Histopathological analysis of bone marrow remodeling process after hematopoietic stem cell transplantation and identification of cells responsible for engraftment failure

• Project/Area Number: 19K16585
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49020:Human pathology-related
• Research Institution: Osaka University
• Principal Investigator: Kurashige Masako 大阪大学, 医学系研究科, 特任助教(常勤) (10836422)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 骨髄 / ニッチ / 造血幹細胞移植 / CAR / 造血幹細胞ニッチ / 骨髄線維症 / CAR細胞 / ヒト / 病理 / 免疫

Outline of Research at the Start

造血幹細胞移植における致命的合併症の一つにドナー由来の造血が失敗する生着不全がある。その病態については未知の部分が多く、移植片を攻撃する免疫細胞の由来や造血支持する間質細胞が病態に関与する可能性についてはほとんど調べられていない。本研究では、ヒト骨髄の病理組織標本を用いて、まず、正常の生着過程における造血様式の経時的変化を明らかにし、次に、正常生着例を比較対象として、生着不全症例における責任細胞の由来および臨床病理学的特徴を明らかにする。これにより、実臨床では現在ある治療法の適切な選択が可能となり、また、新たな治療法の開発にも寄与するものと考える。

Outline of Final Research Achievements

Histopathological analysis of bone marrow after hematopoietic stem cell transplantation (HSCT) revealed that hematopoietic cells proliferate in a unique manner during the normal engraftment process. The cellularity of the bone marrow showed different secular changes depending on the hematopoietic stem cell source. After confirming that the human counterpart of mouse CAR cells (hCAR cells) can be histologically identified with EBF3 and CD271, we performed in-situ chimerism analysis of hCAR cells after HSCT in cases of normal engraftment and revealed that almost all hCAR cells after HSCT were derived from the recipient. In situ gene expression analysis of patients with myelofibrosis revealed that CXCL12 expression in hCAR cells was significantly elevated after HSCT compared with preconditioning.

Academic Significance and Societal Importance of the Research Achievements

ヒト造血幹細胞移植後の骨髄再構築過程を組織学的に解析した研究は極めて少なく、本研究では造血様式や細胞密度の変化のみでなく、移植ソースによる違いや組織マクロファージや造血幹細胞ニッチの主たる構成細胞であるCAR細胞のキメリズムの変化まで含めて明らかにした。また、少数例であるが骨髄線維症患者では移植後にCAR細胞のCXCL12発現レベルが上昇することを示した。これらの結果は血液病理学のみでなく移植医療においても重要な知見になると考えられる。

Research Products

• [Journal Article] Polycythemia Vera Associated with Pulmonary Hypertension and Diffuse Large B-Cell Lymphoma: A Case Report (2021)
  • Author(s): Kameda Satoshi、Sera Fusako、Sato Kazuaki、Kurashige Masako、Higo Shuichiro、Ohtani Tomohito、Tsuboi Akihiro、Hikoso Shungo、Morii Eiichi、Yamaguchi Osamu、Yamauchi-Takihara Keiko、Sakata Yasushi
  • Journal Title: American Journal of Case Reports Volume: 22
  • DOI: 10.12659/ajcr.932956
• [Journal Article] Identification of CXCL12-abundant reticular cells in human adult bone marrow (2021)
  • Author(s): Aoki K, Kurashige M, Ichii M, Higaki K, Sugiyama T, Kaito T, Ando W, Sugano N, Sakai T, Shibayama H; HANDAI Clinical Blood Club, Takaori-Kondo A, Morii E, Kanakura Y, Nagasawa T.
  • Journal Title: Br J Haematol . Volume: x Issue: 3 Pages: 659-668
  • DOI: 10.1111/bjh.17396
  • Peer Reviewed / Open Access
• [Journal Article] Bcl‐2‐negative <i>IGH‐BCL2</i> translocation‐negative follicular lymphoma of the thyroid differs genetically and epigenetically from Bcl‐2‐positive <i>IGH‐BCL2</i> translocation‐positive follicular lymphoma (2021)
  • Author(s): Hamamoto Yuichiro、Kukita Yoji、Kitamura Masanori、Kurashige Masako、Masaie Hiroaki、Fuji Shigeo、Ishikawa Jun、Honma Keiichiro、Wakasa Tomoko、Hanamoto Hitoshi、Hirokawa Mitsuyoshi、Suzuki Ayana、Morii Eiichi、Nakatsuka Shin‐ichi
  • Journal Title: Histopathology Volume: 79 Issue: 4 Pages: 521-532
  • DOI: 10.1111/his.14378
• [Journal Article] An immature inhibin‐α‐expressing subpopulation of ovarian clear cell carcinoma cells is related to an unfavorable prognosis (2021)
  • Author(s): Kusumoto Shinya、Kurashige Masako、Ohshima Kenji、Tahara Shinichiro、Matsui Takahiro、Nojima Satoshi、Hattori Satoshi、Morii Eiichi
  • Journal Title: Cancer Medicine Volume: 10 Issue: 5 Pages: 1485-1500
  • DOI: 10.1002/cam4.3801
  • Peer Reviewed / Open Access
• [Journal Article] Genomic and Pathological Characterization of Multiple Renal Cell Carcinoma Regions in Patient With Tuberous Sclerosis Complex: A Case Report (2021)
  • Author(s): Yamamoto Tetsuya、Kato Taigo、Hatano Koji、Kawashima Atsunari、Ujike Takeshi、Fukuhara Shinichiro、Kiuchi Hiroshi、Imamura Ryoichi、Ibuki Naokazu、Kiyotani Kazuma、Kurashige Masako、Morii Eichi、Fujita Kazutoshi、Nonomura Norio、Uemura Motohide
  • Journal Title: Frontiers in Oncology Volume: 11 Pages: 691996-691996
  • DOI: 10.3389/fonc.2021.691996
  • Peer Reviewed
• [Journal Article] Long-term Effects of the Janus Kinase 1/2 Inhibitor Ruxolitinib on Pulmonary Hypertension and the Cardiac Function in a Patient with Myelofibrosis (2020)
  • Author(s): Miyawaki H, Kioka H, Sato K, Kurashige M, Ozawa T, Shibayama H, Hikoso S, Morii E, Yamauchi-Takihara K, Sakata Y.
  • Journal Title: Internal Medicine Volume: 59 Issue: 2 Pages: 229-233
  • DOI: 10.2169/internalmedicine.3528-19
  • NAID: 130007785096
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2020-01-15
  • Peer Reviewed / Open Access
• [Journal Article] FAM111B enhances proliferation of KRAS ‐driven lung adenocarcinoma by degrading p16 (2020)
  • Author(s): Kawasaki Keisuke、Nojima Satoshi、Hijiki Sachiko、Tahara Shinichiro、Ohshima Kenji、Matsui Takahiro、Hori Yumiko、Kurashige Masako、Umeda Daisuke、Kiyokawa Hiroki、Kido Kansuke、Okuzaki Daisuke、Morii Eiichi
  • Journal Title: Cancer Science Volume: 111 Issue: 7 Pages: 2635-2646
  • DOI: 10.1111/cas.14483
  • Peer Reviewed / Open Access
• [Journal Article] Serine racemase enhances growth of colorectal cancer by producing pyruvate from serine (2020)
  • Author(s): Kenji Ohshima, Satoshi Nojima, Shinichiro Tahara, Masako Kurashige, Keisuke Kawasaki, Yumiko Hori, Moyu Taniguchi, Yutaka Umakoshi, Daisuke Okuzaki, Naoki Wada, Jun-ichiro Ikeda, Eiichiro Fukusaki & Eiichi Morii
  • Journal Title: Nature Metabolism volume Volume: 2 Issue: 1 Pages: 81-96
  • DOI: 10.1038/s42255-019-0156-2
  • Peer Reviewed
• [Journal Article] Ectonucleotidase CD39 is highly expressed on ATLL cells and is responsible for their immunosuppressive function. (2020)
  • Author(s): Yasuhiro Nagate, Sachiko Ezoe, Jiro Fujita, Daisuke Okuzakis, Daisuke Motooka, Tomohiko Ishibashi, Michiko Ichii, Akira Tanimura, Masako Kurashige, Eiichi Morii, Takuya Fukushima, Youko Suehiro, Takafumi Yokota, Hirohiko Shibayama, Kenji Oritani, Yuzuru Kanakura
  • Journal Title: Leukemia Volume: － Issue: 1 Pages: 107-118
  • DOI: 10.1038/s41375-020-0788-y
  • Peer Reviewed / Open Access
• [Presentation] 骨髄の病理:基礎から病理診断まで 骨髄造血を病理医が理解するための骨髄病理 (2021)
  • Author(s): 倉重 真沙子
  • Organizer: 日本病理学会会誌 2021年3月 (一社)日本病理学会
  • Invited
• [Presentation] Morphology of hematopoietic system reconstruction following hematopoietic stem cell transplantation (2020)
  • Author(s): 倉重真沙子
  • Organizer: 第109回日本病理学会総会
  • Invited