Generation of 3D lacrimal gland organoids from human pluripotent stem cells

Hayashi, Ryuhei; Okubo, Toru; Kudo, Yuji; Ishikawa, Yuki; Imaizumi, Tsutomu; Suzuki, Kenji; Shibata, Shun; Katayama, Tetsuya; Park, Sung‐Joon; Young, Robert D.; Quantock, Andrew J.; Nishida, Kohji

doi:10.1038/s41586-022-04613-4

Cited by 33 publications

(28 citation statements)

References 43 publications

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“…4c,d). Most recently, a method for the induction of hiPSC-derived lacrimal glands was reported 21 , but PAX6-a master regulator for the lacrimal gland-was not expressed in hiSGs (Fig. 4d).…”

Section: Single-cell Rna-seq Reveals the Cellular Components Of Hisgsmentioning

confidence: 95%

Human induced pluripotent stem cell-derived salivary gland organoids model SARS-CoV-2 infection and replication

et al. 2022

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Salivary glands act as virus reservoirs in various infectious diseases and have been reported to be targeted by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the mechanisms underlying infection and replication in salivary glands are still enigmatic due to the lack of proper in vitro models. Here, we show that human induced salivary glands (hiSGs) generated from human induced pluripotent stem cells can be infected with SARS-CoV-2. The hiSGs exhibit properties similar to those of embryonic salivary glands and are a valuable tool for the functional analysis of genes during development. Orthotopically transplanted hiSGs can be engrafted at a recipient site in mice and show a mature phenotype. In addition, we confirm SARS-CoV-2 infection and replication in hiSGs. SARS-CoV-2 derived from saliva in asymptomatic individuals may participate in the spread of the virus. hiSGs may be a promising model for investigating the role of salivary glands as a virus reservoir.Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and spreads quickly worldwide. The main target organs of SARS-CoV-2 are considered to belong to the respiratory system, including the lungs and upper respiratory tract, but accumulating evidence has shown that multiple organs, such as the heart, kidneys, liver, spleen and gastrointestinal tract, can be affected 1 . SARS-CoV-2-infected individuals are a potential source of virus transmission, which occurs through aerosol droplets, close contact and facial-oral transmission 2 . The majority of infected individuals (approximately 80%) are asymptomatic and have the ability to spread the virus 3 . It was recently reported that saliva from asymptomatic individuals with COVID-19 can be a potential source of viral transmission 4 . SARS-CoV-2 has been identified in the oral mucosa and salivary glands of patients with COVID-19. The viral entry factors

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Section: Single-cell Rna-seq Reveals the Cellular Components Of Hisgsmentioning

confidence: 95%

Human induced pluripotent stem cell-derived salivary gland organoids model SARS-CoV-2 infection and replication

et al. 2022

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“…´laoue ¨t et al, 2021) and PSCs (Hayashi et al, 2022). Tear or lacrimal glands secrete tears to lubricate and protect the eye upon release of neurotransmitters by the parasympathetic nerves.…”

Section: New Players In the Organoid Fieldmentioning

confidence: 99%

“…Excitingly, lacrimal gland organoids were able to develop tear-duct-like structures and produced mature tears upon transplantation into mice. In another recent study, lacrimal organoids were generated from lacrimal gland primordia isolated from 2D eye-like cultures produced from iPSCs (Hayashi et al, 2022). When cultured in 3D, these cells gave rise to lacrimal gland organoids with ducts and acini that were notably similar to in vivo lacrimal glands.…”

Section: New Players In the Organoid Fieldmentioning

confidence: 99%

Human organoids: New strategies and methods for analyzing human development and disease

Corsini¹,

Knoblich²

2022

Cell

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“…Utilization of iPSCs to generate lacrimal gland organoids as a tool for aqueous tear secretion improvement and treatment stands out as a more comprehensive option. Human iPSC derived lacrimal gland organoids have been shown to form branching morphogenesis under well identi ed in vitro culture conditions [30]. In this study, iPSC-derived lacrimal gland organoids' secretion ability was not only assessed cell type related markers but also with lysosomal secretion analysis with forskolin and carbachol stimulation.…”

Section: Conclusion and Future Aspectsmentioning

confidence: 99%

“…So far, human iPSCs have been used to develop organoids of ocular lineage such as cornea, retina, and lens [23][24][25][26][27][28][29]. Recently Hayashi et al demonstrated for the rst-time method to generate lacrimal gland organoids from human iPSCs [30]. Tissue targeted differentiation of iPSCs is achieved through recapitulation of speci c developmental gene expressions, signaling and protein expressions.…”

mentioning

confidence: 99%

Development of lacrimal gland organoids from iPSC derived multizonal ocular cells

Asal

Koçak

Sarı

et al. 2022

Preprint

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Background Lacrimal gland plays a vital role in maintaining the health and function of the ocular surface. Dysfunction of the gland leads to disruption of ocular surface homeostasis and can lead to severe outcomes. Approaches evolving through regenerative medicine have recently gained importance to restore the function of the gland. The aim of this study is to use tissue engineering strategy to develop a functional lacrimal gland from human induced pluripotent stem cells (iPSCs). Methods Using human iPSCs, we generated functional in vitro lacrimal gland organoids by adopting the multi zonal ocular differentiation approach. We differentiated human iPSCs and confirmed commitment to neuro ectodermal lineage, following ocular differentiation. Gene expression and protein levels were measured at several time points up to 45 days for differentiation. Results We identified emergence of mesenchymal and epithelial lacrimal gland progenitor cells by the third week of differentiation. Differentiated progenitors underwent branching morphogenesis in the following weeks, typical of lacrimal gland development. We were able to confirm the presence of lacrimal gland specific acinar, ductal, and myoepithelial cells and structures during weeks 4–7. Further on, we demonstrated the role of miR-205 in regulation of the lacrimal gland organoid development by monitoring miR-205 and FGF10 mRNA levels throughout the differentiation process. In addition, we assessed the functionality of the organoids using the β-Hexosaminidase assay, confirming the secretory function of lacrimal organoids. Finally, metabolomics analysis revealed a shift from amino acid metabolism to lipid metabolism in differentiated organoids. Conclusions These functional, tear proteins secreting human lacrimal gland organoids harbor a great potential for the improvement of existing treatment options of lacrimal gland dysfunction and can serve as a platform to study human lacrimal gland development and morphogenesis.

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Generation of 3D lacrimal gland organoids from human pluripotent stem cells

Cited by 33 publications

References 43 publications

Human induced pluripotent stem cell-derived salivary gland organoids model SARS-CoV-2 infection and replication

Human induced pluripotent stem cell-derived salivary gland organoids model SARS-CoV-2 infection and replication

Human organoids: New strategies and methods for analyzing human development and disease

Development of lacrimal gland organoids from iPSC derived multizonal ocular cells

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