記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Cells  

Akhirin (AKH) is secreted by choroid plexus epithelial cells and localizes to the ventricular surface during embryonic brain development. Loss of AKH disrupts neural stem cell homeostasis by inducing inflammatory cytokines in the cerebrospinal fluid. AKH is cleaved under inflammatory conditions, and its LCCL domain directly binds bacteria, providing innate immune protection in the developing neurogenic niche. AKH functions as a barrier molecule that integrates immune defense with the maintenance of neural stem cell niche integrity during early neurodevelopment. Highlights: Neurogenesis is tightly regulated by complex interactions among neural stem and progenitor cells (NSCs/NPCs), blood vessels, microglia, and extracellular matrix components within the neurogenic niche. In the embryonic brain, NSCs reside along the ventricular surface, where cerebrospinal fluid (CSF) directly regulates their proliferation. Here, we identify Akhirin (AKH) as a critical regulator that preserves the integrity of the NSC niche during mouse brain development. At embryonic day 14.5, AKH is secreted and enriched at the apical surface of choroid plexus epithelial cells and the ventricular lining. Loss of AKH leads to increases the inflammatory cytokine expression in the CSF and disrupts NSC niche homeostasis. Furthermore, AKH is cleaved upon inflammatory stimulation, and its LCCL domain directly binds bacteria, thereby preventing their spread. These findings reveal that AKH functions as a protective barrier molecule within the developing neurogenic niche, providing immune protection and preserving NSC niche homeostasis during periods when the innate immune defenses are still immature.

DOI： 10.3390/cells15020151

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記述言語：英語   掲載種別：論文集(書籍)内論文   出版者・発行元：Methods in Molecular Biology  

In recent years, direct reprogramming methods have attracted attention as they can bypass the immature stem cell state and directly induce the desired cell type by introducing key transcription factors into somatic cells. This technique offers advantages such as shorter induction times compared to inducing the desired cells from induced pluripotent stem cells. Furthermore, this approach enables the provision of the requisite cell types to patients requiring treatment without eliciting an immune rejection response. Microglia, the resident immune cells of the central nervous system, exhibit high proliferative and regenerative capacities, allowing them to repopulate even after almost complete depletion. In response to injury, microglia accumulate in damaged brain regions and become the primary cell type that forms the glial scar. Given these properties, microglia are promising candidates for direct reprogramming into neurons in the injured area without depleting cell sources. This chapter outlines a protocol for directly reprogramming cortical microglia into neurons, utilizing primary culture and lentiviral-mediated gene transfer techniques.

DOI： 10.1007/978-1-0716-4807-0_13

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Neural Regeneration Research  

DOI： 10.4103/NRR.NRR-D-24-00545

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BMC Oral Health  

Background: Isaacs’ syndrome, also known as neuromyotonia or peripheral nerve hyperexcitability, is a rare disorder that affects the peripheral nervous system. Clinical findings include cramps, fasciculations, and myokymia; however, there are few reports of dental treatment for trismus. Case presentation: A patient with trismus due to Isaacs’ syndrome experienced swelling and pain in the gingiva surrounding his right lower first molar. He was diagnosed with chronic apical periodontitis by a dentist near his home. However, the patient was informed that dental treatment and medication could not be administered because of the presence of Isaacs’ syndrome, and he visited the Geriatric Dentistry and Perioperative Oral Care Center at Kyushu University Hospital 2 weeks later. The patient’s painless mouth-opening distance (between incisors) was 20 mm at that time, and medication, including amoxicillin capsules and acetaminophen, was administered because the dental extraction forceps or endodontic instruments were difficult to insert into the oral cavity for treatment. Two months after his initial visit, the patient visited us complaining of pain in the same area. However, he had recently undergone plasmapheresis treatment in neurology to alleviate limited mouth opening and systemic myalgia, resulting in a pain-free mouth-opening distance of approximately 35 mm. During this temporary period in which he had no restriction in mouth opening, we performed tooth extraction and bridge restoration on the mandibular right first molar and created an oral appliance for sleep bruxism. Conclusions: Plasmapheresis therapy transiently reduced trismus, rendering dental interventions feasible, albeit temporarily. This case report underscores the importance of close collaboration between neurologists and dentists who encounter similar cases while furnishing valuable insights to inform dental treatment planning.

DOI： 10.1186/s12903-024-04485-2

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Proceedings of the National Academy of Sciences of the United States of America  

Although generating new neurons in the ischemic injured brain would be an ideal approach to replenish the lost neurons for repairing the damage, the adult mammalian brain retains only limited neurogenic capability. Here, we show that direct conversion of microglia/macrophages into neurons in the brain has great potential as a therapeutic strategy for ischemic brain injury. After transient middle cerebral artery occlusion in adult mice, microglia/macrophages converge at the lesion core of the striatum, where neuronal loss is prominent. Targeted expression of a neurogenic transcription factor, NeuroD1, in microglia/macrophages in the injured striatum enables their conversion into induced neuronal cells that functionally integrate into the existing neuronal circuits. Furthermore, NeuroD1-mediated induced neuronal cell generation significantly improves neurological function in the mouse stroke model, and ablation of these cells abolishes the gained functional recovery. Our findings thus demonstrate that neuronal conversion contributes directly to functional recovery after stroke.

DOI： 10.1073/pnas.2307972120

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総ページ数：285   担当ページ：8  

開催年月日： 2026年5月

記述言語：英語   会議種別：ポスター発表  

開催年月日： 2025年5月

記述言語：日本語   会議種別：口頭発表（一般）  

開催年月日： 2025年3月

記述言語：日本語   会議種別：ポスター発表  

開催年月日： 2024年11月

記述言語：日本語   会議種別：ポスター発表  

開催年月日： 2024年7月

記述言語：英語   会議種別：ポスター発表  

記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経免疫学会  

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記述言語：日本語   出版者・発行元：医歯薬出版(株)  

＜文献概要＞現在,中枢神経損傷の治療に関して細胞移植などにより失われた神経細胞(ニューロン)を補充するような根本的治療法は確立していない.しかし近年,特定の転写因子遺伝子を導入することで,本来は神経活動を行わない細胞からニューロン(induced neuronal cell:iN細胞)を産出する直接分化転換(ダイレクトリプログラミング)が開発された.筆者らは,これまでにミクログリアに転写因子NeuroD1を強制発現させるレンチウイルスベクターを使用し,線条体に存在するミクログリアをiN細胞へとダイレクトリプログラミングさせることに成功している.さらに,局所脳虚血モデルマウスにおいても,急性期の梗塞巣でミクログリアを機能的なiN細胞へと転換させ,iN細胞が脳梗塞後の機能回復に直接寄与していることを明らかにした.今後,失われたニューロンをダイレクトリプログラミングによって補充することで神経機能を回復させるという,新しい治療法の開発が期待される.

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