Loss of TJP1 disrupts gastrulation patterning and increases differentiation toward the germ cell lineage in human pluripotent stem cells

Vasic, Ivana; Libby, Ashley R.G.; Maslan, Annie; Bulger, Emily A.; Zalazar, David; Compagno, Martina Z. Krakora; Streets, Aaron; Tomoda, Kiichiro; Yamanaka, Shinya; McDevitt, Todd C.

doi:10.1016/j.devcel.2023.05.019

Cited by 6 publications

(3 citation statements)

References 61 publications

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“…Herein, we identified SOX9 as a dynamic, fundamental, intrinsic transcriptional link between loss of epithelial integrity and regenerative response in vivo. Recently, Yamanaka and colleagues linked apicobasolateral polarity, maintained by the tight junction protein ZO-1, with receptivity to signaling proteins and multicellular patterning in an in vitro human gastrulation platform ( 57 ). Genetic removal of ZO-1 led to sustained BMP4 signaling pathway (BMP4/pSMAD1/5) activation and the ensuing distinct cell-state specification.…”

Section: Discussionmentioning

confidence: 99%

SOX9 switch links regeneration to fibrosis at the single-cell level in mammalian kidneys

Aggarwal,

Wang,

Rincon Fernandez Pacheco

et al. 2024

Science

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The steps governing healing with or without fibrosis within the same microenvironment are unclear. After acute kidney injury (AKI), injured proximal tubular epithelial cells activate SOX9 for self-restoration. Using a multimodal approach for a head-to-head comparison of injury-induced SOX9 lineages, we identified a dynamic SOX9 switch in repairing epithelia. Lineages that regenerated epithelia silenced SOX9 and healed without fibrosis (SOX9 on-off ). By contrast, lineages with unrestored apicobasal polarity maintained SOX9 activity in sustained efforts to regenerate, which were identified as a SOX9 on-on Cadherin6 pos cell state. These reprogrammed cells generated substantial single-cell WNT activity to provoke a fibroproliferative response in adjacent fibroblasts, driving AKI to chronic kidney disease. Transplanted human kidneys displayed similar SOX9/CDH6/WNT2B responses. Thus, we have uncovered a sensor of epithelial repair status, the activity of which determines regeneration with or without fibrosis.

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Section: Discussionmentioning

confidence: 99%

SOX9 switch links regeneration to fibrosis at the single-cell level in mammalian kidneys

Aggarwal,

Wang,

Rincon Fernandez Pacheco

et al. 2024

Science

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“…It has been shown to be associated with tumor growth and metastasis in pancreatic cancer (56). In human pluripotent stem cells, disrupting TJP1 leads to the activation of bone morphogenic protein-4 (BMP4) signaling and loss of patterning phenotype (57). CTSG has also been implicated in triple-negative breast cancer (TNBC), where it is overexpressed and correlated with a poor prognosis.…”

Section: Discussionmentioning

confidence: 99%

Identification of Key Regulators in Pancreatic Ductal Adenocarcinoma using Network theoretical Approach

Bhattacharjee,

Ghosh

2024

Preprint

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Pancreatic Ductal Adenocarcinoma (PDAC) is a devastating disease with poor clinical outcomes which is mainly because of delayed disease detection resistance to chemotherapy and lack of specific targeted therapies. The disease's development involves complex interactions among immunological, genetic, and environmental factors, yet its molecular mechanism remains elusive. A major challenge in understanding PDAC etiology lies in unraveling the genetic profiling that governs the PDAC network. To address this, we examined the gene expression profile of PDAC and compared it with that of healthy controls, identifying differentially expressed genes (DEGs). These DEGs formed the basis for constructing the PDAC protein interaction network, and their network topological properties were calculated. It was found that the PDAC network self-organizes into a scale-free fractal state with weakly hierarchical organization. Newman and Girvan algorithm (leading eigenvector (LEV) method) of community detection enumerated four communities leading to at least one motif. Our analysis revealed 33 key regulators were predominantly enriched in neuroactive ligand-receptor interaction, Cell adhesion molecules, Leukocyte transendothelial migration pathways; positive regulation of cell proliferation, positive regulation of protein kinase B signaling biological functions; G-protein beta-subunit binding, receptor binding molecular functions etc. Transcription Factor and mi-RNA of the key regulators were obtained. Recognizing the therapeutic potential and biomarker significance of PDAC Key regulators, we also identified approved drugs for specific genes. However, it is imperative to subject Key regulators to experimental validation to establish their efficacy in the context of PDAC.

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“…The increased presence of VRC in the plasma of PVOD patients, but not in IPAH patients or control individuals, highlights the potential of this complex as a diagnostic biomarker for PVOD, a finding that carries significant clinical implications. In addition to its barrier function, it is reported that ZO-1 (TJP-1) plays a role in modulating the potency of the BMP-Smad signaling pathway in pluripotent stem cells 55 . Thus, it is plausible that MMC-mediated depletion of ZO-1 in the vascular endothelium could alter the BMP-Smad signaling activity, which then contributes to vascular remodeling.…”

Section: Discussionmentioning

confidence: 99%

Reversal of pulmonary veno-occlusive disease phenotypes by inhibition of the integrated stress response

Prabhakar,

Kumar,

Wadhwa

et al. 2023

Preprint

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Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension arising from EIF2AK4 gene mutations or mitomycin C (MMC) administration. The lack of effective PVOD therapies is compounded by a limited understanding of the mechanisms driving the vascular remodeling in PVOD. We show that the administration of MMC in rats mediates the activation of protein kinase R (PKR) and the integrated stress response (ISR), which lead to the release of the endothelial adhesion molecule VE-Cadherin in the complex with Rad51 to the circulation, disruption of endothelial barrier, and vascular remodeling. Pharmacological inhibition of PKR or ISR attenuates the depletion of VE-Cadherin, elevation of vascular permeability, and vascular remodeling instigated by MMC, suggesting potential clinical intervention for PVOD. Finally, the severity of PVOD phenotypes was increased by a heterozygousBMPR2mutation that truncates the carboxyl tail of BMPR2, underscoring the role of deregulated BMP signal in the development of PVOD.

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Loss of TJP1 disrupts gastrulation patterning and increases differentiation toward the germ cell lineage in human pluripotent stem cells

Cited by 6 publications

References 61 publications

SOX9 switch links regeneration to fibrosis at the single-cell level in mammalian kidneys

SOX9 switch links regeneration to fibrosis at the single-cell level in mammalian kidneys

Identification of Key Regulators in Pancreatic Ductal Adenocarcinoma using Network theoretical Approach

Reversal of pulmonary veno-occlusive disease phenotypes by inhibition of the integrated stress response

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