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PubMed2006

Optical tissue window: a novel model for optimizing engraftment of intestinal stem cell organoids.

BACKGROUND: Intestinal malabsorption disorders and short bowel syndrome lead to significant morbidity. We recently demonstrated that grafting of intestinal organoids can grow a bioengineered intestinal neomucosa and cure bile acid malabsorption in rats. Now we have developed a novel system that permits direct observation of intestinal organoids in vivo to optimize conditions for engraftment. METHODS: Optical Windows were created in C57BL/6J mice by externalizing an omental pedicle into a dorsal skin flap chamber. Following creation of windows, 5000 intestinal organoids from green-fluorescent protein transgene (GFP)+ donor mice were seeded directly either on omentum or on polyglycolic acid (PGA) disks that had been placed on omentum at 1 or 5 days. Engraftment of green fluorescent cells was evaluated on postseeding days 1, 3, 5, 7, 10, 12, and 21 using fluorescence microscopy. RESULTS: An initial group had seeding onto omentum (n = 5) or biopolymer disks (n = 5) on postoperative day 1. After 7 days, there was mucosal cell engraftment onto omental tissue and biopolymers. GFP+ organoids engrafted significantly better when seeded onto biopolymers compared to omentum (P < 0.05). In a second study with increased sample size (n = 24) up to day 12, all four groups demonstrated adherence and growth. However, GFP+ organoids seeded onto delayed PGA biopolymer demonstrated significantly better engraftment (P < 0.05). CONCLUSIONS: This novel system allows continuous in vivo observation of engrafted cells that are seeded on externalized omentum. The use of PGA mesh biopolymer may improve engraftment of intestinal organoids.

Animals↗

PubMed2026

HIF-1 signaling contributes to lenvatinib resistance in patient-derived HCC organoids.

Resistance to lenvatinib remains an important limitation in hepatocellular carcinoma treatment. Six patient-derived organoid lines were established and classified as sensitive or resistant according to ex vivo drug responses, retaining histological and immunophenotypic features of matched parental tumors. Resistant organoids showed unchanged ATP activity, whereas sensitive ones exhibited pronounced morphological changes and reduced ATP activity at higher concentrations. Transcriptome sequencing identified 408 upregulated and 269 downregulated genes in resistant versus sensitive organoids, with HIF-1 signaling among altered pathways. In resistant organoids, lenvatinib increased HIF-1α, ANGPT2, and HK3 mRNA, whereas comparable changes were not detected in sensitive organoids. KC7F2 reduced these transcripts and further decreased ATP activity when combined with lenvatinib. In organoid-derived xenografts, this combination suppressed tumor growth and HIF-1 target expression more than lenvatinib alone, indicating HIF-1 signaling contributes to the resistant phenotype and its inhibition may enhance response.

Drug resistance↗

PubMed2025

Splice modulation of COL4A5 reinstates collagen IV assembly in an organoid model of Alport syndrome.

Kidney organoids are an emerging tool for disease modeling, especially genetic diseases. Among these diseases, X-linked Alport syndrome (XLAS) is a hematuric nephropathy affecting the glomerular basement membrane (GBM) secondary to pathogenic variations in the COL4A5 gene encoding the α5 subunit of type IV collagen [α5(IV)]. In patients carrying pathogenic variations affecting splicing, the use of antisense oligonucleotides (ASOs) offers immense therapeutic hope. In this study, we develop a framework combining the use of patient-derived cells and kidney organoids to provide evidence of the therapeutic efficacy of ASOs in XLAS patients. Using multiomics analysis, we describe the development of GBM in WT and mutated human kidney organoids. We show that GBM maturation is a dynamic process, which requires long organoid culture. Then, using semi-automated quantification of α5(IV) at basement membranes in organoids carrying the splicing variants identified in patients, we demonstrate the efficacy of ASO treatment for α5(IV) restoration. These data contribute to our understanding of the development of GBM in kidney organoids and pave the way for a therapeutic screening platform for patients.

Nephritis, Hereditary↗

PubMed2026

Advances in organoids for personalized medicine: from technological development to clinical application.

Organoids, three-dimensional cell culture models derived from patient tissues or stem cells, have emerged as a cutting-edge technology in personalized medicine, owing to their remarkable ability to closely recapitulate in vivo tissue architecture and function. This review provides a comprehensive overview of the technological evolution and construction methodologies of organoids, highlighting their significant applications in oncology, genetic disorders, infectious diseases, and drug screening. This review examines how organoids enable precision medicine by preserving genomic fidelity, predicting drug sensitivity, and creating disease models via gene editing. Despite these advances, organoid technology faces several technical challenges that impede its full clinical translation. Addressing these obstacles is critical for realizing the potential of organoids in individualized therapeutic strategies. This article aims to delineate current progress and future directions in organoid research, furnishing a theoretical foundation and guiding future investigations towards enhancing personalized treatment paradigms.

disease modeling↗

PubMed2025

Stem cell derived neural organoid approaches for neurological diseases.

Traditional two-dimensional cultures and animal models often fall short in capturing the complexities of neurodevelopmental and neurodegenerative diseases. However, recently developed neural organoid approaches, three-dimensional structures derived from human pluripotent stem cells, have become powerful tools for modeling human neuronal development and disease. Unlike traditional models, neural organoids provide significant insights and improved modeling capabilities. Here, we explore various types of neural organoids in disease modeling and outline distinct protocols for generating each type, including specific patterning methods, growth factors, and differentiation durations. The potential and advantages of co-culturing neural organoids with other cells and tissues are also discussed. While neural organoids have already made significant contributions to neuroscience research, future directions should focus on enhancing their maturation and functionality. The progression of neural organoids approaches will generate more accurate and comprehensive disease models, ultimately adding to our understanding of disease pathogenesis and paving the way for future precision therapies for neurological diseases.

neural differentiation↗

PubMedDate not supplied

Histologic appearance of the islet organoid.

The authors have attempted to develop a hybrid organoid capable of supporting the engraftment of human pancreatic islet tissue transplants. In this report, they we report the histologic appearance of this organoid structure for implantation periods up to 16 days. Both pancreatic duct-like and glandular cells were present inside the organoid. Insulin positive cells were identified within the pancreatic tissue. Although polymorphonuclear (PMN) cells were seen in association with tissue necrosis, the authors observed no lymphocyte infiltration in the area of the xenografted human pancreatic islet tissue in the implanted organoid. Endothelial cell growth factor induced neovascularization inside the organoid sufficient to support the engraftment of transplanted pancreatic islet tissue. This organoid model may provide an alternative for clinical pancreatic transplantation.

Animals↗

PubMed2025

Incubator-Free Organoid Culture in a Sealed Recirculatory System.

Organoids are powerful tools for studying development and disease, offering realistic organ-like human and animal tissues and facilitating experimental observation compared to live animal models. However, traditional organoid culture methods require a humidified incubator. This requirement complicates culture due to evaporative losses and restricted access to instrumentation, hindering the potential of organoids as physiologically accurate models easily subjected to detailed experimental observation. We introduce a compact, automated, sealed, incubator-free recirculatory organoid culture platform that replaces the air-liquid interface with a nonporous polymer gas exchanger and a liquid-phase gas buffer. This design prevents evaporation and stabilizes oxygen, pH, and osmolarity without feedback control. It enables single-actuator media exchange, simplifying automation. Dispensing with the incubator, we improve access for instruments such as live cell microscopes. We demonstrate compatibility with continuous multi-week live imaging of vascular organoids and show that brain organoids in this system maintain metabolic viability, structural fidelity, and electrophysiological activity comparable to traditional shaker-based cultures in an incubator.

Journal Article↗

PubMed2006

Orthotopic transplantation of intestinal mucosal organoids in rodents.

BACKGROUND: Orthotopic transplantation of intestinal mucosal organoids that contain putative mucosal stem cells serves as an important step toward implementing intestinal gene therapy and treatment for malabsorption syndromes in animals and humans. We hypothesized that intestinal mucosal organoids can be transplanted along the axis of the small bowel giving rise to a neomucosa expressing proteins of its donor origin. METHODS: Epithelial organoids were harvested from neonatal mice or rat small intestine with the use of a combination of enzymatic digestion with dispase and collagenase, and gravity sedimentation. In adult syngeneic recipients, a 7-cm segment of midjejunum was isolated, leaving its vascular pedicle intact. The remaining proximal and distal segments were anastomosed to restore intestinal continuity. The isolated segments were randomly subjected to surgical or chemical mucosectomy with a chelator solution for 30, 45, or 60 minutes and then compared. Histologic examination was used to confirm the presence of enterocytes, goblet cells, enteroendocrine cells, and Paneth cells in the neomucosal segments. To confirm the presence of ileal bile acid transporter (IBAT) gene message and function, we measured sodium-dependent bile acid uptake and IBAT-messenger RNA. Immunohistochemical examination using anti-IBAT antibodies was performed to demonstrate the expression of IBAT in the neomucosal segments. Experiments were repeated in a murine model transgenic for the green fluorescent protein to verify donor origin of the engrafted mucosa expressing IBAT. RESULTS: The area of peak IBAT function was found to be located in the terminal ileum. Organoid units harvested from this region were capable of generating a small-bowel neoileal mucosa after being seeded into the jejunum. This mucosa was histologically confirmed to differentiate into all 4 intestinal lineages and to express IBAT signal, confirming its donor-derived origin. Optimal engraftment of mucosa expressing the IBAT protein was found in isolated jejunal segments debrided for 45 minutes. Sodium-dependent bile acid uptake was 5-fold higher in the neoileum, compared with the jejunum. IBAT-mRNA levels in the neoileum were 18-100-fold higher than those in the jejunum. Areas of green fluorescent protein-positive mucosa stained positively with anti-IBAT antibody in adjacent sections, suggesting that the regenerated mucosa is from transplanted ileal stem cells. CONCLUSIONS: Orthotopic transplantation of epithelial organoids containing ileal stem cells was used to generate a neoileal mucosa that expressed all 4 intestinal lineages along with a new zone of active bile acid uptake and IBAT expression in a recipient jejunal segment.

Animals↗

PubMed2026

Modeling reptile virus infection in vitro using Python regius airway organoids.

Zoonoses pose substantial global health risks, highlighting the need to better understand animal-to-human transmission. Reptiles are increasingly recognized as hosts of diverse pathogens, including numerous viruses, yet the diversity and prevalence of reptile pathogens, as well as their potential risk to humans, remain poorly understood. Here, we establish and characterize airway organoids derived from Python regius, providing an in vitro model to study reptile airway infection. Through de novo assembly of a Python regius reference genome, we characterize airway organoids at single-cell resolution, which suggests the presence of diverse cell populations including ionocytes, ciliated, secretory, goblet, endocrine, tuft, and basal cells. The organoids support productive infection with Ball Python Nidovirus (BPNV) and mount a robust epithelial antiviral response through the induction of interferon-stimulated genes, cytokines, and genes involved in chemical defense. As a proof-of-concept, treating organoids with antiviral drugs during infection reduces BPNV levels, highlighting the model's utility for drug testing. By providing a reductionist system of the serpentes airway, these organoids constitute a physiologically relevant in vitro model to study reptile viruses and host-pathogen interactions in their native host.

Animals↗

PubMedDate not supplied

Extracellular matrix induces formation of organoids and changes in cell surface morphology in cultured human breast carcinoma cells PMC42-LA.

In the lactating breast, the development of secretory alveoli consisting of differentiated cells arranged around a central lumen is dependent on signals from the extracellular environment of the cells. There are few cell lines that model this process. We previously showed that the human breast carcinoma line PMC42-LA can be induced to form organoids, reminiscent of secretory alveoli found in the lactating human breast. In this report, we used high-resolution scanning electron microscopy to show that the formation of organoids is accompanied by development of cell surface microvilli. Extracellular matrix-induced formation of microvilli occurred on the internal and external surfaces of cells in the organoids and not on surfaces in contact with the extracellular matrix. Organoid formation of PMC42-LA cells induced a rearrangement of the extracellular matrix, seen in the form of radiating fibers from the organoids. In summary, there is an interaction between PMC42-LA cells and the underlying extracellular matrix, which leads to the formation of polarized cells with well-developed microvilli. This is accompanied by organization of the extracellular matrix. PMC42-LA is a relevant model of the human breast for investigations into cell-cell and cell-matrix interactions.

Breast Neoplasms↗

PubMed1984

Epithelial organoids and mononuclear phagocytes from DMBA-induced mammary tumors of the rat secrete collagenase in vitro.

The production of collagenase has been examined in primary cultures of multicellular epithelial organoids and of stromal cells isolated from DMBA-induced mammary tumors of the rat. Plastic culture dishes and dishes coated with collagen fibrils were used to study the effect of such a substrate on collagenase release. Cultures of 51-micron epithelial organoids consisted of cuboidal cells and a myoepithelial-like cell type which formed a continuous layer under the cuboidal cells. A transient low production of collagenase with an apparent molecular weight (MW) of 72 kD was detected on both substrates. Upon separation by trypsin only cuboidal cells released collagenase. Cultures of 27-micron organoids contained only few myoepithelial-like cells. On plastic, they formed dense monolayers of cuboidal cells and released more collagenase than the greater aggregates. On collagen fibrils, these organoids formed cords and ridges and collagenase production was about 4- to 6-fold higher. These results indicate that collagenase release is influenced by the nature of the interaction of cuboidal cells with the substrate on which they grow. Similar organoids prepared from virgin mammary glands failed to secrete collagenase on either substrate. Primary cultures of stromal cells derived from tumor tissues comprised one basic cell type that expressed a series of properties characteristic for monocytes/macrophages. These cultures were capable of producing collagenase with an apparent MW of 56 kD. Collagenase with a similar size was detected in the extracts of 51 from 65 mammary tumors.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1996

Ophthalmic features of the organoid nevus syndrome.

BACKGROUND/PURPOSE: The organoid nevus (sebaceous nevus) syndrome is characterized primarily by cutaneous sebaceous nevus, seizures, and epibulbar choristomas. On the basis of ophthalmoscopic and computed tomographic studies, a yellow fundus lesion recently observed in this syndrome has been called a coloboma by some investigators and a choroidal osteoma by others. This study was undertaken to review our personal experience with the organoid nevus syndrome, to review the English language literature on the subject, and to address some misconceptions regarding its ocular manifestations. METHODS: We reviewed the records of patients with the organoid nevus syndrome who were personally evaluated by the investigators. The ocular findings were studied in more detail, with emphasis on the epibulbar and fundus lesions. RESULTS: We identified five patients with the organoid nevus syndrome. Four had a classic sebaceous nevus in the facial and scalp area, and 2 had seizures and arachnoid cysts. All 5 patients had an epibulbar tumor, which proved to be a complex choristoma in one case that was studied histopathologically. A characteristic ophthalmoscopic feature, observed in the 4 patients with clear ocular media, was a flat yellow discoloration of the posterior fundus, of variable size and shape, which appeared to correlate with a dense plaque noted on ultrasonography and computed tomography. In 1 case, histopathologic examination showed that this posterior lesion contained intrascleral cartilage. CONCLUSIONS: Our observations and a review of the literature indicated that the organoid nevus syndrome has varied manifestations. Like the closely related phakomatoses, it often occurs as a forme fruste, without full expression of the syndrome. The most important ocular manifestations are an epibulbar mass, compatible with a complex choristoma, and focal yellow discoloration in the fundus, probably related to intrascleral cartilage.

Adolescent↗

PubMed1997

Ocular manifestations of the organoid nevus syndrome.

BACKGROUND: The organoid nevus (sebaceous nevus) syndrome is characterized primarily by cutaneous sebaceous nevus, seizures, and epibulbar choristomas. Based on ophthalmoscopy and computed tomography (CT), a yellow fundus lesion recently observed in this syndrome has been called a coloboma by some authors or a choroidal osteoma by others. This study was undertaken to review the authors' personal experience with the organoid nevus syndrome, to review the English language literature on the subject, and to address some misconceptions regarding its ocular manifestations. METHODS: The authors reviewed the records of patients with the organoid nevus syndrome who were personally evaluated by the authors. The ocular findings were studied in more detail, with emphasis on the epibulbar and fundus lesions. RESULTS: The authors identified five patients with the organoid nevus syndrome. Four had a classic sebaceous nevus in the facial and scalp area and two had seizures and arachnoid cysts. All five patients had an epibulbar tumor, which proved to be a complex choristoma in one case that was studied histopathologically. A characteristic ophthalmoscopic feature, observed in the four patients with clear ocular media, was a flat, yellow discoloration of the posterior fundus, of variable size and shape, that appeared to correlate with a dense plaque noted on ultrasonography and CT. In one case, histopathologic studies showed that this posterior lesion contained intrascleral cartilage. CONCLUSIONS: The authors' observations and a review of the literature indicated that the organoid nevus syndrome has varied manifestations. Just like the closely related phakomatoses, it often occurs as a forme fruste, without full expression of the syndrome. The most important ocular manifestations are an epibulbar mass, compatible with a complex choristoma, and focal, yellow discoloration in the fundus, probably related to intrascleral cartilage.

Adolescent↗

PubMed1995

Effect of TGF-beta on differentiated organoids of the colon carcinoma cell line LIM 1863.

The LIM 1863 colon carcinoma cell line grows in suspension as morphologically and functionally organized organoids in serum-containing medium. Addition of TGF-beta caused the organoids to adhere and inhibited DNA synthesis. A 20 min incubation with TGF-beta was sufficient to induce adherence and this could be inhibited by cycloheximide. The adhesion and DNA synthesis inhibition were demonstrated to be separate events. We were not able to detect any changes in matrix or cell membrane antigens. Similarly there were no changes in synthesized proteins (by two-dimensional gel electrophoresis), and no upregulation of proteoglycan. When adhered organoids were lysed from the tissue culture plastic surface, untreated organoids adhered to this surface. This 'conditioned' surface was destroyed by trypsin but not collagenase or medium from normal LIM 1863 cultures. However, the adherent phenotype was prevented when organoids were treated with transforming growth factor-beta (TGF-beta) in the presence of medium conditioned by normal LIM 1863 cultures rather than in fresh medium. The adhesion process was inhibited by an antibody (QE2E5) against beta 1 integrin although no quantitative changes in integrins were observed (by immunoprecipitation or RNA analysis). A second anti-beta 1 integrin antibody (61.2C4) inhibited LIM 1863 adhesion to collagen but not TGF-beta induced adhesion, implying that TGF-beta induced a specific conformational change or interaction of a beta 1 integrin. In this morphologically structured system TGF-beta induced a number of subtle effects including formation of new extracellular matrix and conformational change of a beta 1 integrin, rather than the major quantitative changes in cell/matrix molecules reported previously.

Carcinoma↗

PubMed1998

Proliferation and differentiation of organoid hair follicle cells co-cultured with fat cells in collagen gel matrix culture.

Using rat skin, we studied the influence of fat cells on the proliferation and differentiation of organoid hair follicle cells in a three-dimensional collagen gel matrix culture system. We cultured organoid hair follicles embedded in collagen gel under each of the following three conditions: cell-free collagen gel for control experiments (condition 1); co-culture with fat cells in close apposition (condition 2); and co-culture with fat cells in spatial separation (condition 3). Outgrowths of epithelial cells from the organoid hair follicles associated with perifollicular proliferation of fibroblasts were observed under conditions 1 and 3. Under condition 2, proliferation of both organoid hair follicle cells and fibroblasts was inhibited, but differentiation of the hair follicle cells appeared to be accelerated. Fat cells are considered to have an inhibitory effect on the proliferation of perifollicular fibroblasts, which might have resulted in the inhibition of hair follicle cell proliferation and also in the better maintenance of normal follicular structure and integrity, allowing for hair-type differentiation to proceed. A direct accelerating effect of fat cells on hair follicle differentiation may also have been responsible. In a physiological state (co-culture with keratinocytes on the collagen gel), similar results were observed under conditions 1 and 2. The different findings under conditions 2 and 3 may be due to either of two possibilities: either the concentration gradient of the soluble factors released from fat cells, acting on either the hair follicle cells or the perifollicular fibroblasts as an inhibitor of proliferation, caused the difference in the results, or direct contact between the organoid hair follicle cells and fat cells may have influenced the accelerating effect of fat cells on the differentiation of hair follicle cells.

Adipocytes↗

PubMed2002

Hepatocytes undergo phenotypic transformation to biliary epithelium in organoid cultures.

Organoid cultures of hepatocytes in the presence of hepatocyte growth factor (HGF) and epidermal growth factor (EGF) display characteristic histologic organization. Biliary epithelium covers the surface of the tissue exposed to the culture medium. Hepatocytes, stellate cells and endothelial cells compose the underlying structures. In order to investigate the origin of the biliary epithelial cells in the organoid cultures, we utilized the retrorsine/DPPIV system of hepatocyte transplantation to create hybrid livers in which clones of DPPIV hepatocytes colonize variable portions of the lobules. We demonstrate that, as others have shown, biliary epithelium in this in vivo system remains that of the recipient (DPPIV negative) rat. Hepatocytes are the only cells positive for the DPPIV marker enzyme in the hybrid livers. Organoid cultures were prepared from the hybrid livers. Overall, 46.82% of the hepatocytes placed into culture were positive for DPPIV at time zero (after isolation). At 21 days in culture, 47.54% of the biliary epithelium on the surface of the organoid cultures was positive for DPPIV. Since the only DPPIV cells inoculated in the cultures were hepatocytes, this finding demonstrates that, in the conditions of the organoid cultures, hepatocytes do undergo phenotypic transition to biliary epithelial cells.

Animals↗

PubMed2025

A pancreatic cancer organoid biobank links multi-omics signatures to therapeutic response and clinical evaluation of statin combination therapy.

Chemotherapy remains the primary treatment for pancreatic ductal adenocarcinoma (PDAC), but most patients ultimately develop resistance. Here, we established 260 pancreatic cancer organoid lines, followed by extensive multi-omics profiling and therapeutic sensitivity assessments. Integrated analyses uncovered 6 novel coding and 35 noncoding driver candidates. We discovered 2,794 multi-omics features associated with drug sensitivity and 322 features linked to radiation sensitivity. Pharmacogenomic analyses revealed that chemoresistant organoids exhibited enrichment in protein glycosylation and cholesterol metabolism pathways. Notably, statins effectively targeted chemoresistant PDAC organoids. Statin treatment attenuated protein glycosylation, cholesterol levels, and the epithelial-to-mesenchymal transition (EMT) signature in PDAC organoids. We conducted a single-center, single-arm, phase 2 clinical trial (NCT06241352) combining atorvastatin with chemotherapy in patients with advanced pancreatic cancer. Among 37 patients, 26 (70.3%) demonstrated a response, with tumor markers decreasing by more than 20%, suggesting durable responses and potential clinical benefits in this challenging patient population.

Humans↗

PubMed2004

Generation of a synthetic lymphoid tissue-like organoid in mice.

Stromal cells play an important role in the formation of the normal organized microarchitecture of secondary lymphoid organs. Here we demonstrate that a tissue-engineered, lymphoid tissue-like organoid, which was constructed by transplantation of stromal cells embedded in biocompatible scaffolds into the renal subcapsular space in mice, had an organized tissue structure similar to secondary lymphoid organs. This organoid contained compartmentalized B-cell and T-cell clusters, high endothelial venule-like vessels, germinal centers and follicular dendritic cell networks. Furthermore, the organoid was transplantable to naive normal or severe combined immunodeficiency (SCID) mice, and antigen-specific, IgG-isotype antibody formation could be induced soon after intravenous administration of the antigen. This simplified system of lymphoid tissue-like organoid construction will facilitate analyses of cell-cell interactions required for development of secondary lymphoid organs and efficient induction of adaptive immune responses, and may have possible applications in the treatment of immune deficiency.

Animals↗