神経系細胞の分化制御機構及びその再生医療応用に関する研究
キーワード：神経幹細胞、分化、エピジェネティクス、ダイレクトリプログラミング
2013.04～2028.12.
主要原著論文
| 1. |
Irie T, Matsuda T, Hayashi Y, Matsuda-Ito K, Kamiya A, Masuda T, Prinz M, Isobe N, Kira JI, Nakashima K., Direct neuronal conversion of microglia/macrophages reinstates neurological function after stroke, Proc Natl Acad Sci USA, in press, 2023.10, 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.. |
| 2. |
Sayako Katada,Jun Takouda,Takumi Nakagawa,Mizuki Honda,Katsuhide Igarashi,
Takuya Imamura,Yasuyuki Ohkawa,Shoko Sato,Hitoshi Kurumizaka,Kinichi Nakashima, Neural stem/precursor cells dynamically change their epigenetic landscape to differentially respond to BMP signaling for fate switching during brain development, Genes Dev, 10.1101/gad.348797.121., 35, 1431-1444, 2021.11, During neocortical development, tight regulation of neurogenesis-to-astrogenesis switching of neural precursor cells
(NPCs) is critical to generate a balanced number of each neural cell type for proper brain functions. Accumulating
evidence indicates that a complex array of epigenetic modifications and the availability of extracellular factors
control the timing of neuronal and astrocytic differentiation. However, our understanding of NPC fate regulation is
still far from complete. Bone morphogenetic proteins (BMPs) are renowned as cytokines that induce astrogenesis of
gliogenic late-gestational NPCs. They also promote neurogenesis of mid-gestational NPCs, although the underlying
mechanisms remain elusive. By performing multiple genome-wide analyses, we demonstrate that Smads, transcription
factors that act downstream from BMP signaling, target dramatically different genomic regions in neurogenic
and gliogenic NPCs. We found that histone H3K27 trimethylation and DNA methylation around Smadbinding
sites change rapidly as gestation proceeds, strongly associated with the alteration of accessibility of Smads to
their target binding sites. Furthermore, we identified two lineage-specific Smad-interacting partners—Sox11 for
neurogenic and Sox8 for astrocytic differentiation—that further ensure Smad-regulated fate-specific gene induction.
Our findings illuminate an exquisite regulation of NPC property change mediated by the interplay between
cell-extrinsic cues and -intrinsic epigenetic programs during cortical development.. |
| 3. |
Doi, H.
Matsuda, T.
Sakai, A.
Matsubara, S.
Hoka, S.
Yamaura, K.
Nakashima, K., Early-life midazolam exposure persistently changes chromatin accessibility to impair adult hippocampal neurogenesis and cognition, Proc Natl Acad Sci USA, 10.1073/pnas.2107596118, 118, 38, 2021.09, We previously reported that protein tyrosine phosphatase non-receptor type 3 (PTPN3), which is upregulated in activated lymphocytes, acts as an immune checkpoint. However, the mechanism by which PTPN3 expression is enhanced in activated lymphocytes is unknown. In this study, we analyzed the mechanism of PTPN3 expression in activated lymphocytes with a view for developing a novel immune checkpoint inhibitor that suppresses PTPN3. Through the activation process, lymphocytes showed enhanced NFkappaB activation as well as increased PTPN3 expression. NFkappaB enhanced proliferation, migration, and cytotoxicity of lymphocytes. Furthermore, NFkappaB enhanced PTPN3 expression and tyrosine kinase activation. TGFbeta reduced PTPN3 expression and NFkappaB activation in the cancer microenvironment, and suppressed the biological activity of lymphocytes. The results of this study are expected to provide significant implications for improving existing immunotherapy and developing novel immunotherapy.. |
| 4. |
Nakashima, H.
Tsujimura, K.
Irie, K.
Imamura, T.
Trujillo, C. A.
Ishizu, M.
Uesaka, M.
Pan, M.
Noguchi, H.
Okada, K.
Aoyagi, K.
Andoh-Noda, T.
Okano, H.
Muotri, A. R.
Nakashima, K., MeCP2 controls neural stem cell fate specification through miR-199a-mediated inhibition of BMP-Smad signaling, Cell Reports, 10.1016/j.celrep.2021.109124, 35, 7, 2021.05, Rett syndrome (RTT) is a severe neurological disorder, with impaired brain development caused by mutations in MECP2; however, the underlying mechanism remains elusive. We know from previous work that MeCP2 facilitates the processing of a specific microRNA, miR-199a, by associating with the Drosha complex to regulate neuronal functions. Here, we show that the MeCP2/miR-199a axis regulates neural stem/precursor cell (NS/PC) differentiation. A shift occurs from neuronal to astrocytic differentiation of MeCP2- and miR-199a-deficient NS/PCs due to the upregulation of a miR-199a target, Smad1, a downstream transcription factor of bone morphogenetic protein (BMP) signaling. Moreover, miR-199a expression and treatment with BMP inhibitors rectify the differentiation of RTT patient-derived NS/PCs and development of brain organoids, respectively, suggesting that facilitation of BMP signaling accounts for the impaired RTT brain development. Our study illuminates the molecular pathology of RTT and reveals the MeCP2/miR-199a/Smad1 axis as a potential therapeutic target for RTT.. |
特許出願・取得
特許出願件数 2件
特許登録件数 0件
所属学会名
International Society for Stem Cell Research
Society for Neuroscience
日本エピジェネティクス研究会
日本神経科学学会
日本分子生物学会
学協会役員等への就任
2019.01～2020.12, 日本分子生物学会, 理事.
2017.01～2018.12, 日本分子生物学会, 理事.
2012.05～2017.04, 日本エピジェネティクス研究会, 幹事.
学会大会・会議・シンポジウム等における役割
2023.10.31～2023.11.02, 第96回日本生化学会大会, 幹事.
2022.06.09～2022.06.10, 第15回日本エピジェネティクス研究会年会, 組織委員.
2019.12.03～2019.12.06, 第４２回日本分子生物学会年会, 組織委員長.
2017.12.02～2017.12.02, 第13回成体脳ニューロン新生懇談会, 年会長.
2017.01.08～2017.01.12, KEYSTONE SYMPOSIA, Other.
2015.03.19～2015.03.20, 第8回神経発生討論会, その他.
2013.05.30～2013.05.31, 第７回日本エピジェネティクス研究会年会, その他.
学会誌・雑誌・著書の編集への参加状況
2017.01～2023.12, Neuroscience Research, 国際, 査読委員.
2006.05～2023.04, Stem Cells, 国際, 査読委員.
学術論文等の審査
| 年度 |
外国語雑誌査読論文数 |
日本語雑誌査読論文数 |
国際会議録査読論文数 |
国内会議録査読論文数 |
合計 |
| 2013年度 |
19 |
0 |
1 |
0 |
20 |
文部科学大臣表彰若手科学者賞, 2005.04.
日本分子生物学会三菱化学奨励賞, 2006.12.
テルモ財団賞, テルモ生命科学芸術財団, 2012.07.
科学研究費補助金の採択状況(文部科学省、日本学術振興会)
2023年度～2024年度, 挑戦的研究（萌芽）, 代表, 脊髄損傷による遠位脳のニューロン新生低下と認知障害誘発機構の解明及び改善法の創発.
2023年度～2026年度, 基盤研究(A), 代表, 脳老化と神経疾患に共通した脳機能低下に懸かる細胞間相互作用機序の統合的理解.
2016年度～2020年度, 新学術領域研究, 代表, 個性を創発する神経幹細胞におけるエピジェネティックメモリーとその制御.
2017年度～2020年度, 基盤研究(A), 代表, 非神経細胞とマイクロRNA生合成撹乱の観点から探る神経発達障害発症の分子基盤解明.
2019年度～2020年度, 挑戦的研究（萌芽）, 代表, ミクログリア－ニューロン直接分化転換機構の解明と新規脊髄損傷治療法開発の試み.
2020年度～2025年度, 革新的先端研究開発支援事業ユニットタイプ, 代表, 環境変化誘発性精神・神経疾患の発症共通原理の解明ならびに完全非侵襲的細胞置換による治療法の創出.
2019年度～2022年度, 厚生労働科学研究費補助金 (厚生労働省）, 連携, 認知症に関与するマイクロバイオーム・バイオメーカー解析の研究.
2019年度～2021年度, 再生医療実現拠点ネットワークプログラム, 代表, 完全非侵襲的新生ニューロン補充による新規脳梗塞治療法の創出.
2018年度～2020年度, 厚生労働科学研究費補助金 (厚生労働省）, 分担, 家庭用品化学物質が周産期の中枢神経系に及ぼす遅発性毒性の評価系作出に資する研究.
2018.04～2021.03, ゲノム編集技術を用いたモデル動物作出による精神神経筋疾患の病態解明.
