Induction and expansion of PSC-derived HSCs by manipulating culture microenvironment

• Project/Area Number: 26670498
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Pediatrics
• Research Institution: Kyoto University
• Principal Investigator: Nakahata Tatsutoshi 京都大学, iPS細胞研究所, 教授 (20110744)
• Co-Investigator(Renkei-kenkyūsha): NIWA Akira 京都大学, iPS細胞研究所, 助教 (20546999) ; Osawa Mitsujiro 京都大学, iPS細胞研究所, 助教 (70546770)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 造血幹細胞 / ES/iPS細胞 / 移植・再生医療 / 臨床応用 / 細胞内代謝 / ストロマ細胞 / ニッチ / ES／iPS細胞

Outline of Final Research Achievements

Developing the way of hematopoietic stem cell (HSC) expansion or de novo stem cell induction has been of great interest in medical scientific fields. We cleared that pluripotent stem cell (PSC)-derived VE-Cadherin+ endothelial cells function as stromal microenvironment to induce PSC-derived HSC-like cells; they showed serial colony forming potential in vivo and were observed engrafted in NOG mice as long as twelve weeks. Moreover, a small molecule cocktail containing GSK3 and AHR pathway inhibitors successfully expanded them as high as six times in vitro, and increased the chimerism in vivo.

Research Products

• [Journal Article] Specific Antileukemic Activity of PD0332991, a CDK4/6 Inhibitor, against Philadelphia Chromosome-Positive Lymphoid Leukemia. (2016)
  • Author(s): Nemoto A, Saida S, Kato I, Kikuchi J, Furukawa Y, Maeda Y, Akahane K, Honna-Oshiro H, Goi K, Kagami K, Kimura S, Sato Y, Okabe S, Niwa A, Watanabe K, Nakahata T, Heike T, Sugita K, Inukai T.
  • Journal Title: Mol Cancer Ther. Volume: 15 Issue: 1 Pages: 94-105
  • DOI: 10.1158/1535-7163.mct-14-1065
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] High event-free survival rate with minimum-dose-anthracycline treatment in childhood acute promyelocytic leukaemia: a nationwide prospective study by the Japanese Paediatric Leukaemia/Lymphoma Study Group. (2016)
  • Author(s): Takahashi H, Watanabe T, Kinoshita A, Yuza Y, Moritake H, Terui K, Iwamoto S, Nakayama H, Shimada A, Kudo K, Taki T, Yabe M, Matsushita H, Yamashita Y, Koike K, Ogawa A, Kosaka Y, Tomizawa D, Taga T, Saito AM, Horibe K, Nakahata T, Miyachi H, Tawa A, Adachi S.
  • Journal Title: Br J Haematol. Volume: 印刷中 Issue: 3 Pages: 437-443
  • DOI: 10.1111/bjh.14068
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Establishment of isogenic iPSCs from an individual with SCN1A mutation mosaicism as a model for investigating neurocognitive impairment in Dravet syndrome. (2016)
  • Author(s): Maeda H, Chiyonobu T, Yoshida M, Yamashita S, Zuiki M, Kidowaki S, Isoda K, Yamakawa K, Morimoto M, Nakahata T, Saito MK, Hosoi H.
  • Journal Title: J Hum Genet. Volume: 印刷中 Issue: 6 Pages: 565-569
  • DOI: 10.1038/jhg.2016.5
  • NAID: 40020857171
  • Peer Reviewed / Open Access
• [Journal Article] 血液・免疫疾患のiPS細胞研究 (2016)
  • Author(s): 齋藤潤、中畑龍俊
  • Journal Title: 月刊細胞 Volume: 48 Pages: 13-16
• [Journal Article] Early pathogenesis of Duchenne muscular dystrophy modelled in patient-derived human induced pluripotent stem cells (2015)
  • Author(s): Shoji E, Sakurai H, Nishino T, Nakahata T, Heike T, Awaya T, Fujii N, Manabe Y, Matsuo M, Sehara-Fujisawa A
  • Journal Title: Sci Rep Volume: 5 Issue: 1 Pages: 12831-12831
  • DOI: 10.1038/srep12831
  • NAID: 120005649326
  • Peer Reviewed / Open Access
• [Journal Article] iPS細胞を使った血液疾患研究 (2015)
  • Author(s): 齋藤潤、中畑龍俊
  • Journal Title: 病理と臨床 Volume: 33 Pages: 582-586
• [Journal Article] Ⅱ．臨床応用を目指した基礎研究 疾患モデル細胞、iPS細胞を用いた毒性評価と創薬研究「iPS細胞を用いた疾患モデル研究（総論）」 (2015)
  • Author(s): 中畑龍俊
  • Journal Title: 日本臨床 Volume: 37 Pages: 374-380
• [Journal Article] In vitro expansion of CD34(+)CD38(-) cells under stimulation with hematopoietic growth factors on AGM-S3 cells in juvenile myelomonocytic leukemia. (2015)
  • Author(s): Sakashita K, Kato I, Daifu T, Saida S, Hiramatsu H, Nishinaka Y, Ebihara Y, Ma F, Matsuda K, Saito S, Hirabayashi K, Kurata T, Uyen Lt, Nakazawa Y, Tsuji K, Heike T, Nakahata T, Koike K.
  • Journal Title: Leukemia. Volume: 29(3) Issue: 3 Pages: 606-14
  • DOI: 10.1038/leu.2014.239
  • NAID: 120007110642
  • Peer Reviewed / Open Access
• [Journal Article] Enhanced chondrogenesis of induced pluripotent stem cells from patients with neonatal-onset multisystem inflammatory disease occurs via the caspase 1-independent cAMP/protein kinase A/CREB pathway (2015)
  • Author(s): Yokoyama, K. Ikeya, M. Umeda, K. Oda, H. Nodomi, S. Nasu, A. Matsumoto, Y. Izawa, K. Horigome, K. Kusaka, T. Tanaka, T. Saito, M. K. Yasumi, T. Nishikomori, R. Ohara, O. Nakayama, N. Nakahata, T. Heike, T. Toguchida, J.
  • Journal Title: Arthritis Rheumatol Volume: 67 Issue: 1 Pages: 302-314
  • DOI: 10.1002/art.38912
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Pluripotent cell models of Fanconi anemia identify the early pathological defect in human hemoangiogenic progenitors. (2015)
  • Author(s): Suzuki NM, Niwa A, Yabe M, Hira A, Okada C, Amano N, Watanabe A, Watanabe K, Heike T, Takata M, Nakahata T, Saito MK
  • Journal Title: Stem Cells Transl Med Volume: 4 Issue: 4 Pages: 333-338
  • DOI: 10.5966/sctm.2013-0172
  • NAID: 120005980869
  • Peer Reviewed / Open Access
• [Journal Article] Modeling the early phenotype at the euromuscular junction of spinal muscular atrophy using patient-derived iPSCs. (2015)
  • Author(s): Yoshida, M., Kitaoka, S., Egawa N., Yamane M., Ikeda R., Tsukita K., Amano N., Watanabe A., Morimoto, M., Takahashi J., Hosoi H., Nakahatan, T., Inoue, H.,Saito, Megumu K.
  • Journal Title: Stem Cell Reports Volume: 4 Issue: 4 Pages: 1-8
  • DOI: 10.1016/j.stemcr.2015.02.010
  • Peer Reviewed
• [Journal Article] iPS細胞からHTSに耐えうる疾患モデル評価系の構築 (2015)
  • Author(s): 中畑龍俊
  • Journal Title: 国際医薬品情報 Volume: 1025 Pages: 25-27
• [Journal Article] 特集によせて（iPS細胞を用いた難病研究－臨床病態解明と創薬に向けた研究の最新知見） (2015)
  • Author(s): 中畑龍俊
  • Journal Title: 遺伝子医学MOOK Volume: 27 Pages: 23-26
• [Journal Article] The clinical utility of genetic testing for t(8;16)(p11;p13) in congenital acute myeloid leukemia. (2014)
  • Author(s): Daifu T., Kato I., Kozuki K., Umeda K., Hiramatsu H., Watanabe K., Kamiya I., Taki T., Nakahata T., Heike T., Adachi S.
  • Journal Title: J Pediatr Hematol Oncol. Volume: 36 Issue: 5 Pages: e325-e327
  • DOI: 10.1097/mph.0000000000000099
  • Peer Reviewed
• [Journal Article] HAX1 in induced pluripotent stem cells from a patient with severe congenital neutropenia improves defective granulopoiesis. (2014)
  • Author(s): Morishima T, Watanabe K, Niwa A, Hirai H, Saida S, Tanaka T, Kato I, Umeda K, Hiramatsu H, Saito MK, Matsubara K, Adachi S, Kobayashi M, Nakahata T, Heike T
  • Journal Title: Haematologica Volume: 99(1) Issue: 1 Pages: 19-27
  • DOI: 10.3324/haematol.2013.083873
  • Peer Reviewed / Open Access
• [Journal Article] Peripheral blood lymphocyte telomere length as a predictor of response to immunosuppressive therapy in childhood aplastic anemia. (2014)
  • Author(s): Sakaguchi H, Nishio N, Hama A, Kawashima N, Wang X, Narita A, Doisaki S, Xu Y, Muramatsu H, Yoshida N, Takahashi Y, Kudo K, Moritake H, Nakamura K, Kobayashi R, Ito E, Yabe H, Ohga S, Ohara A, Kojima S; Japan Childhood Aplastic Anemia Study Group.
  • Journal Title: Haematologica Volume: 99 Issue: 8 Pages: 1312-1316
  • DOI: 10.3324/haematol.2013.091165
  • Peer Reviewed
• [Journal Article] Clinical characteristics of 15 children with juvenile myelomonocytic leukaemia who developed blast crisis: MDS Committee of Japanese Society of Paediatric Haematology/Oncology. (2014)
  • Author(s): Honda Y, Tsuchida M, Zaike Y, Masunaga A, Yoshimi A, Kojima S, Ito M, Kikuchi A, Nakahata T, Manabe A.
  • Journal Title: Br J Haematol Volume: in press Issue: 5 Pages: 682-687
  • DOI: 10.1111/bjh.12796
  • Peer Reviewed
• [Journal Article] Clinical characteristics and treatment outcome in 65 cases with refractory cytopenia of childhood defined according to the WHO 2008 classification. (2014)
  • Author(s): Hasegawa D, Chen X, Hirabayashi S, Ishida Y, Watanabe S, Zaike Y, Tsuchida M, Masunaga A, Yoshimi A, Hama A, Kojima S, Ito M, Nakahata T, Manabe A.
  • Journal Title: Br J Haematol. Volume: 166 Issue: 5 Pages: 758-66
  • DOI: 10.1111/bjh.12955
  • Peer Reviewed
• [Journal Article] Multicolor staining of globin subtypes reveals impaired globin switching during erythropoiesis in human pluripotent stem cells (2014)
  • Author(s): Ochi K, Takayama N, Hirose S, Nakahata T, Nakauchi H, Eto K
  • Journal Title: Stem cells translational medicine Volume: 3 Issue: 7 Pages: 792-800
  • DOI: 10.5966/sctm.2013-0216
  • Peer Reviewed
• [Journal Article] Derivation of mesenchymal stromal cells from pluripotent stem cells through a neural crest lineage using small molecule compounds with defined media. (2014)
  • Author(s): Fukuta M, Nakai Y, Kirino K, Nakagawa M, Sekiguchi K, Nagata S, Matsumoto Y, Yamamoto T, Umeda K, Heike T, Okumura N, Koizumi N, Sato T, Nakahata T, Saito M, Otsuka T, Kinoshita S, Ueno M, Ikeya M, Toguchida J.
  • Journal Title: PLOS ONE Volume: 9 Issue: 12 Pages: e112291-e112291
  • DOI: 10.1371/journal.pone.0112291
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Cytogenetics and clinical features of pediatric myelodysplastic syndrome in Japan. (2014)
  • Author(s): Moriwaki K, Manabe A, Taketani T, Kikuchi A, Nakahata T, Hayashi Y
  • Journal Title: Int J Hematol. Volume: 100 Issue: 5 Pages: 478-484
  • DOI: 10.1007/s12185-014-1674-z
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] ｉＰＳ細胞を用いた今後の医療 (2015)
  • Author(s): 中畑龍俊
  • Organizer: 第29回日本臨床内科医学会
  • Place of Presentation: ホテル日航熊本（熊本県、熊本市）
  • Year and Date: 2015-10-12
  • Invited
• [Presentation] iPS細胞研究の現状と今後の臨床展開－いよいよ本格化する再生医療の創薬の世界－ (2015)
  • Author(s): 中畑龍俊
  • Organizer: 第39回日本血液事業学会総会
  • Place of Presentation: グランキューブ大阪（大阪市）
  • Year and Date: 2015-10-04
  • Invited
• [Presentation] 疾患特異的iPS細胞を用いた今後の医療 (2015)
  • Author(s): 中畑龍俊
  • Organizer: 第39回阿蘇シンポジウム
  • Place of Presentation: 阿蘇リゾートグランヴィリオホテル（熊本県、阿蘇市）
  • Year and Date: 2015-08-01
  • Invited
• [Presentation] iPS細胞を用いた今後の医療 (2015)
  • Author(s): 中畑龍俊
  • Organizer: 第66回長野県医学会
  • Place of Presentation: 上田東急REIホテル3階「信濃の間」（長野県、上田市）
  • Year and Date: 2015-07-26
  • Invited
• [Presentation] Exploring the pathogenesis of transient my-exploliferative disorder using iPSCs. (2015)
  • Author(s): Nishinaka Yoko, Niwa Akira, Osawa Mitsujiro, Nakahata Tatsutoshi, Saito Megumu K.
  • Organizer: ISSCR 2015 Annual Meeting
  • Place of Presentation: Stockholmsmässan Exhibition and Convention Center(Sweden)
  • Year and Date: 2015-06-26
  • Int'l Joint Research
• [Presentation] Sequential switching of matrices directs human pluripotent stem cells into endothelial lineage. (2015)
  • Author(s): Ohta Ryo, Niwa Akira, Nakahata Tatsutoshi, Saito Megumu
  • Organizer: ISSCR 2015 Annual Meeting
  • Place of Presentation: Stockholmsmässan Exhibition and Convention Center(Sweden)
  • Year and Date: 2015-06-26
  • Int'l Joint Research
• [Presentation] The contribution of metabolites of the TCA cycle to maintenance of pluripotent stem cells. (2015)
  • Author(s): Saiki Norikazu, Ozaki Hitomi, Hirayama Akiyoshi, Soga Tomoyoshi, Tomita Masaru, Nakahata Tatsutoshi, Saito Megumu K.
  • Organizer: ISSCR 2015 Annual Meeting
  • Place of Presentation: Stockholmsmässan Exhibition and Convention Center(Sweden)
  • Year and Date: 2015-06-25
  • Int'l Joint Research
• [Presentation] PSC-Derived hematopoietic cells as a new tool for exploring leukemia pathogenesis. (2015)
  • Author(s): Niwa Akira, Saito Megumu, Nakahata Tatsutoshi
  • Organizer: ISSCR 2015 Annual Meeting
  • Place of Presentation: Stockholmsmässan Exhibition and Convention Center(Sweden)
  • Year and Date: 2015-06-24
  • Int'l Joint Research
• [Presentation] iPS細胞の小児がん治療への様々な応用 (2015)
  • Author(s): 中畑龍俊
  • Organizer: 東京都福祉保健局委託事業小児がん早期診断推進研修会 公開シンポジウム「小児がん治療の現在」
  • Place of Presentation: 聖路加国際大学アリス・C・セントジョンメモリアルホール
  • Year and Date: 2015-02-11
  • Invited
• [Presentation] Risk-Oriented Therapy for Myeloid Leukemia of Down Syndrome: A Nationwide Prospective Study By the Japanese Pediatric Leukemia / Lymphoma Study Group (JPLSG). (2014)
  • Author(s): Taga T, Watanabe T , Kudo K, Tomizawa D, Terui K, Moritake H, Kinoshita A, Iwamoto S, Nakayama H, Takahashi H, Shimada A, Taki T, Toki T, Ito E, Goto H, Koh K, A.M. Saito, Horibe K, Nakahata T, Tawa A, Adachi S
  • Organizer: 56th Annual Meeting of the AMERICAN SOCIETY of HEMATOLOGY
  • Place of Presentation: Mascone Convention Center(San Francisco,USA)
  • Year and Date: 2014-12-06 – 2014-12-09
• [Presentation] High Event-Free Survival Rate with Minimum-Dose-Anthracycline Treatment in Childhood Acute Promyelocytic Leukemia: A Nationwide Prospective Study By the Japanese Pediatric Leukemia / Lymphoma Study Group (JPLSG). (2014)
  • Author(s): Takahashi H, Watanabe T, Kinoshita A, Y, Moritake H, Terui K, Iwamoto S, Nakayama H, Shimada A, Kudo K, Taki T, Yabe M, Matsushita H, Yamashita Y, Koike K, Ogawa A, Kosaka Y, Tomizawa D, Taga T, A.K.Saito, Horibe K, Nakahata T, Miyachi H, Tawa A,Adachi S
  • Organizer: 56th Annual Meeting of the AMERICAN SOCIETY of HEMATOLOGY
  • Place of Presentation: Mascone Convention Center(San Francisco,USA)
  • Year and Date: 2014-12-06 – 2014-12-09
• [Presentation] Exploring the Pathogenesis of Down Syndrome-Related Myeloproliferative Disorders Using iPSCs. (2014)
  • Author(s): Nishinaka Yoko, Akira Niwa, Mitsujiro Osawa,, Akira Watanabe, Tatsutoshi Nakahata,, Megumu K Saito
  • Organizer: 56th Annual Meeting of the AMERICAN SOCIETY of HEMATOLOGY
  • Place of Presentation: Mascone Convention Center(San Francisco,USA)
  • Year and Date: 2014-12-06 – 2014-12-09
• [Presentation] Hematopoietic Stem Cell Transplantation for Patients with Refractory Cytopenia of Childhood. (2014)
  • Author(s): Daisuke Hasegawa , Shinsuke Hirabayashi , Shizuka Watanabe, Yuji Zaike , Masahiro Tsuchida,Atsuko Masunaga, Ayami Yoshimi, Asahito Hama, Seiji Kojima, Masafumi Ito, Tatsutoshi Nakahata, Atsushi Manabe
  • Organizer: 56th Annual Meeting of the AMERICAN SOCIETY of HEMATOLOGY
  • Place of Presentation: Mascone Convention Center(San Francisco,USA)
  • Year and Date: 2014-12-06 – 2014-12-09
• [Presentation] Phenomic Screen in Vivo and in Vitro to Explore Novel Pathogenesis of AML1-ETO-Positive Leukemia Using PSC-Derived Hematopoietic Cells. (2014)
  • Author(s): Akira Niwa, Akitsu Hotta, Megumu K Saito, Tatsutoshi Nakahata
  • Organizer: 56th Annual Meeting of the AMERICAN SOCIETY of HEMATOLOGY
  • Place of Presentation: Mascone Convention Center(San Francisco,USA)
  • Year and Date: 2014-12-06 – 2014-12-09
• [Presentation] Modeling Chediak-Higashi Syndrome using patient’s specific iPS cells. (2014)
  • Author(s): Shigeharu Oh, Akira Niwa, Megumu K. Saito, Tatsutoshi Nakahata
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2014-10-31
• [Presentation] Modeling chronic myelomonocytic leukemia through patient-derived induced pluripotent stem cells. (2014)
  • Author(s): Kazuki Taoka, Syunya Arai, Masataka Hosai, Fimihiko Nakamura, Masashi Miyauchi, Sho Yamazaki, Akira Honda, Keisuke Kataoka, Keiki Kumano, Akihide Yoshimi, Koji Eto, Hiromitsu Nakauchi, Tatsutoshi Nakahata, Mineo Kurokawa
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2014-10-31
• [Presentation] Mechanisms of CDK4/6 inhibitor hypersensitivity in Ph+ lymphoid leukemia. (2014)
  • Author(s): Atsushi Nemoto, Takeshi Inukai, Satoshi Saida, Itaru Kato, Toshio Heike, Tatsutoshi Nakahata, Jiro Kikuchi, Yusuke Furukawa, Kumiko Goi, Kanako Uno, Atsushi Watanabe, Sinpei Somazu, Meixian Huang, Keiko Kagami, Kanji Sugita
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2014-10-31
• [Presentation] 臍帯血中の造血幹細胞発見秘話と最近のiPS細胞研究 (2014)
  • Author(s): 中畑龍俊
  • Organizer: 第38回日本血液事業学会総会
  • Place of Presentation: 広島国際会議場
  • Year and Date: 2014-10-29
  • Invited
• [Presentation] iPS細胞を用いた小児医療の将来 (2014)
  • Author(s): 中畑龍俊
  • Organizer: 第50回中部日本小児学会会
  • Place of Presentation: 信州大学医学部付属病院
  • Year and Date: 2014-08-10
  • Invited
• [Presentation] 末梢血Natural Killer細胞を用いた人口多能性幹細胞の樹立 (2014)
  • Author(s): 桐野浩輔、尾崎富美子、丹羽明、中畑龍俊、齋藤潤、平家勇司
  • Organizer: 第35回日本炎症・再生医学会
  • Place of Presentation: 万国津梁館
  • Year and Date: 2014-07-02
• [Presentation] 疾患特異的iPS細胞を用いたChediak-東症候群の病態解析 (2014)
  • Author(s): 王茂治、丹羽明、齋藤潤、中畑龍俊
  • Organizer: 第35回日本炎症・再生医学会
  • Place of Presentation: 万国津梁館
  • Year and Date: 2014-07-02
• [Presentation] 疾患iPS細胞を用いた破骨細胞分化系の構築と分化能の検討 (2014)
  • Author(s): 伊藤眞理、村上美帆、丹羽明、齋藤潤、中畑龍俊、西本憲弘
  • Organizer: 第1回日本骨免疫会議
  • Place of Presentation: 万国津梁館
  • Year and Date: 2014-07-01
• [Presentation] Impaired neuronal maturation on seckel syndrome is caused by loss of self-organization and centrosome integrity during early neuronal development. (2014)
  • Author(s): Suzuki Naoya, Samata Bumpei, Habu Toshiyuki, Watanabe Akira, Nakahata Tatsutoshi, Takahashi Jun, Saito Megumu
  • Organizer: ISSCR 12th Annual Meeting
  • Place of Presentation: Vancouver Convention Center(CANADA)
  • Year and Date: 2014-06-20
• [Presentation] Efficient and less labor-intensive methods for inducing vascular endothelial cells from human pluripotent stem cells. (2014)
  • Author(s): Niwa Akira, Nakahata Tatsutoshi, Saito Megumu
  • Organizer: ISSCR 12th Annual Meeting
  • Place of Presentation: Vancouver Convention Center(CANADA)
  • Year and Date: 2014-06-18
• [Presentation] 患者由来iPS細胞を用いたCINCA症候群における関節症病態の解明 (2014)
  • Author(s): 横山宏司、西小森隆太、納富誠司郎、田中孝之、齋藤潤、梅田雄嗣、池谷真、中畑龍俊、戸口田淳也、平家俊男
  • Organizer: 第117回日本小児科学会学術集会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2014-04-11