Browsing by Author "Banno, Kimihiko"

Now showing 1 - 6 of 6
  • Thumbnail Image
    Item
    Elimination of protein aggregates prevents premature senescence in human trisomy 21 fibroblasts
    (PLOS, 2019) Nawa, Nobutoshi; Hirata, Katsuya; Kawatani, Keiji; Nambara, Toshihiko; Omori, Sayaka; Banno, Kimihiko; Kokubu, Chikara; Takeda, Junji; Nishimura, Ken; Ohtaka, Manami; Nakanishi, Mahito; Okuzaki, Daisuke; Taniguchi, Hidetoshi; Arahori, Hitomi; Wada, Kazuko; Kitabatake, Yasuji; Ozono, Keiichi; Pediatrics, School of Medicine
    Chromosome abnormalities induces profound alterations in gene expression, leading to various disease phenotypes. Recent studies on yeast and mammalian cells have demonstrated that aneuploidy exerts detrimental effects on organismal growth and development, regardless of the karyotype, suggesting that aneuploidy-associated stress plays an important role in disease pathogenesis. However, whether and how this effect alters cellular homeostasis and long-term features of human disease are not fully understood. Here, we aimed to investigate cellular stress responses in human trisomy syndromes, using fibroblasts and induced pluripotent stem cells (iPSCs). Dermal fibroblasts derived from patients with trisomy 21, 18 and 13 showed a severe impairment of cell proliferation and enhanced premature senescence. These phenomena were accompanied by perturbation of protein homeostasis, leading to the accumulation of protein aggregates. We found that treatment with sodium 4-phenylbutyrate (4-PBA), a chemical chaperone, decreased the protein aggregates in trisomy fibroblasts. Notably, 4-PBA treatment successfully prevented the progression of premature senescence in secondary fibroblasts derived from trisomy 21 iPSCs. Our study reveals aneuploidy-associated stress as a potential therapeutic target for human trisomies, including Down syndrome.
  • Thumbnail Image
    Item
    Endothelial Stem and Progenitor Cells for Regenerative Medicine
    (Springer, 2019) Banno, Kimihiko; Yoder, Mervin C.; Cellular and Integrative Physiology, School of Medicine
    Purpose of Review Vascular endothelial stem cell (VESC) and progenitor cell are emerging as local resident regulators of vascular endothelial repair and replacement in mammalian subjects. However, widely recognized and accepted standard measures of stem cell function have yet to be published and, thus, we summarize some recent evidence that VESCs demonstrate stem cell properties in the process of endothelial cell (EC) lineage emergence, repair, and regeneration. Recent Findings Some rare resident ECs have been identified that are quiescent and reside within blood vessels but are activated and proliferate in response to injury. Transcriptome analyses of these ECs at a single cell level are providing new insights into VESC identity, including tissue specific EC heterogeneity. Summary Blood vessels and circulating blood contain rare immature ECs that display stem cell potential. Continuous efforts to define their precise location, origin, surface marker, and molecular signatures would enhance current approaches for purification of cells that would enable us to build new vessels for regenerative medicine.
  • Thumbnail Image
    Item
    Origin, prospective identification, and function of circulating endothelial colony-forming cells in mice and humans
    (The American Society for Clinical Investigation, 2023-03-08) Lin, Yang; Banno, Kimihiko; Gil, Chang-Hyun; Myslinski, Jered; Hato, Takashi; Shelley, William C.; Gao, Hongyu; Xuei, Xiaoling; Basile, David P.; Yoshimoto, Momoko; Prasain, Nutan; Tarnawsky, Stefan P.; Adams, Ralf H.; Naruse, Katsuhiko; Yoshida, Junko; Murphy, Michael P.; Horie, Kyoji; Yoder, Mervin C.; Pediatrics, School of Medicine
    Most circulating endothelial cells are apoptotic, but rare circulating endothelial colony-forming cells (C-ECFCs), also known as blood outgrowth endothelial cells, with proliferative and vasculogenic activity can be cultured; however, the origin and naive function of these C-ECFCs remains obscure. Herein, detailed lineage tracing revealed murine C-ECFCs emerged in the early postnatal period, displayed high vasculogenic potential with enriched frequency of clonal proliferative cells compared with tissue-resident ECFCs, and were not committed to or derived from the BM hematopoietic system but from tissue-resident ECFCs. In humans, C-ECFCs were present in the CD34bright cord blood mononuclear subset, possessed proliferative potential and in vivo vasculogenic function in a naive or cultured state, and displayed a single cell transcriptome sharing some umbilical venous endothelial cell features, such as a higher protein C receptor and extracellular matrix gene expression. This study provides an advance for the field by identifying the origin, naive function, and antigens to prospectively isolate C-ECFCs for translational studies.
  • Thumbnail Image
    Item
    Specific mesoderm subset derived from human pluripotent stem cells ameliorates microvascular pathology in type 2 diabetic mice
    (American Association for the Advancement of Science, 2022) Gil, Chang-Hyun; Chakraborty, Dibyendu; Vieira, Cristiano P.; Prasain, Nutan; Calzi, Sergio Li; Fortmann, Seth D.; Hu, Ping; Banno, Kimihiko; Jamal, Mohamed; Huang, Chao; Sielski, Micheli S.; Lin, Yang; Huang, Xinxin; Dupont, Mariana D.; Floyd, Jason L.; Prasad, Ram; Longhini, Ana Leda F.; McGill, Trevor J.; Chung, Hyung-Min; Murphy, Michael P.; Kotton, Darrell N.; Boulton, Michael E.; Yoder, Mervin C.; Grant, Maria B.; Pediatrics, School of Medicine
    Human induced pluripotent stem cells (hiPSCs) were differentiated into a specific mesoderm subset characterized by KDR+CD56+APLNR+ (KNA+) expression. KNA+ cells had high clonal proliferative potential and specification into endothelial colony-forming cell (ECFCs) phenotype. KNA+ cells differentiated into perfused blood vessels when implanted subcutaneously into the flank of nonobese diabetic/severe combined immunodeficient mice and when injected into the vitreous of type 2 diabetic mice (db/db mice). Transcriptomic analysis showed that differentiation of hiPSCs derived from diabetics into KNA+ cells was sufficient to change baseline differences in gene expression caused by the diabetic status and reprogram diabetic cells to a pattern similar to KNA+ cells derived from nondiabetic hiPSCs. Proteomic array studies performed on retinas of db/db mice injected with either control or diabetic donor-derived KNA+ cells showed correction of aberrant signaling in db/db retinas toward normal healthy retina. These data provide "proof of principle" that KNA+ cells restore perfusion and correct vascular dysfunction in db/db mice.
  • Thumbnail Image
    Item
    Translation Rescue by Targeting Ppp1r15a through Its Upstream Open Reading Frame in Sepsis-Induced Acute Kidney Injury in a Murine Model
    (Wolters Kluwer, 2023) Kidwell, Ashley; Yadav, Shiv Pratap Singh; Maier, Bernhard; Zollman, Amy; Ni, Kevin; Halim, Arvin; Janosevic, Danielle; Myslinski, Jered; Syed, Farooq; Zeng, Lifan; Waffo, Alain Bopda; Banno, Kimihiko; Xuei, Xiaoling; Doud, Emma H.; Dagher, Pierre C.; Hato, Takashi; Medicine, School of Medicine
    Background: Translation shutdown is a hallmark of late-phase, sepsis-induced kidney injury. Methods for controlling protein synthesis in the kidney are limited. Reversing translation shutdown requires dephosphorylation of the eukaryotic initiation factor 2 (eIF2) subunit eIF2 α ; this is mediated by a key regulatory molecule, protein phosphatase 1 regulatory subunit 15A (Ppp1r15a), also known as GADD34. Methods: To study protein synthesis in the kidney in a murine endotoxemia model and investigate the feasibility of translation control in vivo by boosting the protein expression of Ppp1r15a, we combined multiple tools, including ribosome profiling (Ribo-seq), proteomics, polyribosome profiling, and antisense oligonucleotides, and a newly generated Ppp1r15a knock-in mouse model and multiple mutant cell lines. Results: We report that translation shutdown in established sepsis-induced kidney injury is brought about by excessive eIF2 α phosphorylation and sustained by blunted expression of the counter-regulatory phosphatase Ppp1r15a. We determined the blunted Ppp1r15a expression persists because of the presence of an upstream open reading frame (uORF). Overcoming this barrier with genetic and antisense oligonucleotide approaches enabled the overexpression of Ppp1r15a, which salvaged translation and improved kidney function in an endotoxemia model. Loss of this uORF also had broad effects on the composition and phosphorylation status of the immunopeptidome-peptides associated with the MHC-that extended beyond the eIF2 α axis. Conclusions: We found Ppp1r15a is translationally repressed during late-phase sepsis because of the existence of an uORF, which is a prime therapeutic candidate for this strategic rescue of translation in late-phase sepsis. The ability to accurately control translation dynamics during sepsis may offer new paths for the development of therapies at codon-level precision.
  • Thumbnail Image
    Item
    Translation rescue by targeting Ppp1r15a upstream open reading frame in vivo
    (BioRxiv, 2021-12-12) Kidwell, Ashley; Yadav, Shiv Pratap Singh; Maier, Bernhard; Zollman, Amy; Ni, Kevin; Halim, Arvin; Janosevic, Danielle; Myslinski, Jered; Syed, Farooq; Zeng, Lifan; Waffo, Alain Bopda; Banno, Kimihiko; Xuei, Xiaoling; Doud, Emma H.; Dagher, Pierre C.; Hato, Takashi; Medicine, School of Medicine
    The eIF2 initiation complex is central to maintaining a functional translation machinery. Extreme stress such as life-threatening sepsis exposes vulnerabilities in this tightly regulated system, resulting in an imbalance between the opposing actions of kinases and phosphatases on the main regulatory subunit eIF2α. Here, we report that translation shutdown is a hallmark of established sepsis-induced kidney injury brought about by excessive eIF2α phosphorylation and sustained by blunted expression of the counterregulatory phosphatase subunit Ppp1r15a. We determined that the blunted Ppp1r15a expression persists because of the presence of an upstream open reading frame (uORF). Overcoming this barrier with genetic approaches enabled the derepression of Ppp1r15a, salvaged translation and improved kidney function in an endotoxemia model. We also found that the loss of this uORF has broad effects on the composition and phosphorylation status of the immunopeptidome that extended beyond the eIF2α axis. Collectively, our findings define the breath and potency of the highly conserved Ppp1r15a uORF and provide a paradigm for the design of uORF-based translation rheostat strategies. The ability to accurately control the dynamics of translation during sepsis will open new paths for the development of therapies at codon level precision.