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• 札幌医科大学   形成外科学講座   兼任助教  

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• Cellular senescence and wound healing in aged and diabetic skin

  Arisa Kita, Sena Yamamoto, Yuki Saito, Takako S. Chikenji

  Frontiers in Physiology ( Frontiers Media SA )  15  2024年02月

  　概要を見る

  Cellular senescence is a biological mechanism that prevents abnormal cell proliferation during tissue repair, and it is often accompanied by the secretion of various factors, such as cytokines and chemokines, known as the senescence-associated secretory phenotype (SASP). SASP-mediated cell-to-cell communication promotes tissue repair, regeneration, and development. However, senescent cells can accumulate abnormally at injury sites, leading to excessive inflammation, tissue dysfunction, and intractable wounds. The effects of cellular senescence on skin wound healing can be both beneficial and detrimental, depending on the condition. Here, we reviewed the functional differences in cellular senescence that emerge during wound healing, chronic inflammation, and skin aging. We also review the latest mechanisms of wound healing in the epidermis, dermis, and subcutaneous fat, with a focus on cellular senescence, chronic inflammation, and tissue regeneration. Finally, we discuss the potential clinical applications of promoting and inhibiting cellular senescence to maximize benefits and minimize detrimental effects.

  DOI

• Senescence-associated secretory phenotypes in mesenchymal cells contribute to cytotoxic immune response in oral lichen planus.

  Shogo Ijima, Yuki Saito, Sena Yamamoto, Kentaro Nagaoka, Taiki Iwamoto, Arisa Kita, Maki Miyajima, Tsukasa Sato, Akihiro Miyazaki, Takako S Chikenji

  Immunity & ageing : I & A   20 ( 1 ) 72 - 72  2023年12月  [国際誌]

  　概要を見る

  Oral lichen planus is a chronic inflammatory condition that adversely affects the oral mucosa; however, its etiology remains elusive. Consequently, therapeutic interventions for oral lichen planus are limited to symptomatic management. This study provides evidence of the accumulation of senescent mesenchymal cells, CD8 + T cells, and natural killer cells in patients with oral lichen planus. We profiled the patients' tissues using the National Center for Biotechnology Information Gene Expression Omnibus database and found that senescence-related genes were upregulated in these tissues by gene set enrichment analysis. Immunohistochemical analysis showed increased senescent mesenchymal cells in the subepithelial layer of patients with oral lichen planus. Single-cell RNA-seq data retrieved from the Gene Expression Omnibus database of patients with oral lichen planus revealed that mesenchymal cells were marked by the upregulation of senescence-related genes. Cell-cell communication analysis using CellChat showed that senescent mesenchymal cells significantly influenced CD8 + T cells and natural killer cells via CXCL12-CXCR4 signaling, which is known to activate and recruit CD8 + T cells and NK cells. Finally, in vitro assays demonstrated that the secretion of senescence-associated factors from mesenchymal cells stimulated the activation of T cells and natural killer cells and promoted epithelial cell senescence and cytotoxicity. These findings suggest that the accumulation of mesenchymal cells with senescence-associated secretory phenotype may be a key driver of oral lichen planus pathogenesis.

  DOI PubMed

• Intrathecal Injection of Mesenchymal Stromal Cell Cultured on 3D Fiber Ameliorates Multiple Organ Damage in Murine Lupus

  Yuki Saito, Maki Miyajima, Sena Yamamoto, Norihiro Miura, Tsukasa Sato, Arisa Kita, Shogo Ijima, Mineko Fujimiya, Takako S Chikenji

  Stem Cells Translational Medicine ( Oxford University Press (OUP) )   2022年04月  [査読有り]

  　概要を見る

  Abstract Up to 60% of patients with systemic lupus erythematosus (SLE) experience autonomic symptom. Sympathetic nervous system damage can cause dysfunction of the bone marrow that activates inflammatory cells, potentially causing multiple organ damage. We hypothesized that sympathetic nervous system damage would induce bone marrow dysfunction with multiple organ damage in SLE, and that multiple organ damage could be improved by therapy targeting the nervous system. Here, we showed that damage to autonomic nerves and Schwann cells occurred in the bone marrow and central nervous system of SLE model mice. A neurotoxic drug increased mortality and induced severe neuropathy and multiple organ damage, while a neuroprotective drug prevented multiple organ damage. The administration of bone marrow-derived mesenchymal stromal cells (BMSCs) cultured on a 3-dimensional fiber scaffold improved bone marrow neuropathy, skin lesions, kidney function, and mortality. Our results reveal that bone marrow neuropathy influence multiple organ damage associated with SLE, and improvement of bone marrow neuropathy by intrathecal injection of BMSC may be a target for SLE multiple-organ damage.

  DOI

• Altered regulation of mesenchymal cell senescence in adipose tissue promotes pathological changes associated with diabetic wound healing

  Arisa Kita, Yuki Saito, Norihiro Miura, Maki Miyajima, Sena Yamamoto, Tsukasa Sato, Takatoshi Yotsuyanagi, Mineko Fujimiya, Takako S. Chikenji

  Communications Biology ( Springer Science and Business Media LLC )  5 ( 1 ) 310 - 310  2022年04月  [査読有り]  [国際誌]

  　概要を見る

  Abstract Pathologic diabetic wound healing is caused by sequential and progressive deterioration of hemostasis, inflammation, proliferation, and resolution/remodeling. Cellular senescence promotes wound healing; however, diabetic wounds exhibit low levels of senescent factors and accumulate senescent cells, which impair the healing process. Here we show that the number of p15^INK4B + PDGFRα + senescent mesenchymal cells in adipose tissue increases transiently during early phases of wound healing in both non-diabetic mice and humans. Transplantation of adipose tissue from diabetic mice into non-diabetic mice results in impaired wound healing and an altered cellular senescence–associated secretory phenotype (SASP), suggesting that insufficient induction of adipose tissue senescence after injury is a pathological mechanism of diabetic wound healing. These results provide insight into how regulation of senescence in adipose tissue contributes to wound healing and could constitute a basis for developing therapeutic treatment for wound healing impairment in diabetes.

  DOI PubMed

• 間葉系間質/幹細胞が誘導する細胞老化-クリアランス-リモデリング連鎖は慢性腎不全の線維化を改善する

  千見寺 貴子, 齋藤 悠城, 中野 正子, 北 愛里紗, 藤宮 峯子

  日本腎臓学会誌 ( (一社)日本腎臓学会 )  62 ( 4 ) 260 - 260  2020年07月

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• 細胞老化制御による新たな糖尿病性潰瘍治療の開発

  若手研究

  研究期間:

  2023年04月

  -

  2026年03月

   

  北 愛里紗

• 生体内再生能を有する微小細切化軟骨をコーティングした人工材料移植技術の開発

  基盤研究(C)

  研究期間:

  2022年04月

  -

  2025年03月

   

  四ッ柳 高敏, 浜本 有祐, 北 愛里紗, 山下 建, 柿崎 育子

• 糖尿病性潰瘍を骨髄から治すー骨髄自律神経修復による根治療法の開発

  若手研究

  研究期間:

  2019年04月

  -

  2023年03月

   

  北 愛里紗

  　研究概要を見る

  糖尿病患者では治癒力の低下から皮膚潰瘍が骨にまで達し難治となる。骨髄間葉系幹細胞および脂肪前駆細胞は、糖尿病患者および糖尿病マウスの体内では本来の挙動を示していないことが過去の報告から明らかになっている。本研究ではこの原因として、皮下脂肪と骨髄に着目して研究を進めた。その中で、糖尿病モデルマウス(Leprdb/db)の皮下脂肪を非糖尿病モデルマウス(Leprdb/+)に移植した場合著しく創傷治癒が遅延したことから、皮下脂肪に着目して検討を行った。すると、糖尿病モデルマウスの創傷治癒過程で皮下脂肪に存在する間葉系細胞の細胞老化が非糖尿病モデルマウスと比較して異常化し、創傷治癒を阻害していることが明らかになった。細胞老化は、細胞にダメージが加わったときに異常な増殖を防ぐための生体防御システムであり、老化細胞はすぐには死滅せずに自らの増殖を止めると様々な因子の分泌現象(senescent associated secretary phenotype; SASP)を起こす。この皮下脂肪の老化細胞によるSASPが糖尿病モデルマウスの創傷治癒に影響するのではないかと考え、糖尿病モデルマウスおよび非糖尿病モデルマウスの皮下脂肪組織から培養上清を回収し、メンブレン抗体アレイを行った。糖尿病モデルマウスおよび非糖尿病モデルマウスの皮下脂肪由来分泌物で、構成タンパク質が異なることが明らかになった。さらに、皮膚由来線維芽細胞にそれぞれ糖尿病モデルマウスおよび非糖尿病モデルマウスの皮下脂肪由来分泌物を添加培養してスクラッチアッセイを行った。すると、糖尿病モデルマウス由来分泌物は線維芽細胞の増殖を抑制し、糖尿病の皮下脂肪由来の分泌物が皮膚の創傷治癒に影響することが推測された。糖尿病および非糖尿病のヒトの創部から採取した検体を用いて組織学的に細胞老化の経時的変化を確認したところ、コントロールおよび糖尿病モデルマウスの場合と同様の変化が起こっていることがわかった。