Molecular mechanisms underlining regulation of HSC niche formation and maintenance

2021 Fiscal Year Final Research Report

• Project/Area Number: 18H03998
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Medium-sized Section 44:Biology at cellular to organismal levels, and related fields
• Research Institution: Osaka University
• Principal Investigator: NAGASAWA TAKASHI 大阪大学, 生命機能研究科, 教授 (80281690)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Keywords: 微小環境 / 組織幹細胞 / 発生・分化 / 再生医学

Outline of Final Research Achievements

In bone marrow, the maintenance of hematopoietic stem cells (HSCs) require special microenvironments, known as HSC niches. A population of mesenchymal stem cells, termed CXC chemokine ligand 12 (CXCL12)-abundant reticular (CAR) cells are the major cellular component of HSC niches. The role of Runx transcription factors, Runx1 and Runx2, which are critical for development of HSCs and osteoblasts during ontogeny, respectively in HSC cellular niches remains unclear. We show that Runx1 and Runx2 are predominantly expressed in CAR cells and their progenitors and that mice lacking both Runx1 and Runx2 in CAR cells display an increase in fibrosis with markedly reduced hematopoietic stem and progenitor cells in bone marrow. In vitro, Runx1 is induced by the transcription factor Foxc1 and decreases fibrotic gene expression in CAR cells. Thus, HSC cellular niches require Runx1 or Runx2 to prevent their fibrotic conversion and maintain HSCs and hematopoiesis in adults.

Free Research Field

免疫学、血液学、幹細胞生物学

Academic Significance and Societal Importance of the Research Achievements

骨髄のCAR細胞は造血幹細胞ニッチを構成し、ニッチ形成に必須で、それぞれ脂肪細胞、骨芽細胞への分化を抑制する転写因子Foxc1、Ebf1/3を特異的に高発現することから、骨髄特異的な細胞系列である。本研究で、CAR細胞が線維芽細胞に変化するのを抑制する転写因子Runx1とRunx2が発見され、CAR細胞が、他の線維芽細胞と異なる性質を持って造血幹細胞ニッチを形成する分子基盤の理解が深められた。また、この成果は、Runx1とRunx2の低下が、様々な造血器腫瘍の予後を悪化させる骨髄線維症の病態形成に関与している可能性を提示し、臨床医学においても重要である。