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2 results on '"Sabriya A. Syed"'

1. Wnt-induced, TRP53-mediated Cell Cycle Arrest of Precursors Underlies Interstitial Cell of Cajal Depletion During AgingSummary

Author

Yujiro Hayashi, David T. Asuzu, Michael R. Bardsley, Gabriella B. Gajdos, Sergiy M. Kvasha, David R. Linden, Rea A. Nagy, Siva Arumugam Saravanaperumal, Sabriya A. Syed, Yoshitaka Toyomasu, Huihuang Yan, Eduardo N. Chini, Simon J. Gibbons, Todd A. Kellogg, Khashayarsha Khazaie, Makoto Kuro-o, Jair Machado Espindola Netto, Mahendra Pal Singh, James G. Tidball, Michelle Wehling-Henricks, Gianrico Farrugia, and Tamas Ordog

Subjects
Stem Cell, Senescence, Compliance, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Background & Aims: Gastric dysfunction in the elderly may cause reduced food intake, frailty, and increased mortality. The pacemaker and neuromodulator cells interstitial cells of Cajal (ICC) decline with age in humans, and their loss contributes to gastric dysfunction in progeric klotho mice hypomorphic for the anti-aging Klotho protein. The mechanisms of ICC depletion remain unclear. Klotho attenuates Wnt (wingless-type MMTV integration site) signaling. Here, we examined whether unopposed Wnt signaling could underlie aging-associated ICC loss by up-regulating transformation related protein TRP53 in ICC stem cells (ICC-SC). Methods: Mice aged 1–107 weeks, klotho mice, APCΔ468 mice with overactive Wnt signaling, mouse ICC-SC, and human gastric smooth muscles were studied by RNA sequencing, reverse transcription–polymerase chain reaction, immunoblots, immunofluorescence, histochemistry, flow cytometry, and methyltetrazolium, ethynyl/bromodeoxyuridine incorporation, and ex-vivo gastric compliance assays. Cells were manipulated pharmacologically and by gene overexpression and RNA interference. Results: The klotho and aged mice showed similar ICC loss and impaired gastric compliance. ICC-SC decline preceded ICC depletion. Canonical Wnt signaling and TRP53 increased in gastric muscles of klotho and aged mice and middle-aged humans. Overstimulated canonical Wnt signaling increased DNA damage response and TRP53 and reduced ICC-SC self-renewal and gastric ICC. TRP53 induction persistently inhibited G1/S and G2/M cell cycle phase transitions without activating apoptosis, autophagy, cellular quiescence, or canonical markers/mediators of senescence. G1/S block reflected increased cyclin-dependent kinase inhibitor 1B and reduced cyclin D1 from reduced extracellular signal-regulated kinase activity. Conclusions: Increased Wnt signaling causes age-related ICC loss by up-regulating TRP53, which induces persistent ICC-SC cell cycle arrest without up-regulating canonical senescence markers.

Published
2021
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2. Wnt-induced, TRP53-mediated Cell Cycle Arrest of Precursors Underlies Interstitial Cell of Cajal Depletion During AgingSummary

Author

Huihuang Yan, Khashayarsha Khazaie, Gianrico Farrugia, Sabriya A. Syed, Michelle Wehling-Henricks, Makoto Kuro-o, Simon J. Gibbons, Sergiy M. Kvasha, David T. Asuzu, Rea A. Nagy, Eduardo N. Chini, Mahendra Pal Singh, Yujiro Hayashi, David R. Linden, James G. Tidball, Gabriella B. Gajdos, Michael R. Bardsley, Jair Machado Espindola Netto, Siva Arumugam Saravanaperumal, Todd A. Kellogg, Tamas Ordog, and Yoshitaka Toyomasu

Subjects
PE, R-phycoerythrin, Male, 0301 basic medicine, CL.CASP3, cleaved caspase 3, Aging, Cell cycle checkpoint, BrdU, 5-bromo-2′-deoxyuridine, DMSO, dimethyl sulfoxide, Mice, 0302 clinical medicine, APC, allophycocyanin, ERK, extracellular signal-regulated kinase, GSEA, gene set enrichment analysis, GEO, Gene Expression Omnibus, NES, normalized enrichment score, TRP53, transformation related protein 53, Wnt Signaling Pathway, Klotho, ANOVA, analysis of variance, Cellular Senescence, Original Research, SA-β-gal, senescence-associated beta-galactosidase, KIT, v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog, Stomach, EdU, 5-ethynyl-2′-deoxyuridine, Gastroenterology, Wnt signaling pathway, MTS, methyltetrazolium salt, ICC, interstitial cells of Cajal, Middle Aged, CDKN1A, cyclin-dependent kinase inhibitor 1a, Up-Regulation, Cell biology, CTNNB1, catenin beta 1, GAPDH, glyceraldehyde-3-phosphate dehydrogenase, Models, Animal, symbols, Female, 030211 gastroenterology & hepatology, ANO1, anoctamin-1, RPKM, reads per kilobase of transcript per million mapped reads, Stem cell, Compliance, Senescence, SESN, sestrin, tsTAg, tsA58-mutant SV40 large T antigen, Adenomatous Polyposis Coli Protein, FDR Q, false discovery rate Q value, Mice, Transgenic, KLF4, Kruppel-like factor 4, Biology, DDR, DNA damage response, PI, propidium iodide, Young Adult, 03 medical and health sciences, symbols.namesake, Cyclin D1, RT-qPCR, real-time quantitative reverse-transcription polymerase chain reaction, Stem Cell, MEK, mitogen-activated protein kinase kinase, Animals, Humans, Kinase activity, lcsh:RC799-869, Klotho Proteins, CCND1, cyclin D1, Hepatology, WB, Western immunoblotting, RNA-seq, RNA sequencing, Cell Cycle Checkpoints, Interstitial Cells of Cajal, CDKN1B, cyclin-dependent kinase inhibitor 2B, WT, wild-type, Interstitial cell of Cajal, 030104 developmental biology, siRNA, small interfering RNA, ETV1, ets variant 1, ICC-SC, interstitial cells of Cajal stem cells, lcsh:Diseases of the digestive system. Gastroenterology, Tumor Suppressor Protein p53, MYC, myelocytomatosis oncogene, DAPI, 4′,6-diamidino-2-phenylindole
Abstract

Background & Aims Gastric dysfunction in the elderly may cause reduced food intake, frailty, and increased mortality. The pacemaker and neuromodulator cells interstitial cells of Cajal (ICC) decline with age in humans, and their loss contributes to gastric dysfunction in progeric klotho mice hypomorphic for the anti-aging Klotho protein. The mechanisms of ICC depletion remain unclear. Klotho attenuates Wnt (wingless-type MMTV integration site) signaling. Here, we examined whether unopposed Wnt signaling could underlie aging-associated ICC loss by up-regulating transformation related protein TRP53 in ICC stem cells (ICC-SC). Methods Mice aged 1–107 weeks, klotho mice, APCΔ468 mice with overactive Wnt signaling, mouse ICC-SC, and human gastric smooth muscles were studied by RNA sequencing, reverse transcription–polymerase chain reaction, immunoblots, immunofluorescence, histochemistry, flow cytometry, and methyltetrazolium, ethynyl/bromodeoxyuridine incorporation, and ex-vivo gastric compliance assays. Cells were manipulated pharmacologically and by gene overexpression and RNA interference. Results The klotho and aged mice showed similar ICC loss and impaired gastric compliance. ICC-SC decline preceded ICC depletion. Canonical Wnt signaling and TRP53 increased in gastric muscles of klotho and aged mice and middle-aged humans. Overstimulated canonical Wnt signaling increased DNA damage response and TRP53 and reduced ICC-SC self-renewal and gastric ICC. TRP53 induction persistently inhibited G1/S and G2/M cell cycle phase transitions without activating apoptosis, autophagy, cellular quiescence, or canonical markers/mediators of senescence. G1/S block reflected increased cyclin-dependent kinase inhibitor 1B and reduced cyclin D1 from reduced extracellular signal-regulated kinase activity. Conclusions Increased Wnt signaling causes age-related ICC loss by up-regulating TRP53, which induces persistent ICC-SC cell cycle arrest without up-regulating canonical senescence markers., Graphical abstract

Published
2021

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