Development of a new therapy targeting CXCR4+ hematopoietic stem cells in patients with bone marrow failure

2016 Fiscal Year Final Research Report

• Project/Area Number: 15K15360
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Hematology
• Research Institution: Kanazawa University
• Principal Investigator: Shinji Nakao 金沢大学, 医学系, 教授 (70217660)
• Co-Investigator(Renkei-kenkyūsha): Yoshida Yoshinori 京都大学, iPS細胞研究所, 講師 (20447965) ; Nishiuchi Takumi 金沢大学, 学際科学実験センター, 准教授 (20334790)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Keywords: 再生不良性貧血 / 造血幹前駆細胞 / CXCR4 / BRGSマウス / iPS細胞 / 6pLOH

Outline of Final Research Achievements

A chemokine receptor CXCR4 is preferentially expressed by redundant hematopoietic stem/progenitor cells (HSPCs) that do not contribute to hematopoiesis. Stimulation of residual CXCR4(+) HSPCs may restore hematopoietic function of patients with acquired aplastic anemia (AA). First, we optimized method of engrafting an immune-deficient mouse (BRGS mouse) with cord-blood CD34(+) cells using intra-bone marrow injection, and confirmed the presence of human CD45(+) cells that accounted for 3.3-20.4% of the various tissue-derived cells. Next, we induced HSPCs from iPS cells that were generated from monocytes of AA patients possessing 6pLOH(+) leukocytes, which were predominant in the patients’ blood, as a result of uniparental disomy, and injected the HSPCs to the same mice. Regenerating human 6pLOH(+)CD34(+) cells in the mice expressed CXCR4 to a significantly lesser degree (mean 10.2%) than did 6pLOH(-)CD34(+) cells. We are currently exploring a method to activate CXCR4(+) HSPCs in vivo.

Free Research Field

血液内科学