Genotoxic Stress Abrogates Renewal of Melanocyte Stem Cells by Triggering Their Differentiation

SummarySomatic stem cell depletion due to the accumulation of DNA damage has been implicated in the appearance of aging-related phenotypes. Hair graying, a typical sign of aging in mammals, is caused by the incomplete maintenance of melanocyte stem cells (MSCs) with age. Here, we report that irreparable DNA damage, as caused by ionizing radiation, abrogates renewal of MSCs in mice. Surprisingly, the DNA-damage response triggers MSC differentiation into mature melanocytes in the niche, rather than inducing their apoptosis or senescence. The resulting MSC depletion leads to irreversible hair graying. Furthermore, deficiency of Ataxia-telangiectasia mutated (ATM), a central transducer kinase of the DNA-damage response, sensitizes MSCs to ectopic differentiation, demonstrating that the kinase protects MSCs from their premature differentiation by functioning as a “stemness checkpoint” to maintain the stem cell quality and quantity

Genotoxic stress abrogates renewal of melanocyte stem cells by triggering their differentiation.

金沢大学医薬保健研究域　医学系Somatic stem cell depletion due to the accumulation of DNA damage has been implicated in the appearance of aging-related phenotypes. Hair graying, a typical sign of aging in mammals, is caused by the incomplete maintenance of melanocyte stem cells (MSCs) with age. Here, we report that irreparable DNA damage, as caused by ionizing radiation, abrogates renewal of MSCs in mice. Surprisingly, the DNA-damage response triggers MSC differentiation into mature melanocytes in the niche, rather than inducing their apoptosis or senescence. The resulting MSC depletion leads to irreversible hair graying. Furthermore, deficiency of Ataxia-telangiectasia mutated (ATM), a central transducer kinase of the DNA-damage response, sensitizes MSCs to ectopic differentiation, demonstrating that the kinase protects MSCs from their premature differentiation by functioning as a "stemness checkpoint" to maintain the stem cell quality and quantity. © 2009 Elsevier Inc. All rights reserved

Epithelial-mesenchymal transition-converted tumor cells can induce T-cell apoptosis through upregulation of programmed death ligand 1 expression in esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC) is an aggressive tumor, and it is urgently needed to develop novel therapeutic strategies including immunotherapy. In this study, we investigated the upregulation of the programmed death ligand 1 (PD-L1) due to epithelial-mesenchymal transition (EMT) in ESCC using an in vitro treatment system with the EMT inducer, glycogen synthase kinase (GSK)-3 inhibitor, and we also analyzed the correlation of EMT and PD-L1 expression in the clinical tumor samples of both tissue microarray (TMA) samples (n = 177) and whole tissue samples (n = 21). As a result, the inhibition of GSK-3β induces EMT phenotype with upregulated vimentin and downregulated E-cadherin as well as increased Snail and Zinc finger E box-binding homeobox (ZEB)-1 gene expression. Simultaneously, we showed that EMT-converted ESCC indicated the upregulation of PD-L1 at both protein (total and surface) and mRNA levels. Of importance, we showed that EMT-converted tumor cells have a capability to induce T-cell apoptosis to a greater extent in comparison to original epithelial type tumor cells. Furthermore, the immunohistochemical stains of ESCC showed that PD-L1 expression on tumor cells was positively correlated with EMT status in TMA samples (P = .0004) and whole tissue samples (P = .0029). In conclusion, our in vitro and in vivo study clearly demonstrated that PD-L1 expression was upregulated in mesenchymal type tumors of ESCC. These findings provide a strong rationale for the clinical use of anti-PD- 1/ anti-PD- L1 monoclonal antibodies for advanced ESCC patients

色素幹細胞のゲノム損傷応答から明らかにするメラノーマ発生機序の解明

東京医科歯科大学 / 金沢大学がん進展制御研究所これまでに加齢に伴い色素幹細胞ニッシェにおいて、本来なら毛母に存在するはずの分化した色素を含んだ細胞が異所性に出現しており、常に白髪に先だっていたことを見出していたが、内在性のゲノム修復応答異常を呈するマウスでは若齢時や低線量放射線照射時においても同様にメラニン色素を沈着した分化した細胞群が色素幹細胞ニッシェ出現することを見出した。また活性酸素などの腫瘍の発生や維持に関与すると考えられるゲノム損傷刺激が同様に若齢時マウスにメラニン色素を持つ分化した細胞群を幹細胞ニッシェに誘導できることがわかった。このときDNA損傷のマーカーであるγ-H2AXフォーカスや癌抑制遺伝子であるATMの活性化などが幹細胞で認められたことから、色素幹細胞においてはDNA損傷応答と細胞の分化プログラムは未知の分子機構により密接にリンクしていることを意味する。これらは、加齢に伴うゲノム損傷と癌抑制遺伝子群の活性化が色素幹細胞の性質変化をもたらす要因であることを強く示唆し、また通常幹細胞しか存在しないはずのニッシェにおいても、ゲノム障害は幹細胞の自己複製に破綻もしくは機能異常をもたらすことで幹細胞システム全体の調節に影響することを示唆するものである。Ectopically differentiated melanocytes have been found in the melanocyte stem cell niche of mouse hair follicle preceding hair graying, but the mechanism of how this occurs are largely unknown. I found genotoxic stress, including X-ray or free-radical species, can reproduce these phenomena even in young mice. In addition, DNA repair deficient mice are subjected to premature differentiation of stem cells as well as acceralated hair graying, suggesting accumulated exogeneous damage or endogenous DNA damage due to metabolic process are candidate factor leading to hair graying. Ectopically differentiated cells shows DNA damage response such as γ-H2AX foci during aging process. Furthermore, I found ATM, a well known tumor suppressor, protects stem cell differentiation to prevent hair graying in normal condition. Collectively, these data indicates genotoxic stress induce premature stem cell differentiation, and affect the homeostatic control of stem cell systems.研究課題/領域番号:20890084, 研究期間(年度):2008 – 200

マウス ハイセイ カンサイボウ ノ シンケイ ブンカ ダンカイ ニ オケル カクナイ セイギョ キコウ

細胞分化は、内在性のプログラムを通して、幹細胞および前駆細胞が特定の系譜に変化することである。このエピジェネティックな機構には、ＤＮＡメチル化やクロマチンの修飾および核内構造体などが関わることが示唆されている。初期胚に由来する胚性幹細胞（ＥＳ細胞）は未分化性の維持、自己複製能および全ての胚組織を形成できる全分化能を有している。また神経幹細胞を含む組織幹細胞は自己複製能と限られた種類の異なる細胞に分化できる多分化能をもち、最終分化した細胞群を産出する。細胞の分化過程におけるエピジェネティックな制御と遺伝子発現の関連性を明らかにするために、マウスＥＳ細胞の神経分化において、（i）クロモセンターやＰＭＬ､ボディなどの機能的な核内サブドメインの動態､(ii）選択的に不活性化されるOct3/４遺伝子を含む主要組織適合抗原遺伝子群（MHC-Oct3/4）領域のクロマチンの修飾変動について解析し、ＤＮＡメチル化、クロマチンそして核構造の３つの階層的なエピジェネティック制御と発生・分化プロセスにおける遺伝子発現調節との関係を検討した

マウス ハイセイ カンサイボウ ノ シンケイ ブンカ ダンカイ ニ オケル カクナイ セイギョ キコウ

細胞分化は、内在性のプログラムを通して、幹細胞および前駆細胞が特定の系譜に変化することである。このエピジェネティックな機構には、ＤＮＡメチル化やクロマチンの修飾および核内構造体などが関わることが示唆されている。初期胚に由来する胚性幹細胞（ＥＳ細胞）は未分化性の維持、自己複製能および全ての胚組織を形成できる全分化能を有している。また神経幹細胞を含む組織幹細胞は自己複製能と限られた種類の異なる細胞に分化できる多分化能をもち、最終分化した細胞群を産出する。細胞の分化過程におけるエピジェネティックな制御と遺伝子発現の関連性を明らかにするために、マウスＥＳ細胞の神経分化において、（i）クロモセンターやＰＭＬ､ボディなどの機能的な核内サブドメインの動態､(ii）選択的に不活性化されるOct3/４遺伝子を含む主要組織適合抗原遺伝子群（MHC-Oct3/4）領域のクロマチンの修飾変動について解析し、ＤＮＡメチル化、クロマチンそして核構造の３つの階層的なエピジェネティック制御と発生・分化プロセスにおける遺伝子発現調節との関係を検討した

Spatio-temporal Phase Disambiguation in Depth Sensing

2019 IEEE International Conference on Computational Photography (ICCP) May 15 2019 to May 17 2019,Tokyo, JapanPhase ambiguity is a major problem in the depth measurement in either time-of-flight or phase shifting. Resolving the ambiguity using a low frequency pattern sacrifices the depth precision, and using multiple frequencies requires a number of observations. In this paper, we propose a phase disambiguation method that combines temporal and spatial modulation so that the high depth precision is preserved while the number of observation is small. A key observation is that the phase ambiguities of temporal and spatial domains appear differently with respect to the depth. Using this difference, the phase can disambiguate for a wider range of interest. We develop a prototype to show the effectiveness of our method through real-world experiments