Phenotypical and functional characterization of mesenchymal stem cells in the spleen

• Project/Area Number: 25292194
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Integrative animal science
• Research Institution: Tokyo University of Science
• Principal Investigator: GOITSUKA RYO 東京理科大学, 研究推進機構生命医科学研究所, 教授 (50301552)
• Co-Investigator(Renkei-kenkyūsha): MATSUZAKI YUMI 島根大学, 医学部, 教授 (50338183) ; KAWAI YASUHIRO 国立感染症研究所, 動物管理室, 研究員 (00416281)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥19,240,000 (Direct Cost: ¥14,800,000、Indirect Cost: ¥4,440,000); Fiscal Year 2015: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2014: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2013: ¥8,450,000 (Direct Cost: ¥6,500,000、Indirect Cost: ¥1,950,000)
• Keywords: 間葉系細胞 / 幹細胞 / 脾臓 / 発生 / 再生 / 微小環境 / 免疫 / 分化 / 間葉系幹細胞 / 転写因子 / リンパ器官 / 再生医療 / ニッチ / 造血

Outline of Final Research Achievements

Tlx1 is a transcription factor essential for spleen organogenesis, and is preferentially expressed in cultured mesenchymal stem cells derived from postnatal spleen. To characterize mesenchymal stemr cells in the spleen, we generated a reporter mouse line in which the CreER-Venus cassette was knocked into the Tlx1 gene locus, with the ROSA26-tdTomato allele, which enables both visualization of Tlx1+ cells by Venus and their lineage-tracing by tdTomato. A majority of Tlx1+ cells was localized in the red pulp, and these cells did not express mature stromal cell markers, but express mesenchymal stem markers. Tlx1+ cells have an ability to differentiate into adipocytes, osteoblasts and chondrocytes in vitro, and are capable to differentiate nearly all of the mesenchymal cell components of the spleen. Thus, these findings indicate that the Tlx1+ cells function as a spleen-selective mesenchymal stem/progenitor cells, participating in the homeostatic maintenance of the adult spleen.

Research Products

• [Journal Article] MEIS1-mediated transactivation of synaptotagmin-like 1 promotes CXCL12/CXCR4 signaling and leukemogenesis. (2016)
  • Author(s): Yokoyama T, Nakatake M, Kuwata T, Couiznet A, Goitsuka R, Tsutsumi S, Aburatani H, Valk PJ, Delwel R, Nakamura T.
  • Journal Title: J Clin Invest. Volume: 印刷中 Issue: 5 Pages: 1664-1678
  • DOI: 10.1172/jci81516
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Loss of the Homeodomain Transcription Factor Prep1 Perturbs Adult Hematopoiesis in the Bone Marrow. (2015)
  • Author(s): Yoshioka K, Oda A, Notsu C, Ohtsuka T, Kawai Y, Suzuki S, Nakamura T, Mabuchi Y, Matsuzaki Y, Goitsuka R.
  • Journal Title: PLoS One. Volume: 10(8) Issue: 8 Pages: e0136107-e0136107
  • DOI: 10.1371/journal.pone.0136107
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] An asymmetric antibody repertoire is shaped between plasmablasts and plasma cells after secondary immunization with (4-hydroxy-3-nitrophenyl)acetyl chicken γ-globulin. (2015)
  • Author(s): Tashiro Y, Murakami A, Goizuka R, Shimizu T, Kishimoto H, Azuma T
  • Journal Title: Int Immunol Volume: 12 Pages: 609-20
  • DOI: 10.1093/intimm/dxv040
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Promotion of crystalline cellulose degradation by expansins from Orysa sativa (2015)
  • Author(s): Seki, Y., Kikuchi, Y., Yoshimoto, R., Aburai, K., Kanai, Y., Ruike, T., Iwabata, K., Goitsuka, R., Sugawara, F., Abe, M., and Sakaguchi, K.
  • Journal Title: Planta Volume: 241 Issue: 1 Pages: 83-93
  • DOI: 10.1007/s00425-014-2163-6
  • Peer Reviewed
• [Journal Article] Generation of a Tlx1(CreER-Venus) knock-in mouse strain for the study of spleen development. (2014)
  • Author(s): Nakahara R, Kawai Y, Oda A, Nishimura M, Murakami A, Azuma T, Kaifu T, Goitsuka, R.
  • Journal Title: Genesis. Volume: 52 Issue: 11 Pages: 916-923
  • DOI: 10.1002/dvg.22829
  • Peer Reviewed
• [Journal Article] Meis1 regulates epidermal stem cells and is required for skin tumorigenesis (2014)
  • Author(s): Okumura K, Saito M, Isogai E, Aoto Y, Hachiya T, Sakakibara Y, Katsuragi Y, Hirose S, Kominami R, Goitsuka R, Nakamura T and Wakabayashi Y.
  • Journal Title: PLOS ONE Volume: 9 Issue: 7 Pages: e102111-e102111
  • DOI: 10.1371/journal.pone.0102111
  • Peer Reviewed / Open Access
• [Journal Article] Homeodomain transcription factor meis1 is a critical regulator of adult bone marrow hematopoiesis. (2014)
  • Author(s): Ariki R, Morikawa S, Mabuchi Y, Suzuki S, Nakatake M, Yoshioka K, Hidano S, Nakauchi H, Matsuzaki Y, Nakamura T, Goitsuka R.
  • Journal Title: PLoS One. Volume: 9 Issue: 2 Pages: 87646-87646
  • DOI: 10.1371/journal.pone.0087646
  • Peer Reviewed / Open Access
• [Journal Article] Meis1 is required for the maintenance of postnatal thymic epithelial cells. (2014)
  • Author(s): Hirayama T, Asano Y, Iida H, Watanabe T, Nakamura T, Goitsuka R.
  • Journal Title: PLOS One Volume: 9 Issue: 3 Pages: e89885-e89885
  • DOI: 10.1371/journal.pone.0089885
  • Peer Reviewed / Open Access
• [Presentation] 髄外造血ニッチとしての脾臓微小環境の形成機構 (2016)
  • Author(s): 後飯塚僚
  • Organizer: 福岡大学医学部再生医学研究所セミナー
  • Place of Presentation: 福岡大学医学部、福岡
  • Year and Date: 2016-02-24
  • Invited
• [Presentation] Transcription factor Tlx1 regulates cell migration of the spleno-pancreatic mesenchyme in spleen organogenesis. (2015)
  • Author(s): Toru Kasahara, Akihisa Oda, and Ryo Goitsuka
  • Organizer: 第44回日本免疫学会学術集会
  • Place of Presentation: 札幌コンベンションセンター、札幌
  • Year and Date: 2015-11-18
• [Presentation] Overexpression of Tlx1 in situ causes extramedullary hematopoiesis in the adult spleen. (2015)
  • Author(s): Akihisa Oda, Chihiro Notsu, and Ryo Goitsuka
  • Organizer: 第44回日本免疫学会学術集会
  • Place of Presentation: 札幌コンベンションセンター、札幌
  • Year and Date: 2015-11-18
• [Presentation] Maintenance of the white pulp architecture in the postnatal spleen requires Meis1 expression in mesenchymal progenitor cells. (2015)
  • Author(s): Chihiro Notsu, Akihisa Oda, and Ryo Goitsuka
  • Organizer: 第44回日本免疫学会学術集会
  • Place of Presentation: 札幌コンベンションセンター、札幌
  • Year and Date: 2015-11-18
• [Presentation] n asymmetric antibody repertoire is shaped between plasmablasts and plasma cells after secondary immunization with (4-hydroxy-3-nitrophenyl acetyl; NP) hapten. (2015)
  • Author(s): Yasuyuki Tashiro, Akikazu Murakami, Ryo Goitsuka, Takeyuki Shimizu, Hidehiro Kishimoto and Takachika Azuma
  • Organizer: 第44回日本免疫学会学術集会
  • Place of Presentation: 札幌コンベンションセンター、札幌
  • Year and Date: 2015-11-18
• [Presentation] Endogenous MOZ was essential for MOZ-TIF2-induced Meis1 upregulation and AML development. (2015)
  • Author(s): Katsumoto, T., Yamagata, K., Ogawara, Y., Nakamura, T., Goitsuka, R., and Kitabayashi, I
  • Organizer: 第77回日本血液学会学術集会
  • Place of Presentation: ホテル日航金沢（石川県）
  • Year and Date: 2015-10-16
• [Presentation] Cell fate mapping of embryonic spleen primordium cells expressing the transcription factor Tlx1. (2015)
  • Author(s): Kasahara, T., Oda, A., and Goitsuka, R
  • Organizer: 第24回日本バイオイメージング学会学術集会
  • Place of Presentation: 東京理科大学葛飾キャンパス、東京
  • Year and Date: 2015-09-26
• [Presentation] ホメオドメイン転写因子Tlx1は脾臓原基間葉系細胞の分化運命を規定する。 (2015)
  • Author(s): 笠原透、中原亮、野津智尋、小田朗永、後飯塚僚
  • Organizer: 第25回学術集会Kyoto T cell conference
  • Place of Presentation: 京都大学芝蘭会館（京都）
  • Year and Date: 2015-05-15 – 2015-05-16
• [Presentation] ホメオドメイン転写因子Tlx1は赤脾髄における赤芽球・マクロファージの維持に関与する (2015)
  • Author(s): 小田朗永、笠原透、野津智尋、後飯塚僚（
  • Organizer: 第25回学術集会Kyoto T cell conference
  • Place of Presentation: 京都大学芝蘭会館（京都）
  • Year and Date: 2015-05-15 – 2015-05-16
• [Presentation] メオドメイン転写因子Tlx1は脾臓原基間葉系細胞の分化運命を規定する (2015)
  • Author(s): 笠原透、中原亮、野津智尋、小田朗永、後飯塚僚
  • Organizer: 第25回学術集会Kyoto T cell conference
  • Place of Presentation: 京都大学芝蘭会館、京都
  • Year and Date: 2015-05-15
• [Presentation] ホメオドメイン転写因子Tlx1は赤脾髄における赤芽球・マクロファージの維持に関与する (2015)
  • Author(s): 小田朗永、笠原透、野津智尋、後飯塚僚
  • Organizer: 第25回学術集会Kyoto T cell conference
  • Place of Presentation: 京都大学芝蘭会館、京都
  • Year and Date: 2015-05-15
• [Presentation] Contribution of Tlx1-expresssing mesenchymal cells to splenic microenvironment formation during organogenesis and regeneration. (2015)
  • Author(s): Akihisa Oda, Ryo Nakahara, Chihiro Notsu, and Ryo Goitsuka
  • Organizer: Venice Thymus Meeting 2015
  • Place of Presentation: Venice International University (Venice)
  • Year and Date: 2015-04-09 – 2015-04-13
• [Presentation] Contribution of Tlx1-expressing mesenchymal cells to splenic microenvironment formation during organogenesis and regeneration. (2015)
  • Author(s): Akihisa Oda, Ryo Nakahara, Chihiro Notsu, Toru Kasahara, and Ryo Goitsuka
  • Organizer: Venice Thymus Meeting 2015
  • Place of Presentation: Venice International University, Italy
  • Year and Date: 2015-04-09
  • Int'l Joint Research
• [Presentation] sotype-specific regulation of antibody secretion and affinity maturation during immune response to (4-hydroxy-3-nitrophenyl acetyl; NP) hapten. (2014)
  • Author(s): Yasuyuki Tashiro, Ryo Goitsuka and Takachika Azuma
  • Organizer: 第43回日本免疫学会学術集会
  • Place of Presentation: 国立京都国際会館（京都）
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] The role of postnatal mesenchymal cell population retaining a potential to give rise to various types of mature stromal cells in the spleen. (2014)
  • Author(s): Akihisa Oda, Ryo Nakahara, Chihiro Notsu, Toru Kasahara, and Ryo Goitsuka
  • Organizer: 第43回日本免疫学会学術集会
  • Place of Presentation: 国立京都国際会館（京都）
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] Contribution of Tlx1-expresssing mesenchymal cells to splenic microenvironment formation during organogenesis and regeneration. (2014)
  • Author(s): Ryo Nakahara, Chihiro Notsu, Akihisa Oda, and Ryo Goitsuka
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（横浜）
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] eis1 is a crucial regulator of epidermal stem cell maintenance and skin carcinogenesis (2014)
  • Author(s): Yuichi Wakabayashi, Kazuhiro Okumura, Megumi Saito, Yoshimasa Aoto, Yasubumi Sakakibara, Ryo Kominami, Ryo Goitsuka, Takuro Nakamura, and Eriko Isogai
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（横浜）
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] Role of Meis1 in the cerebellar development (2014)
  • Author(s): Tomoo Owa, Shinichiro Taya, Tomoki Nishioka, Takuro Nakamura, Ryo Goitsuka, Kozo Kaibuchi, Mikio Hoshino
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（横浜）
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] 脾臓の微小環境を構成する間葉系細胞の起源と機能 (2014)
  • Author(s): 後飯塚僚
  • Organizer: 第157回日本獣医学会学術集会
  • Place of Presentation: 北海道大学高等教育推進機構（札幌）
  • Year and Date: 2014-09-09 – 2014-09-12
• [Presentation] 成体脾臓微小環境の維持におけるTlx1発現間葉系細胞の役割. (2014)
  • Author(s): 小田朗永、野津智尋、中原亮、後飯塚僚
  • Organizer: 第24回学術集会Kyoto T cell conference
  • Place of Presentation: 京都平安ホテル（京都）
  • Year and Date: 2014-05-16 – 2014-05-17
• [Presentation] Homeodomain transcription factor Tlx1 marks a unique population of postnatal spleen mesenchymal cells. (2013)
  • Author(s): Nakahara, R., Kawai, Y., Hirayama, T., Iwakura, Y. and Goitsuka, R
  • Organizer: International Workshop on T Lymphocytes
  • Place of Presentation: Kyoto
• [Presentation] A new mouse line for dissecting the lineage relationship and functions of mesenchymal cell components consisting of the spleen microenvironment. (2013)
  • Author(s): Goitsuka, R.
  • Organizer: International Workshop on T Lymphocytes
  • Place of Presentation: Kyoto
  • Invited
• [Presentation] Differentiation potentials of mesenchymal cells expressing the homeodomain transcription factor Tlx1 in embryonic and postnatal spleen. (2013)
  • Author(s): Goitsuka, R., Nakahara, R., Oda, A. and Notsu
  • Organizer: 4th Workshop of Synthetic Immunology
  • Place of Presentation: Kyoto
  • Invited
• [Presentation] Mesenchymal progenitor-like cells in the neonatal spleen identified by homeodomain transcription factor Tlx1. (2013)
  • Author(s): Notsu, C., Oda, A., Nakahara, R. and Goitsuka, R.
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸
• [Presentation] Perivascular mural cells in the postnatal spleen express homeodomain transcription factor Tlx1. (2013)
  • Author(s): Nakahara, R., Oda, A. and Notsu, C., and Goitsuka, R.
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸
• [Presentation] Developmental regulation of the splenic microenvironment by mesenchymal cells expressing homeodomain transcription factor Tlx1. (2013)
  • Author(s): Oda, A., Notsu, C., Nakahara, R. and Goitsuka, R.
  • Organizer: 第36回日本分子生物学会年会
  • Place of Presentation: 神戸
• [Presentation] Homeodomain transcription factor Tlx1 marks a unique population of postnatal spleen mesenchymal cells. (2013)
  • Author(s): Nahara, R., Oda, A. and Notsu, C., and Goitsuka, R.
  • Organizer: 第42回日本免疫学会学術集会
  • Place of Presentation: 幕張
• [Remarks] 東京理科大学 生命医科学研究所/大学院 生命科学研究科 発生及び老化研究部門
  • URL: http://www.ribs.tus.ac.jp/laboratories/block05/