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PubMed2001

Hybrid artificial liver using hepatocyte organoid culture.

We developed 2 types of hybrid artificial liver modules using hepatocyte organoid culture. One was a polyurethane foam (PUF)/hepatocyte spheroid packed-bed module. Hepatocytes spontaneously formed spheroids in the PUF pores, and they maintained liver-specific functions well for at least 2 weeks in vitro. As a preclinical experiment, a hybrid artificial liver with 200 g porcine hepatocytes was applied to a pig (25 kg) with liver failure and showed that the hybrid artificial liver was effective in support of liver functions and stabilization of general conditions. We established a new technique of hepatocyte organoid formation using centrifugal force. A hepatocyte organoid formed by centrifugation in hollow fibers maintained functions for more than 4 months in vitro. We developed a new sinusoid-like structure module having hollow fibers arranged by spacers in a micro-regular arrangement. Inoculated hepatocytes in the extra-fiber space of the module formed the organoid by centrifugation, and they maintained the functions for at least 1 month in vitro. The results indicated that this module seems to be promising as a hybrid artificial liver.

Animals↗
PubMed2025

Understanding proneural-mesenchymal transition using patient-derived glioma stem-like cell (GSC) organoids and engineered extracellular matrix.

Glioblastoma multiforme (GBM) is a highly aggressive, angiogenic WHO grade IV glioma marked by rapid progression, therapeutic resistance, and poor prognosis. A defining feature of GBM is the presence of glioma stem-like cells (GSCs), which reside in specialized perivascular niches and drive tumor progression, recurrence, and therapeutic resistance. The blood-brain barrier, coupled with the complex and dynamic tumor microenvironment, poses significant challenges for both treatment and mechanistic investigation. Current in vitro GBM models inadequately recapitulate the structural and biochemical cues of the native perivascular niche due to the absence of functional vasculature and brain-mimetic extracellular matrix (ECM), limiting their physiological relevance and predictive power. To address the limitations of existing in vitro GBM models, we developed a patient-derived glioma stem cells (GSC) derived Matrigel spheroid system that transitions into organoids and enables integration into engineered microenvironments. Our model incorporates GSC organoids representing proneural and mesenchymal GBM subtypes, a synthetic engineered extracellular matrix (eECM), and endothelial cells (ECs) seeded on the matrix surface. We evaluated the expression of subtype-specific, pro-angiogenic, stemness, and differentiation markers under increasingly complex co-culture conditions. Our results show that Matrigel-derived GSC spheroids progressively differentiate into organoids over two weeks, with significantly enhanced expression of cell-specific markers in the presence of ECs. Encapsulation of these organoids within eECM, combined with EC co-culture, further promoted cellular invasion and induction of GBM associated genes. This in situ encapsulation strategy enables real-time observation of GSC behavior in a tunable microenvironment that mimics key features of the native tumor niche. Together, this platform provides a physiologically relevant and modular in vitro system for investigating GBM pathophysiology. It holds promise for uncovering tumor-specific cellular dependencies, studying GSC-vascular interactions, and conducting high-throughput drug screening under controlled, biomimetic conditions.

Engineered extracellular matrix↗
PubMed2026

Ex Vivo Tumor-Derived Organoid Pharmacotyping Identifies Personalized Therapeutic Options for Patients with Biliary Tract Cancer.

UNLABELLED: Biliary tract cancers (BTC) pose clinical challenges due to poor chemotherapy response and aggressive disease course. We evaluated patient-derived tumor organoid-based drug sensitivity testing as a tool to guide therapy. In this multicenter study, 26 tumor organoids were successfully derived from 43 patients with BTC and tested with an average of 50 cancer-directed therapies using the Clinical Laboratory Improvement Amendments-certified PARIS assay. Despite most organoids being from late-stage disease, 24/26 (92.3%) exhibited strong sensitivity to one or more targeted agents. Active drugs included inhibitors of EGFR/HER2, MEK, ERK, BCR-ABL and SRC family, mTOR, PI3K, MDM2, BCL2, and BET. Drug sensitivities aligned with known genetic biomarkers but were also observed in cultures lacking them, indicating ex vivo testing can expand actionability beyond genomics. In five cases, results guided therapy; one patient with an FGFR-BICC1 fusion refractory to FGFR inhibitors responded to dasatinib, achieving symptomatic improvement, stable disease, and >8-month survival. SIGNIFICANCE: Ex vivo drug testing of tumor-derived organoids is clinically feasible and can be used to identify personalized treatment options for patients with BTC, to evaluate the functional relevance of genomic biomarkers, and to guide treatment in real time.

Humans↗
PubMed2026

Altered ECM deposition and cell adhesion signaling in a human cortical organoid model of fragile X syndrome.

Fragile X Syndrome (FXS) is the most common inherited intellectual disability, and the most common monogenic cause of autism spectrum disorder (ASD). It is caused by epigenetic silencing of the FMR1 gene leading to the loss of FMRP, an RNA-binding protein that regulates local mRNA translation in neuronal dendrites, crucial for synapse development. Three-dimensional (3D) brain organoid models derived through in vitro differentiation of pluripotent stem cells offer a powerful tool to dissect the underlying mechanisms of neurodevelopmental disorders. Here, we generated human FXS and control organoids using isogenic human embryonic stem cell clones with and without the FXS mutation. Our results show that mature FXS cortical brain organoids can be derived by inhibiting the TGFβ and Wnt pathways. Moreover, expression analyses including immunofluorescence, qRT-PCR, proteomics and western blotting reveal altered levels of neuronal markers and ECM deposition along with modulated downstream signaling molecules. Interestingly, in silico analysis of proteomics revealed several altered pathways, such as cell adhesion, regulation of neurogenesis and cell cycle that are implicated in FXS. Collectively, our unique FXS-organoids derived from isogenic hESC lines may serve as a model for studying the pathology of FXS disorder and for developing therapeutical intervention.

Humans↗
PubMed1994

Preservation of functioning human thyroid "organoids" in the severe combined immunodeficient mouse. III. Thyrotropin independence of thyroid follicle formation.

The severe combined immunodeficient (scid) mouse allows the in vivo reconstitution of thyroid follicles from thyroid monolayer cells when transplanted sc within an extracellular basement membrane matrix. After 2-3 weeks, these human thyroid organoids show an active microfollicular histology and secrete human thyroglobulin into the murine serum in response to the administration of recombinant human TSH. Furthermore, such organoids survive for more than 3 months in this functional state. To assess whether thyroid follicular reconstitution was TSH dependent, we examined organoid follicular reconstruction in T3-induced hyperthyroid scid mice, in which endogenous murine TSH was presumed to be totally suppressed. By providing water with 12 micrograms/ml T3, we increased the murine serum T3 levels from a mean of 1.9 nmol/liter in controls to greater than 12.0 nmol/liter. After 3 weeks, thyroid cells derived from normal human thyroid monolayers were suspended in an extracellular basement membrane matrix, and the suspension was transplanted sc into scid mice (with or without T3-induced hyperthyroidism) and allowed to reconstitute. Histological examination 4 weeks later showed a similar degree of thyroid follicle formation in mice treated with or without T3, indicating that the hyperthyroid state had caused no interference with thyroid follicle reconstitution. This was further confirmed by transmission electron microscopy, which demonstrated normal human thyroid follicle cell polarity in the organoids of both euthyroid and hyperthyroid mice. In addition, using an extracellular basement membrane preparation with reduced growth factor (epidermal growth factor, insulin-like growth factor-I, and platelet-derived growth factor) levels also allowed normal thyroid follicle formation in T3-fed mice. These data demonstrate that in vivo thyroid follicle formation is TSH independent and that extrathyroidal epidermal growth factor, insulin-like growth factor-I, and platelet-derived growth factor may be relatively unimportant. The factors and molecular mechanisms leading to follicular reorganization of adult human thyroid cells remain to be determined, but are likely to depend largely on intrathyroidal growth factor secretion and cell-cell interaction.

Animals↗
PubMed1993

Preservation of functioning human thyroid organoids in the scid mouse: 1. System characterization.

We have characterized a system for preserving reconstituted human thyroid follicles in vivo by transplanting human thyrocytes into mice with severe combined immunodeficiency (scid mice). Human thyroid organoids were constructed from thyroid monolayer cells derived from both normal and abnormal thyroid tissue, and embedded within a basement membrane preparation which was then transferred sc to scid mice. As early as 4 weeks, and as late as 3 months post transplantation, histological examination of human thyroid organoids demonstrated widespread neofollicle formation and colloid accumulation which stained positive for human thyroglobulin (hTg). Although there were no changes in murine serum T4 levels; the transplanted thyroid epithelial cells secreted hTg into the scid mouse circulation (with an average level of 29 micrograms/L). In addition, hTg release was stimulated in vivo by ip administration of recombinant human TSH (0.1-1.0 IU/mouse) achieving greater than 20-fold increases in scid mouse serum hTg levels. In situ immunohistochemistry showed that thyroid organoids derived from patients with Graves' disease retained scattered lymphocytes in peripolesis with the thyroid epithelial cells; those lymphocytes were identified as human T cells of the memory (CD45RO +), rather than naive, type. These data demonstrate that functioning human thyroid organoids establish in scid mice and remain responsive to TSH stimulation. The system offers a unique opportunity to examine human thyroid-lymphocyte interaction within the confines of a predictable animal model.

Animals↗
PubMed1993

Preservation of functioning human thyroid organoids in the scid mouse: II. Biased use of intrathyroidal T cell receptor V genes.

The severe combined immunodeficiency (scid) mouse, which lacks functional B cells and T cells, has proven a useful model for exploring the survival of transplanted human lymphocytes and thyrocytes. In order to further characterize T cell infiltrates in reconstituted sc human thyroid organoids, we examined for the presence of 18 human T cell receptor (hTcR) V alpha and 21 hTcR V beta gene families using polymerase chain reaction (PCR) analysis. Human TcR V gene activity was confirmed by Southern blot analysis of the PCR fragments from all but one of the thyroid organoids, confirming the continued survival of human T cells within the thyroid organoids. However, only 3.5 out of 18 V alpha and 5.9 out of 21 V beta gene families were detected in these human thyroid organoids indicating a marked bias in T cell survival. Sequencing of the V-D-J regions of the amplified TcR fragments showed that approximately 60% of the sequences were representative of clonally expanded T cells. Hence, these passenger T cells exhibited highly biased use of particular TcR V gene families similar to that observed previously in thyroid tissue and intrathyroidal T cell cultures. Furthermore, variations in the V-D-J regions of sequences from similar V gene families indicated that the V gene region was important in T cell selection rather than the CD3 region.

Animals↗
PubMed1987

A new colon carcinoma cell line (LIM1863) that grows as organoids with spontaneous differentiation into crypt-like structures in vitro.

A new colon carcinoma cell line (LIM1863) has been characterized. This cell line is unique in that the culture consists of organoids which are morphologically and functionally organized. Histological studies of the organoids show that the cells are arranged around a central lumen and the nuclei are polarized to the periphery. Two major morphological types are present: a columnar cell with a polarized, structurally normal brush border and goblet cells. The cells are also functionally mature and express the brush border enzymes aminopeptidase N, dipeptidyl peptidase IV, alkaline phosphatase, and sucrase-isomaltase. These enzymes are localized to the luminal membrane and the apical cytoplasm (of some cells). The goblet cells contain mucus and this mucus is secreted into the lumen. This functional differentiation suggests that the organoids contain precursor cells capable of differentiating along both the columnar and goblet cell pathways. At present no endocrine cells have been detected by morphological or histochemical analysis. The organoids have been in continuous culture with regular passaging for 21 months and also grow and differentiate normally in serum-free medium.

Aged↗
PubMed1994

Neuroblastoma with a distinct organoid pattern: a clinicopathologic, immunohistochemical, and ultrastructural study.

We studied the organoid pattern in neuroblastoma, defined here as a characteristic histologic feature of the thin fibrovascular meshwork regularly surrounding the individual nests of neuroblastic cells. Among 75 neuroblastomas in our files, 11 cases were qualified as having the recognizable organoid pattern by hematoxylin-eosin stain morphology. The patients comprised five girls and six boys with ages at diagnosis ranging from 1 to 60 months (mean age, 14 months). Nine of the tumors were adrenal and two were retroperitoneal primary. The stages were I (four cases), III (two cases), IV (two cases), and IVS (two cases). All eight patients younger than 1 year are alive and well, whereas two of three patients older than 1 year died of disease. Immunohistochemical staining of those tumors having an organoid pattern showed a considerable number of S-100 protein-positive spindle cells present, mainly in the meshwork areas. Putative Schwann cells were identified ultrastructurally in five of the six tumors examined. In conclusion, organoid pattern in neuroblastoma is easily recognizable, is an indicator of good prognosis in younger children, and may well represent a close relationship between neuroblasts and putative Schwann cells.

Adrenal Gland Neoplasms↗
PubMed1987

Lung organoid culture.

An organoid culture system for lung cells is described in which morphogenesis of lung histotypic structures and differentiation of both pneumocytes type II and mesenchyme occur. The principle of this technique is the culture of mouse fetal lung cells at high density on a membrane filter at the medium/air interface. In the course of cultivation, cell sorting-out, epithelial cell aggregation, formation of an alveolar-like lumen in the organoids and formation of a basal lamina occur. Epithelial differentiation culminates in the production of lamellar bodies, and the mesenchyme develops into mature connective tissue. Morphogenesis and differentiation depend on the stage of fetal development from which the lung cells were derived but appear independent of the formation of a basal lamina. Various drugs have been tested for their effects on morphogenesis and differentiation in this lung organoid culture: some of them inhibit differentiation or damage the mesenchyme, others stimulate surfactant production. Due to the quite complex morphogenetic and cellular events occurring in lung organoid culture, it may be an applicable tool for alternative in vitro screening methods.

Adrenal Cortex Hormones↗
PubMed2025

Individualized patient tumor organoids faithfully preserve human brain tumor ecosystems and predict patient response to therapy.

Tumor organoids are important tools for cancer research, but current models have drawbacks that limit their applications for predicting response to therapy. Here, we developed a fast, efficient, and complex culture system (IPTO, individualized patient tumor organoid) that accurately recapitulates the cellular and molecular pathology of human brain tumors. Patient-derived tumor explants were cultured in induced pluripotent stem cell (iPSC)-derived cerebral organoids, thus enabling culture of a wide range of human tumors in the central nervous system (CNS), including adult, pediatric, and metastatic brain cancers. Histopathological, genomic, epigenomic, and single-cell RNA sequencing (scRNA-seq) analyses demonstrated that the IPTO model recapitulates cellular heterogeneity and molecular features of original tumors. Crucially, we showed that the IPTO model predicts patient-specific drug responses, including resistance mechanisms, in a prospective patient cohort. Collectively, the IPTO model represents a major breakthrough in preclinical modeling of human cancers, which provides a path toward personalized cancer therapy.

Humans↗
PubMed2026

Long-term functional synaptic integration of genome-edited retinal organoids in a primate model of macular degeneration.

Retinal organoids represent a promising regenerative strategy for restoring vision in retinal degenerative diseases, but the capacity of host cone bipolar cells in the primate macula to rewire with transplanted photoreceptors has not been established. In this study, we transplanted genome-edited ISL1-/- human retinal organoids lacking ON-bipolar cells into an acute laser-induced macular photoreceptor ablation non-human primate model. Using immunohistochemistry, ultrastructural imaging, and focal macular electroretinography, we demonstrate that host rod and cone bipolar cells actively extend dendrites toward grafted photoreceptors and form synaptic contacts, with evidence of functional signal transmission in a subset of transplanted eyes. Longitudinal, per-eye analyses revealed that host ON-bipolar responses improved in two of four eyes with ISL1-/- graft by up to 21.6% and remained stable for up to 2 years post transplantation. Moreover, OFF-pathway connectivity showed potential progressive maturation, with delayed increase in d-wave after 13 months in one of those eyes. These findings provide the first demonstration of long-term anatomical host-graft synaptic integration in the primate macula, establishing that central cone bipolar circuits retain the capacity for durable rewiring with human stem-cell-derived grafts. Our results highlight ISL1-/- retinal organoids as a promising approach for central vision restoration in macular degeneration.

Animals↗
PubMed2026

Patient-Derived Organoid Models and Precision HIPEC in Diffuse Malignant Peritoneal Mesothelioma: Modeling Heterogeneity to Address Recurrence.

Diffuse malignant peritoneal mesothelioma (DMPM) is a rare malignancy for which cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is central to treatment in appropriately selected patients. Recurrence remains common even after complete macroscopic cytoreduction. Current HIPEC regimens are protocolized at the institutional and population levels but are not individualized using site-specific molecular or functional tumor biology. We performed a narrative review of clinical, genomic, epigenetic, immune, microenvironmental, and patient-derived organoid evidence relevant to DMPM, CRS/HIPEC, and treatment resistance. Recurrence is multifactorial, with plausible contributions from spatial, histologic, genomic, epigenetic, immune, stromal, and pharmacokinetic heterogeneity. Three primary reports provide direct DMPM organoid evidence, including preliminary demonstrations of patient-specific drug response and discordant responses among anatomically distinct implants. However, these platforms differ biologically, and predictive thresholds, analytical reproducibility, turnaround time, and microenvironmental modeling remain unvalidated. Multi-site organoid pharmacotyping integrated with molecular profiling is therefore a plausible strategy for studying HIPEC resistance. Translation requires a staged pathway encompassing analytical validity, blinded clinical validity, and clinical-utility testing. Precision HIPEC should presently be considered an investigational, validation-ready framework rather than a standard of care.

Humans↗
PubMed1987

Maintenance of normal human breast organoids within rat mammary fat pads in organ culture.

Normal human breast organoids, derived by collagenase digestion of reduction mammaplasty tissue specimens, have been cultured in vitro for up to 28 days after injection into organ cultures of virgin rat mammary fat pads. The culture medium was serum-free Waymouth's MB 752/1 with hormonal additives. The rat mammary tissue responded well to growth-promoting and lactogenic stimuli in the culture medium, in agreement with previous investigations. Using immunohistochemistry casein was identified in rat epithelia exposed to lactogenic medium. Human organoids in culture remained viable but did not show hormone-responsiveness. Electron microscopy confirmed the presence of both luminal epithelial cells and myoepithelial cells. The serum-free culture of normal human breast organoids in a three-dimensional matrix provides a system in which to study factors controlling growth and differentiation.

Adipose Tissue↗
PubMed1992

Mucin histochemistry of pancreatic duct cell carcinoma, with special reference to organoid differentiation simulating gastric pyloric mucosa.

The present study was undertaken to explore mucins produced in normal, metaplastic, and hyperplastic ductal epithelia as well as in carcinoma tissues of the pancreas, and used a battery of histochemical techniques. Thirty-five cases of ordinary pancreatic duct cell carcinoma and nine cases of duct cell carcinoma, which fulfilled the clinical criteria of "mucin-producing carcinoma of the pancreas," were examined. The results indicated that all lesions of mucinous metaplasia with or without papillary hyperplasia as well as atypical hyperplasia characteristically had gastric mucins and showed organoid differentiation simulating the gastric pyloric mucosa, but never stained for 8-O-acetyl-N-acetylneuraminic acid, which is a histochemical marker of the large intestine. Ordinary duct cell carcinoma also contained gastric mucins and small intestinal mucins and showed organoid differentiation, but rarely had 8-O-acetyl-N-acetylneuraminic acid. Mucin-producing carcinomas were classified into two groups: the ordinary duct cell carcinoma group and a group that showed marked atrophy and extensive fibrosis of the parenchyma, a lack of organoid differentiation and gastric mucins, and an abundance of large and small intestinal mucins. These results suggest that gastrointestinal mucins are useful markers to detect cancer-related lesions and cancers of the pancreas.

Adult↗
PubMed2003

Rapid formation of hepatic organoid in collagen sponge by rat small hepatocytes and hepatic nonparenchymal cells.

BACKGROUND/AIMS: Hybrid bioartificial liver devices supporting a large mass of metabolically active hepatocytes are thought to be necessary for the successful treatment of patients with severe acute liver failure. However, it is very difficult to obtain cells with both growth activity and differentiated functions. Rat small hepatocytes (SHs), which are hepatic progenitor cells, can differentiate into mature hepatocytes and reconstruct a hepatic organoid by interacting with hepatic nonparenchymal cells (NPCs). METHODS: Colonies of SHs were collected and replated on a collagen sponge. Hepatic functions were examined by ELISA, immunoblotting, and Northern blotting. Cells in the sponge were characterized by immunocytochemistry and transmission electron microscopy. Urea synthesis was measured and metabolization of fluorescein diacetate was examined. RESULTS: SHs could proliferate and expand to form a hepatic organoid in the sponge. Albumin secretion and other hepatic protein production of the cells in the sponge increased with time in culture and the amounts were much larger than for those obtained from cells grown on dishes. Morphologically and functionally differentiated hepatocytes were observed and some CK19-positive cells formed duct-like structures within the sponge. Excretion of fluorescein was observed in bile canaliculi. CONCLUSIONS: Hepatic organoids can be rapidly reconstructed in a collagen sponge by rat SHs and NPCs.

Animals↗
PubMed1999

Regenerative signals for intestinal epithelial organoid units transplanted on biodegradable polymer scaffolds for tissue engineering of small intestine.

BACKGROUND: Our laboratory is investigating the tissue engineering of small intestine using intestinal epithelial organoid units seeded onto highly porous biodegradable polymer tubes. This study investigated methods of stimulation for optimizing neointestinal regeneration. METHODS: Intestinal epithelial organoid units harvested from neonatal Lewis rats were seeded onto porous biodegradable polymer tubes and implanted into the omentum of adult Lewis rats in the following groups: (1) the control group (group C), implantation alone (n=9); (2) the small bowel resection (SBr) group, after 75% SBr (n=9); (3) the portacaval shunt (PCS) group, after PCS (n=8); and (4) the partial hepatectomy (PH) group, after 75% PH (n=8). Neointestinal cyst size was recorded using ultrasonography. Constructs were harvested at 10 weeks and were examined using histology. Morphometric analysis of the neomucosa was obtained using a computer image analysis program (NIH Image, version 1.59). RESULTS: Cyst development was noted in all animals. Cyst lengths and diameters were significantly larger in the SBr group at 7 and 10 weeks compared with the other three groups (P<0.05; analysis of variance [ANOVA], Fisher's protected least significant difference). Histology revealed a well-vascularized tissue with a neomucosa lining the lumen with invaginations resembling crypt-villus structures. Morphometric analysis demonstrated a significantly greater villus number, height, area, and mucosal surface in the SBr group compared with the other three groups and a significantly greater crypt number and area in the PCS group compared with group C (P<0.05; ANOVA, Fisher's protected least significant difference). CONCLUSIONS: Intestinal epithelial organoid units transplanted on porous biodegradable polymer tubes can successfully vascularize, survive, and regenerate into complex tissue resembling small intestine. SBr and, to a lesser extent, PCS provide significant regenerative stimuli for the morphogenesis and differentiation of tissue-engineered small intestine.

Animals↗
PubMed1991

'Organoid' thymoma: a well-differentiated variant with distinctive clinicopathological features.

The present paper describes the clinical, histological and immunohistochemical features of five cases of 'organoid' thymoma. The histological hallmark of this lesion is the prominent and diffuse 'organoid' pattern, defined by the presence of several areas of medullary differentiation. These areas, which are strictly reminiscent of the medullary area of the normal thymus, are scattered within a neoplastic tissue resembling the thymus cortex, the overall appearance mimicking that of normal thymus. All cases shared common clinical features; they were non-invasive or minimally invasive tumours arising in young or middle-aged female patients. Although the incidence of 'organoid' thymoma is low (5.2% in our series), our morphological, immunohistochemical and clinical data suggest that this peculiar tumour may represent a well-differentiated variant of thymoma, with low-grade aggressiveness and a distinct clinicopathological profile.

Adult↗