ratio close to the natural volume ratio of the hepatocyte cell components. The nuclei and mitochondria were most active during drug binding. The microsomes were less important. Rifampicin formed mobile complexes with organoids and was easily released from the subcellular fractions recovering its activity on washing. The intracellular distribution was the following: 37.7 per cent of rifampicin in the active form was accumulated in cytosol and the remaining amount was reversibly bound in the fractions of the nuclei, mitochondria and microsomes. The characteristic features of the cell pharmacokinetics of rifampicin, i.e. significant concentration in cytosol, possible deposition in the subcellular structures and at the same time the capacity for recovery of the activity might define the antimicrobial potential of this antibiotic in respect to the intracellular microorganisms.

Animals↗
PubMed1981

Becker's melanosis: an organoid hamartoma.

Herein we have reported the histologic findings in two cases of Becker's melanosis. In one patient the lesion showed hyperplasia or hair muscles and in the other patient the lesion was associated with an underlying neurofibroma. The proliferative changes seen in the epidermis and dermis in Becker's melanosis can best be explained by the concept of an organoid hamartoma with involvement of the epidermis, pilar structures, and some other dermal components. The localization of the plexiform neurofibroma within the Becker's nervus is a unique observation. It may fall within the spectrum of an organoid hamartoma or it may only represent a chance occurrence.

Adult↗
PubMed2025

A three-dimensional mouse liver organoid platform for assessing EDCs metabolites simulating liver metabolism.

Hepatic metabolism is an important process for evaluate the potential activity and toxicity of endocrine disrupting chemicals (EDCs) metabolites. Organization for Economic Co-operation and Development (OECD) has advocated the development of in vitro assays that mimic in vivo hepatic metabolism to eventually replace classical animal tests. In response to this need, we established a 3D mouse liver organoid (mLO) platform that mimics the animal model and is distinct from existing models. We evaluated the effects the activity of EDC metabolites generated through mLOs based on human cell-based reporter gene assays in addition to existing models. This study emphasizes the importance of hepatic ex-vivo and suggests the need a new metabolic model through a 3D mLOs platform. These results indicate that mLOs provides a novel biological method to screen for potential endocrine-disrupting activities of EDC metabolites.

Animals↗
PubMed2026

Organoids in translation: a bench-to-bedside framework for pancreatic cancer precision medicine.

INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies with a 5-year survival rate of < 13%. Standard treatments such as FOLFIRINOX or gemcitabine/nab-paclitaxel yield modest response rates, underscoring the urgent need for precision oncology approaches. Patient-derived organoids (PDOs) preserve the genomic, phenotypic, and histopathological features of the source tumor and offer a promising platform for drug screening, biomarker development, and personalized therapy. However, a systematic evaluation of their translational capacities is lacking. METHODS: A systematic review was conducted according to the PRISMA 2020 guidelines (PROSPERO registration pending) using PubMed, EMBASE, and Cochrane CENTRAL (December 10, 2024) to identify English-language PDAC PDO studies that incorporated therapeutic testing. Ninety-five studies met the inclusion criteria. Data extraction captured >75 variables per study, including spanning culture methodology, therapeutic profiling, biomarker integration, and clinical correlation. A 13-domain weighted Translatability Scoring Framework adapted from Wehling et al. assessed predictive validity, biomarker strength, pharmacogenetics, and clinical trial alignment. Scores ranged from 0 to 5 and were categorized as good (>4.0), moderate (3.0-4.0), or low (<3.0) translational potential. RESULTS: Of the 95 studies, 70.5% have been published since 2021, reflecting the rapid growth in this field. The mean PDO generation success rate was 89.7%, with the primary tumor tissue being the predominant source (48.4%). Only 24.8% were directly linked to clinical trials and 5.3% incorporated multi-omic profiling. The median translatability score was 3.13 (range, 1.72-4.59): 45.3% of the studies had low translatability, 50.5% moderate, and only 4.2% had good translational potential. High-scoring studies consistently combine multi-omic biomarker platforms, in vivo validation, clinical outcome correlation, and prospective trial integration. Conversely, the weakest domains were pharmacogenetics, endpoint strategies, and biomarker validation, limiting their overall clinical relevance. CONCLUSIONS: PDOs have demonstrated strong feasibility and in vitro clinical correlation in PDAC; however, their clinical translation remains constrained by limited multi-omic integration, absence of pharmacogenomic modeling, and sparse clinical trial embedding. Standardization of protocols, adoption of harmonized and clinically relevant endpoints, and systematic incorporation of biomarker-driven co-clinical trial frameworks are urgently needed to transition PDOs from promising experimental surrogates to validating precision oncology tools capable of informing therapeutic decision-making in PDAC.

Humans↗
PubMed2022

Organoids and microphysiological systems: Promising models for accelerating AAV gene therapy studies.

The FDA has predicted that at least 10-20 gene therapy products will be approved by 2025. The surge in the development of such therapies can be attributed to the advent of safe and effective gene delivery vectors such as adeno-associated virus (AAV). The enormous potential of AAV has been demonstrated by its use in over 100 clinical trials and the FDA's approval of two AAV-based gene therapy products. Despite its demonstrated success in some clinical settings, AAV-based gene therapy is still plagued by issues related to host immunity, and recent studies have suggested that AAV vectors may actually integrate into the host cell genome, raising concerns over the potential for genotoxicity. To better understand these issues and develop means to overcome them, preclinical model systems that accurately recapitulate human physiology are needed. The objective of this review is to provide a brief overview of AAV gene therapy and its current hurdles, to discuss how 3D organoids, microphysiological systems, and body-on-a-chip platforms could serve as powerful models that could be adopted in the preclinical stage, and to provide some examples of the successful application of these models to answer critical questions regarding AAV biology and toxicity that could not have been answered using current animal models. Finally, technical considerations while adopting these models to study AAV gene therapy are also discussed.

Animals↗
PubMed1985

Radial gradient culture on the inner surface of collagen tubes: organoid growth of normal rat bladder and rat bladder cancer cell line NBT-II.

Radial histophysiologic gradient culture uses thin walled, permeable collagen tubes to house inocula in the form of either tissue explants, aggregates of cells, or dissociated cells. The outgrowth from these inocula spreads on the inner surface of the cylindrical tube, completely lining the lumen. Metabolites are exchanged through the wall of the collagen tube by diffusion from the pool of medium surrounding the cylinder. Urothelial cells form organoid stratified epithelium. A histophysiologic gradient occurs with the basal surface of the epithelium attached to the collagen wall. At this interface, for normal bladder, the initiation of epithelial renewal is seen in the basal zone, as shown by incorporation of tritiated thymidine. The simulation of conditions in nature is attained by the exchange of metabolites between the pool of medium and the basal zone of the epithelium. NBT-II appears as two concentric stratified epithelia. Isotopic labelling is seen throughout the epithelium attached to the collagen membrane. In the superficial stratified epithelium remnants of nuclei are seen without isotopic labelling. Preparation of living cultures and, after fixation, of histologic sections is technically easy.

Animals↗
PubMed1986

Formation of organoid structures and extracellular matrix production in an intestinal epithelial cell line during long-term in vitro culture.

During the long-term in vitro maintenance of an epithelial cell line established from rat duodenum (IEC-17) we have observed progressive morphological changes which, after approximately 4-5 months in culture, led to a loss of substrate adherence and to the formation of organoid structures characterized by organized layers of cells separated by continuous extracellular-like material and delimiting close lumina. The cells exhibited a defined polarity with deposition of extracellular matrix components on one side and development of microvilli on the opposite surface. The morphological changes observed did not appear to be the expression of spontaneous transformation since the cells retained a normal diploid rat karyotype and did not grow in soft agar. In this report we present the optical and electron microscopical characterization of the progressive organotypic differentiation of the cell line. Further studies are currently in progress to characterize the extracellular matrix during the process of differentiation.

Animals↗
PubMed2026

Base editing rescues a hereditary motor neuron disease in mouse and patient-derived iPSC organoid models.

In hereditary motor neuron diseases (MNDs), including forms of amyotrophic lateral sclerosis (ALS) caused by single-nucleotide variants, effective therapeutic strategies need to address both gain- and loss-of-function mechanisms. Genome editing-based gene therapy represents a promising approach for simultaneously targeting these mechanisms. To establish proof-of-concept for base editing in a hereditary MND, we targeted the P285L variant in the TRK-fused gene (TFG), which causes hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P), a disorder that shares clinical and histopathological features with ALS. We identified the optimal adenine base editor by comparing candidate editors in HMSN-P patient-derived induced pluripotent stem cells (iPSCs). We then generated a transgenic mouse model expressing human TFG P285L and evaluated the selected editor by subpial delivery of adeno-associated virus (AAV) vectors to the spinal cord. AAV-mediated base editing prolonged survival, preserved motor neurons, and attenuated axon loss in ventral nerve roots. Treatment with the selected base editing vector reduced TFG aggregation and suppressed neuronal death in HMSN-P iPSC-derived neuromuscular organoids. Collectively, these findings support the therapeutic potential of base editing for hereditary MNDs.

AAV↗