The Hippo signaling pathway effector YAP promotes salivary gland regeneration after injury

Rocchi, Cecilia; Cinat, Davide; Martinez, Paola Serrano; Bruin, Anne L. Jellema-de; Baanstra, Mirjam; Brouwer, Uilke; Zuivre, Cinthya Del Angel; Schepers, Hein; Os, Ronald van; Barazzuol, Lara; Coppes, Robert P.

doi:10.1126/scisignal.abk0599

Cited by 8 publications

(7 citation statements)

References 44 publications

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“…Following the collection of submandibular salivary glands, tissue isolation was performed as previously described 56 . In summary, after mechanic and enzymatic digestion, cells were cultured in DMEM/F12 complemented with penicillin-streptomycin (Pen/Strep) antibiotics, glutamax (2 mM), EGF (20 ng/ml); FGF2 (20 ng/ml), N2 (1x), insulin (10 µg/ml) and dexamethasone (1 uM).…”

Section: Organoid Culture and Self-renewal Assaymentioning

confidence: 99%

Derepression of transposable elements enhances interferon beta signaling and stem/progenitor cell activity after proton irradiation

Cinat,

van der Wal,

Baanstra

et al. 2024

Preprint

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The release and subsequent detection of nucleic acids into the cytoplasm constitute a hallmark of the radiation-induced DNA damage response. However, different radiation types, such as photons and protons, may elicit distinct DNA damage responses, uniquely influencing normal stem cell activity and tissue regeneration. Here, we show that proton irradiation leads to enhanced derepression of transposable elements (TEs) with consequent activation of salivary gland stem/progenitor cells. This response is mediated by a pronounced loss of heterochromatin regulators and accumulation of cytoplasmic TE-derived dsRNA, resulting in upregulation of RIG-I and augmented interferon-beta (IFN-β) signaling. Single cell RNA sequencing (scRNA-seq) and TE dynamics analyses corroborate these findings, specifically in a subpopulation of Sox9-expressing stem/progenitor cells with increased INF-β response. These data reveal that the presence of TE-derived IFN-β in the microenvironment of irradiated organoids increases stem/progenitor cell activity and organoid growth, pointing to advantages of proton therapy over photon-based radiotherapy.

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Section: Organoid Culture and Self-renewal Assaymentioning

confidence: 99%

Derepression of transposable elements enhances interferon beta signaling and stem/progenitor cell activity after proton irradiation

Cinat,

van der Wal,

Baanstra

et al. 2024

Preprint

Self Cite

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“…The deletion of the YAP gene in mice resulted in a lack of epithelial patterning in the developing gland [ 48 ]. Rocchi et al reported that YAP overexpression resulted in the stem/progenitor cell mediated SG organoid expansion in three-dimensional cultures [ 49 ]. They also reported that translocation of YAP to the nucleus can induce activation of new ductal cells, which can be utilized for SG regeneration after severe radiation injuries [ 49 ].…”

Section: Tuning Ideal Hydrogel Properties For Sg Tissue Engineeringmentioning

confidence: 99%

“…Rocchi et al reported that YAP overexpression resulted in the stem/progenitor cell mediated SG organoid expansion in three-dimensional cultures [ 49 ]. They also reported that translocation of YAP to the nucleus can induce activation of new ductal cells, which can be utilized for SG regeneration after severe radiation injuries [ 49 ]. It is noted by other researchers that this cytoplasm-to-nuclear translocation of YAP occurs in response to an increment in the ECM stiffness, leading to the proliferation of different cell types such as fibroblasts [ 50 ].…”

Section: Tuning Ideal Hydrogel Properties For Sg Tissue Engineeringmentioning

confidence: 99%

“…A similar behavior is seen with the translocation of mechanosensing protein YAP within the cell cytoplasm. Spatial confinement due to small pore sizes can lead to YAP retention in the cell cytoplasm, which can potentially affect the SG stem/progenitor cell expansion, recruitment, and can inhibit the dedifferentiation of adult epithelial cells [ 49 , 57 ]. The nuclear morphology is different among various SG cell types.…”

Section: Tuning Ideal Hydrogel Properties For Sg Tissue Engineeringmentioning

confidence: 99%

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Hydrogels for Salivary Gland Tissue Engineering

Pillai

Munguia-Lopez

Tran

2022

Gels

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Mimicking the complex architecture of salivary glands (SGs) outside their native niche is challenging due their multicellular and highly branched organization. However, significant progress has been made to recapitulate the gland structure and function using several in vitro and ex vivo models. Hydrogels are polymers with the potential to retain a large volume of water inside their three-dimensional structure, thus simulating extracellular matrix properties that are essential for the cell and tissue integrity. Hydrogel-based culture of SG cells has seen a tremendous success in terms of developing platforms for cell expansion, building an artificial gland, and for use in transplantation to rescue loss of SG function. Both natural and synthetic hydrogels have been used widely in SG tissue engineering applications owing to their properties that support the proliferation, reorganization, and polarization of SG epithelial cells. While recent improvements in hydrogel properties are essential to establish more sophisticated models, the emphasis should still be made towards supporting factors such as mechanotransduction and associated signaling cues. In this concise review, we discuss considerations of an ideal hydrogel-based biomaterial for SG engineering and their associated signaling pathways. We also discuss the current advances made in natural and synthetic hydrogels for SG tissue engineering applications.

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“…35−37 Furthermore, efforts have been directed toward comprehending how ECM remodelling and the physicochemical properties of biomaterials influence the SG phenotype and secretory functions, which are paramount for successful clinical applications. 34,38,39 Clinical trials, on the other hand, have centered on delivering stem cells and their derivatives from different sources to alleviate xerostomia. In recent times, a handful of human clinical trials have demonstrated the promising potential of autologous mesenchymal stem cells (MSCs) in the treatment of radiation-injured salivary glands.…”

Section: ■ Introductionmentioning

confidence: 99%

Bioengineered Salivary Gland Microtissues─A Review of 3D Cellular Models and their Applications

Pillai,

Munguia-Lopez,

Tran

2024

ACS Appl. Bio Mater.

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Salivary glands (SGs) play a vital role in maintaining oral health through the production and release of saliva. Injury to SGs can lead to gland hypofunction and a decrease in saliva secretion manifesting as xerostomia. While symptomatic treatments for xerostomia exist, effective permanent solutions are still lacking, emphasizing the need for innovative approaches. Significant progress has been made in the field of three-dimensional (3D) SG bioengineering for applications in gland regeneration. This has been achieved through a major focus on cell culture techniques, including soluble cues and biomaterial components of the 3D niche. Cells derived from both adult and embryonic SGs have highlighted key in vitro characteristics of SG 3D models. While still in its first decade of exploration, SG spheroids and organoids have so far served as crucial tools to study SG pathophysiology. This review, based on a literature search over the past decade, covers the importance of SG cell types in the realm of their isolation, sourcing, and culture conditions that modulate the 3D microenvironment. We discuss different biomaterials employed for SG culture and the current advances made in bioengineering SG models using them. The success of these 3D cellular models are further evaluated in the context of their applications in organ transplantation and in vitro disease modeling.

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The Hippo signaling pathway effector YAP promotes salivary gland regeneration after injury

Abstract: YAP stimulates the proliferation and regenerative potential of ductal cells after salivary gland injury.

Cited by 8 publications

References 44 publications

Derepression of transposable elements enhances interferon beta signaling and stem/progenitor cell activity after proton irradiation

Derepression of transposable elements enhances interferon beta signaling and stem/progenitor cell activity after proton irradiation

Hydrogels for Salivary Gland Tissue Engineering

Bioengineered Salivary Gland Microtissues─A Review of 3D Cellular Models and their Applications

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