ROCK inhibitor increases proacinar cells in adult salivary gland organoids

Koslow, Matthew; O’Keefe, Kevin J.; Hosseini, Zeinab F.; Nelson, Deirdre A.; Larsen, Melinda

doi:10.1016/j.scr.2019.101608

Cited by 28 publications

(34 citation statements)

References 44 publications

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“…In addition, RHO signal-related gene sets were identified as negatively correlating gene sets in the cells in cluster C1. These observations support the notion that cluster C1 contains stem-like cells (Koslow et al, 2019;Ohata et al, 2012).…”

Section: Cellular Composition Of Crc Pdossupporting

confidence: 89%

Comparative Analysis of Patient-Matched PDOs Revealed a Reduction in OLFM4-Associated Clusters in Metastatic Lesions in Colorectal Cancer

et al. 2021

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Metastasis is the major cause of cancer-related death, but whether metastatic lesions exhibit the same cellular composition as primary tumors has yet to be elucidated. To investigate the cellular heterogeneity of metastatic colorectal cancer (CRC), we established 72 patientderived organoids (PDOs) from 21 patients. Combined bulk transcriptomic and single-cell RNA-sequencing analysis revealed decreased gene expression of markers for differentiated cells in PDOs derived from metastatic lesions. Paradoxically, expression of potential intestinal stem cell markers was also decreased. We identified OLFM4 as the gene most strongly correlating with a stem-like cell cluster, and found OLFM4 + cells to be capable of initiating organoid culture growth and differentiation capacity in primary PDOs. These cells were required for the efficient growth of primary PDOs but dispensable for metastatic PDOs. These observations demonstrate that metastatic lesions have a cellular composition distinct from that of primary tumors; patient-matched PDOs are a useful resource for analyzing metastatic CRC.

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Section: Cellular Composition Of Crc Pdossupporting

confidence: 89%

Comparative Analysis of Patient-Matched PDOs Revealed a Reduction in OLFM4-Associated Clusters in Metastatic Lesions in Colorectal Cancer

et al. 2021

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“…These tissues include vasculature, nerves, and mesenchyme, which are intrinsic to salivary gland development, homeostasis, and regeneration 13 – 15 , 112 . For example, primary embryonic mesenchyme supported salivary organoid formation with robust AQP5 expression in co-culture with E16 salivary epithelium 113 , 114 . Additionally, incorporation of parasympathetic ganglion (PSG) cells in cultured E13 murine SMG and sublingual glands or salivary gland salispheres promoted differentiated AQP5-positive acinar cells 22 , 115 .…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have also documented the effects of neural factors in promoting the branching and development of glandular tissues, although these factors may not be sufficient 129 – 131 . Additionally, the ROCK inhibitor Y-27632 has been used to reduce cell stress-related loss of secretory function in salivary gland cultures 14 , 106 , 113 . Alternatively, induction of acinar-to-ductal metaplasia or transdifferentiation via TGFβ inhibition 114 , 132 , EGFR inhibition 22 , 133 , or Src and p38 MAPK inhibition 134 may prevent acinar cell loss.…”

Section: Discussionmentioning

confidence: 99%

Development of a functional salivary gland tissue chip with potential for high-content drug screening

et al. 2021

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Radiation therapy for head and neck cancers causes salivary gland dysfunction leading to permanent xerostomia. Limited progress in the discovery of new therapeutic strategies is attributed to the lack of in vitro models that mimic salivary gland function and allow high-throughput drug screening. We address this limitation by combining engineered extracellular matrices with microbubble (MB) array technology to develop functional tissue mimetics for mouse and human salivary glands. We demonstrate that mouse and human salivary tissues encapsulated within matrix metalloproteinase-degradable poly(ethylene glycol) hydrogels formed in MB arrays are viable, express key salivary gland markers, and exhibit polarized localization of functional proteins. The salivary gland mimetics (SGm) respond to calcium signaling agonists and secrete salivary proteins. SGm were then used to evaluate radiosensitivity and mitigation of radiation damage using a radioprotective compound. Altogether, SGm exhibit phenotypic and functional parameters of salivary glands, and provide an enabling technology for high-content/throughput drug testing.

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“…It has been reported that Y-27632 increased the population of proacinar cells in salivary gland organoids [ 10 ]. In SGSCs with high EpCAM expression, the treatment with Wnt3a, Rspo1, and Y-27632 formed organoids with lobular structures and enabled the long-term in vitro culture of SGSCs [ 7 ].…”

Section: Discussionmentioning

confidence: 99%

“…The transplantation of SGSCs attenuated radiation-induced hyposalivation [4,5,7]. SGSCs with regenerative potential Molecules 2021, 26, 2658 2 of 12 were successfully isolated, yet many in vitro experiments used primary SGSCs without subculture [6,10,11], possibly due to decreased cell survival.…”

Section: Introductionmentioning

confidence: 99%

A Rho Kinase (ROCK) Inhibitor, Y-27632, Inhibits the Dissociation-Induced Cell Death of Salivary Gland Stem Cells

et al. 2021

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Salivary gland stem cells (SGSCs) are potential cell sources for the treatment of salivary gland diseases. The control of cell survival is an essential factor for applying stem cells to regenerative medicine or stem cell-based research. The purpose of this study was to investigate the effects of the ROCK inhibitor Y-27632 on the survival of SGSCs and its underlying mechanisms. SGSCs were isolated from mouse submandibular glands and cultured in suspension. Treatment with Y-27632 restored the viability of SGSCs that was significantly decreased during isolation and the subsequent culture. Y-27632 upregulated the expression of anti-apoptotic protein BCL-2 in SGSCs and, in the apoptosis assay, significantly reduced apoptotic and necrotic cell populations. Matrigel was used to mimic the extracellular environment of an intact salivary gland. The expression of genes regulating apoptosis and the ROCK signaling pathway was significantly reduced when SGSCs were embedded in Matrigel. SGSCs cultured in Matrigel and treated with Y-27632 showed no difference in the total numbers of spheroids and expression levels of apoptosis-regulating genes. Matrigel-embedded SGSCs treated with Y-27632 increased the number of spheroids with budding structures and the expression of acinar cell-specific marker AQP5. We demonstrate the protective effects of Y-27632 against dissociation-induced apoptosis of SGSCs during their culture in vitro.

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ROCK inhibitor increases proacinar cells in adult salivary gland organoids

Cited by 28 publications

References 44 publications

Comparative Analysis of Patient-Matched PDOs Revealed a Reduction in OLFM4-Associated Clusters in Metastatic Lesions in Colorectal Cancer

Comparative Analysis of Patient-Matched PDOs Revealed a Reduction in OLFM4-Associated Clusters in Metastatic Lesions in Colorectal Cancer

Development of a functional salivary gland tissue chip with potential for high-content drug screening

A Rho Kinase (ROCK) Inhibitor, Y-27632, Inhibits the Dissociation-Induced Cell Death of Salivary Gland Stem Cells

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