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Vascular Progenitors Generated from Tankyrase Inhibitor-Regulated Naive Diabetic Human iPSC Potentiate Efficient Revascularization of Ischemic Retina

ABSTRACT: We propose that reprogramming of patient donor cells to tankyrase inhibitor-regulated naive hiPSC (N-hiPSC) improves the functionality of differentiated progenitors for subsequent regenerative therapies, and more effectively erases donor epigenetic aberrations sustained from chronic diseases such as diabetes .

ORGANISM(S): Homo sapiens

PROVIDER: GSE141639 | GEO | 2020/01/24

REPOSITORIES: GEO

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Vascular progenitors generated from tankyrase inhibitor-regulated naive diabetic human iPSC potentiate efficient revascularization of ischemic retina.

Project description:Here, we report that the functionality of vascular progenitors (VP) generated from normal and disease-primed conventional human induced pluripotent stem cells (hiPSC) can be significantly improved by reversion to a tankyrase inhibitor-regulated human naïve epiblast-like pluripotent state. Naïve diabetic vascular progenitors (N-DVP) differentiated from patient-specific naïve diabetic hiPSC (N-DhiPSC) possessed higher vascular functionality, maintained greater genomic stability, harbored decreased lineage-primed gene expression, and were more efficient in migrating to and re-vascularizing the deep neural layers of the ischemic retina than isogenic diabetic vascular progenitors (DVP). These findings suggest that reprogramming to a stable naïve human pluripotent stem cell state may effectively erase dysfunctional epigenetic donor cell memory or disease-associated aberrations in patient-specific hiPSC. More broadly, tankyrase inhibitor-regulated naïve hiPSC (N-hiPSC) represent a class of human stem cells with high epigenetic plasticity, improved multi-lineage functionality, and potentially high impact for regenerative medicine.

| S-EPMC7058090 | biostudies-literature

Vascular Progenitors Generated from Tankyrase Inhibitor-Regulated Naive Diabetic Human iPSC Potentiate Efficient Revascularization of Ischemic Retina

Project description:Vascular Progenitors Generated from Tankyrase Inhibitor-Regulated Naive Diabetic Human iPSC Potentiate Efficient Revascularization of Ischemic Retina

| PRJNA594287 | ENA

Gene expression profiling of tankyrase-inhibited mouse articular chondrocytes

Project description:Osteoarthritis (OA) is a prevalent degenerative disease, which involves progressive and irreversible destruction of cartilage matrix. Despite efforts to reconstruct cartilage matrix in osteoarthritic joints, it has been a difficult task as adult cartilage exhibits marginal repair capacity. Here we report the identification of tankyrase as a regulator of the cartilage anabolism axis based on systems-level factor analysis of mouse reference populations. Tankyrase inhibition drives the expression of a cartilage-signature matrisome and elicits a transcriptomic pattern that is inversely correlated with OA progression. Furthermore, tankyrase inhibitors ameliorate surgically-induced OA in mice, and stem cell transplantation coupled with tankyrase knockdown results in superior regeneration of cartilage lesions. Mechanistically, the pro-regenerative features of tankyrase inhibition are mainly triggered by uncoupling SOX9 from a poly(ADP-ribosyl)ation (PARylation)-dependent protein degradation pathway. Our findings provide insights into the development of future OA therapies aimed at reconstruction of articular cartilage.

2019-09-24 | GSE137899 | GEO

Gene expression data of colorectal cancer patient-derived cells treated with tankyrase inhibitors

Project description:Tankyrase, a poly(ADP-ribose) polymerase family member, regulates multiple cellular processes. Tankyrase inhibitors efficiently suppress colorectal cancer (CRC) cell proliferation. To examine the mechanism of anti-proliferative effect of tankyrase inhibitors (G007LK and RK582), we analyzed gene expression profiles of patient-derived CRC cells (JC11 and JC494) left untreated or treated with 0.3 µM G007LK or RK582 for 24 h by cDNA microarray analysis.

2024-01-17 | GSE217758 | GEO

Expression data from tumor samples treated with a tankyrase inhibitor in a mouse xenograft model

Project description:Tankyrase enhances beta-catenin signaling via PARsylation and subsequent degradation of Axin, a negative regulator of beta-catenin. Tankyrase inhibitors stabilize Axin and suppress beta-catenin signaling. We developed a novel tankyrase inhibitor, RK-287107. We used microarrays to elucidate the gene expression profile of human colorectal cancer cells treated with RK-287107 in a mouse xenograft model.

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Tankyrase inhibitors target colorectal cancer stem cells via AXIN-dependent downregulation of c-KIT tyrosine kinase

Project description:Tankyrase, a poly(ADP-ribose) polymerase family member, destabilizes Axin and positively regulates the Wnt/β-catenin signaling. We demonstrated that tankyrase inhibitors can target the colorectal cancer stem-like cells. Tankyrase inhibitors efficiently suppress colorectal cancer stem-like cell proliferation via AXIN-dependent manner. We sorted CD44-positive COLO-320DM cells, which showed a characteristic of CSCs and were targeted by tankyrase inhibitors. We analyzed gene expression profile of CD44-positive cells (CD44-positive 01, 02, 03) and CD44-negative cells (CD44-negative 01, 02, 03).

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Gene expression data of APC-mutated colorectal cancer patient-derived cells treated with tankyrase inhibitors

Project description:Tankyrase, a poly(ADP-ribose) polymerase family member, regulates multiple cellular processes. Tankyrase inhibitors efficiently suppress APC-mutated colorectal cancer (CRC) cell proliferation. To examine the mechanism of anti-proliferative effect of tankyrase inhibitors (G007LK and RK582), we analyzed gene expression profiles of patient-derived APC-mutated CRC cells (JC21 and JC475) left untreated or treated with 0.3 µM G007LK or RK582 for 24 h by cDNA microarray analysis.

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Expression data of colon cancer COLO320DM cells and tankyrase inhibitor-resistant variant 320-IWR cells

Project description:Wnt/β-catenin signaling is activated in colorectal cancer (CRC) and is involved in CRC growth. Tankyrase, a poly(ADP-ribose) polymerase family member, destabilizes Axin and positively regulates the Wnt/β-catenin signaling. Tankyrase inhibitors efficiently suppress CRC cell proliferation. We established 320-IWR cells, which showed resistance to tankyrase inhibitor IWR-1, from human CRC COLO-320DM cells. We analyzed gene expression profile of 320-IWR cells (320IWR_1,_2) and parental COLO-320DM cells (COLO320_1,_2).

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BET protein-dependent E2F pathway confers bell-shaped type resistance to tankyrase inhibitors in APC-mutated colorectal cancer [RNA-seq]

Project description:In colorectal cancer (CRC), WNT/β-catenin signaling is aberrantly activated mainly by loss-of-function mutations in adenomatous polyposis coli (APC) and is involved in tumor progression. Tankyrase inhibitors, which suppress WNT/β-catenin signaling, are under pre-clinical and clinical trials, while their resistance mechanisms remain unclear. In this study, we established tankyrase inhibitor-resistant CRC cells, JC73-RK100, from APC-mutated patient-derived CRC cells. JC73-RK100 cells and several CRC cells were sensitive to tankyrase inhibitors at low concentrations but were resistant at high concentrations (i.e., bell-shaped dose response: BSDR). Mechanistically, tankyrase inhibitors at high concentrations promoted BRD3/4-dependent E2F target gene transcription and over-activated cell cycle progression in the BSDR cells. BET inhibitors canceled the bell-shaped dose response to tankyrase inhibitors. Taken together, these observations suggest that combination of tankyrase and BET inhibitors would be a useful therapeutic approach to overcome a subset of resistance to tankyrase inhibitors.

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BET protein-dependent E2F pathway confers bell-shaped type resistance to tankyrase inhibitors in APC-mutated colorectal cancer [CUT&RUN]

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