Patient-derived organoids from endometrial disease capture clinical heterogeneity and are amenable to drug screening

Boretto, Matteo; Maenhoudt, Nina; Luo, Xinlong; Hennes, Aurélie; Boeckx, Bram; Bui, Bich Ngoc; Heremans, Ruben; Perneel, Lisa; Kobayashi, Hiroto; Zundert, Indra Van; Brems, Hilde; Cox, Benoit; Ferrante, Marc; Uji‐i, Hiroshi; Koh, Kian Peng; D’Hooghe, Thomas; Vanhie, Arne; Vergote, Ignace; Meuleman, Christel; Tomassetti, Carla; Lambrechts, Diether; Vriens, Joris; Timmerman, Dirk; Vankelecom, Hugo

doi:10.1038/s41556-019-0360-z

Cited by 297 publications

(342 citation statements)

References 52 publications

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“…More recently, Boretto et al derived organoids from patients with low-to high grade endometrial cancers. Interestingly, these organoids capture accurately cancer subtypes, recapitulate disease phenotype and display patientspecific drug responses (Boretto et al, 2019). Patient-derived endometrial organoids can also be exploited for modeling endometriosis, a disease that affects between 10 and 15% of all women of reproductive age and 70% of women with chronic pelvic pain (Giudice and Kao, 2004;Vercellini et al, 2013).…”

Section: Advantages and Applications Of Endometrial Organoidsmentioning

confidence: 99%

Organoid Models of Human Endometrial Development and Disease

Hibaoui

Féki

2020

Front. Cell Dev. Biol.

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Section: Advantages and Applications Of Endometrial Organoidsmentioning

confidence: 99%

Organoid Models of Human Endometrial Development and Disease

Hibaoui

Féki

2020

Front. Cell Dev. Biol.

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“…Another report used 100 ng/ml WNT3A and 600 ng/ml RSPO1 in the organoid culture [26]. In another study, a 10% homemade RSPO1 conditioned medium and 200 ng/ml WNT3A was used [27]. In our study, we used a less amount of WNT3A and RSPO1 (50 ng/ml each).…”

Section: Discussionmentioning

confidence: 78%

Human fallopian tube epithelial cells exhibit stemness features, self-renewal capacity, and Wnt-related organoid formation

2020

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Background: Fallopian tube epithelial cells (FTEC) were thought to be the origin of high-grade serous ovarian carcinoma (HGSOC). Knowledge of the stemness or initiating characteristics of FTEC is insufficient. Previously, we have characterized the stemness cell marker of FTEC, this study aims to further characterize the clonogenicity and spheroid features of FTEC. Methods: We successfully derived FTECs from the epithelial layer of the human fallopian tubes. We examined the morphology, proliferation rate, doubling time, and clonal growth of them. At passage 3, the sphere formations on gelatin-coated culture, suspension culture, and matrigel culture were observed, and the expression of LGR5, SSEA3, SSEA4, and other stemness markers was examined. Furthermore, tissue-reconstituted organoids from coculture of FTEC, fallopian stromal cells (FTMSC) and endothelial cells (HUVEC) were examined.Results: FTEC exhibited cuboidal cell morphology and maintained at a constant proliferation rate for up to nine passages (P9). FTEC could proliferate from a single cell with a clonogenic efficiency of 4%. Flow cytometry revealed expressions of normal stem cell markers (SSEA3, SSEA4, and LGR5) and cancer stem cell markers (CD24, CD44, CD117, ROR1, and CD133). FTEC formed spheres and colonies when cultured on low attach dish. In the presence of Matrigel, the stemness and colony formation activity were much enhanced. In co-culturing with FTMSC and HUVEC, FTEC could form organoids that could be blocked by Wnt inhibitor DKK1. Expressions of LGR5 and FOXJ1 expression were also decreased by adding DKK1. Conclusion: We demonstrated abundantly presence of stem cells in human FTECs which are efficient in forming colonies, spheres and organoids, relying on Wnt signaling. We also reported for the first time the generation of organoid from reconstitutied cell lineages in the tissue. This may provide a new model for studying the regneration and malignant transformation of the tubal epithelium.

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“…In addition, when (glandular) endometrial organoids were stimulated with pregnancy-associated hormones (chorionic gonadotropin, placental lactogen, prolactin), they started producing components such as progestagen-associated endometrial protein (PAEP), of the so-called "uterine milk", characteristic of gestational endometrium [146]. Endometrial organoids have already been isolated from patients with a broad spectrum of endometrial pathologies, such as endometriosis, endometrial hyperplasia, Lynch syndrome, and endometrial highand low-grade cancer, and used as a disease model for drug discovery and better understanding of the pathologies [146,147].…”

Section: Stem Cells For Human Placental Development and Organoidsmentioning

confidence: 99%

The TGFβ Family in Human Placental Development at the Fetal-Maternal Interface

2020

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Emerging data suggest that a trophoblast stem cell (TSC) population exists in the early human placenta. However, in vitro stem cell culture models are still in development and it remains under debate how well they reflect primary trophoblast (TB) cells. The absence of robust protocols to generate TSCs from humans has resulted in limited knowledge of the molecular mechanisms that regulate human placental development and TB lineage specification when compared to other human embryonic stem cells (hESCs). As placentation in mouse and human differ considerably, it is only with the development of human-based disease models using TSCs that we will be able to understand the various diseases caused by abnormal placentation in humans, such as preeclampsia. In this review, we summarize the knowledge on normal human placental development, the placental disease preeclampsia, and current stem cell model systems used to mimic TB differentiation. A special focus is given to the transforming growth factor-beta (TGFβ) family as it has been shown that the TGFβ family has an important role in human placental development and disease.

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Patient-derived organoids from endometrial disease capture clinical heterogeneity and are amenable to drug screening

Cited by 297 publications

References 52 publications

Organoid Models of Human Endometrial Development and Disease

Organoid Models of Human Endometrial Development and Disease

Human fallopian tube epithelial cells exhibit stemness features, self-renewal capacity, and Wnt-related organoid formation

The TGFβ Family in Human Placental Development at the Fetal-Maternal Interface

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