CAMT-iPS Cells Exhibiting Defective MPL Signaling Dysregulate hematopoiesis

2012 Fiscal Year Final Research Report

• Project/Area Number: 23791154
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pediatrics
• Research Institution: Kyoto University
• Principal Investigator: TAKAYAMA Naoya 京都大学, iPS 細胞研究所, 助教 (10584229)
• Project Period (FY): 2011 – 2012
• Keywords: 疾患特異的iPS細胞 / CAMT / c-MPL / 巨核球分化 / 赤血球分化

Research Abstract

Congenital amegakaryocytic thrombocytopenia (CAMT) is caused by the loss of thrombopoietin receptor (MPL)-mediated signaling, which causes severe pancytopenia leading to bone marrow failure with onset of thrombocytopenia and anemia prior to leukopenia. We used an in vitro disease tracing system with iPSCs derived from a CAMT patient (CAMT-iPSCs) and normal iPSCs to investigate the role of MPL signaling in hematopoiesis. In this study, we found that1) MPL signaling is essential for maintenance of the CD34+multipotent hematopoietic progenitor (MPP) population and 2) for development of the CD41+Glycophorin-A (GPA)+ megakaryocyte-erythrocyte progenitor (MEP) population 3) complementation of appropriate expression level of MPL into CAMT-iPSCs using a retroviral vector improved potential of MK and erythrocyte differentiation 4) excessive MPL expression led to aberrant megakaryopoiesis and generation of GPIba and GPIV null platelets.These results recapitulate the clinical course seen in CAMT-patients in vitro and suggest importance of appropriate gene complementation as cell therapy for CAMT-patients.

Research Products

• [Journal Article] CAMT-iPS Cells Exhibiting Defective MPL Signaling Dysregulate Megakaryopoiesis and Erythropoiesis. (2013)
  • Author(s): Hirata S., Takayama N.(Corresponding author),Jono-Ohnishi R., Endo H., Nakamura S., Dohda T., Nishi M., Hamazaki Y., IshiiE.,Kaneko S., Otsu M., NakauchiH.,Kunishima S., and Eto K.
  • Journal Title: Journal of Clinical Investigation
  • Peer Reviewed
• [Journal Article] Generation of rejuvenated antigen- specific T cells by reprogramming to pluripotency and redifferentiation. (2013)
  • Author(s): ishimura T,Kaneko S,Kawana A,Tajima Y,Goto H,Zhu D,NakayamaK, Uemura Y ,Takayama N, Yamada D,Nishimura K,Ohtaka M,Watanabe N,Takahashi S,Iwamoto A,Koseki H,Nakanishi M,Eto K,Nakauchi H
  • Journal Title: Cell StemCell. Volume: 12 Pages: 114-126
  • DOI: doi:10.1016/ j.stem.2012.11.002.
  • Peer Reviewed
• [Journal Article] Role of SOX17 in hematopoietic development fromhuman embryonic stemcells. (2012)
  • Author(s): Nakajima- Takagi Y, Osawa M, Oshima M, Takagi H, Miyagi S, Endoh M, Endo TA, Takayama N, Eto K, Toyoda T, Koseki H, Nakauchi H, Iwama A..
  • Journal Title: Blood. Volume: 121 Pages: 447-458
  • DOI: doi:10.1182/ blood- 2012- 05-431403.
  • Peer Reviewed
• [Journal Article] Pluripotent stemcells reveal the developmental biology of human megakaryocytes and provide a source of platelets for clinical application. (2012)
  • Author(s): Takayama N, Eto K.
  • Journal Title: Cell Mol Life Sci. Volume: 69 Pages: 3419- 3428
  • DOI: doi:10.1007/ s00018- 012- 0995- 4.
  • Peer Reviewed
• [Journal Article] Generation of induced pluripotent stemcells fromprimary chronic myelogenous leukemia patient samples. (2011)
  • Author(s): Kumano K, Arai S, Hosoi M, Taoka K, Takayama N, Otsu M, Nagae G, Ueda K, Nakazaki K, Kamikubo Y, Eto K, Aburatani H, Nakauchi H, Kurokawa M..
  • Journal Title: Blood Volume: 119 Pages: 6234-6242
  • DOI: doi:10.1182/ blood- 2011- 07-367441
  • Peer Reviewed
• [Journal Article] Donor- dependent variations in hepatic differentiation fromhumaninduced pluripotent stemcells.
  • Author(s): Kajiwara M, Aoi T, Okita K, Takahashi R, Inoue H, Takayama N, Endo H, Eto K, Toguchida J, Uemoto S, Yamanaka S.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 109 Pages: 12538-12543.
  • DOI: doi:10.1073/pnas.1209979109.
  • Peer Reviewed