Pathological analysis of hematopoietic failure caused by differentiation abnormalities in mesenchymal stem/stromal cells

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K16258
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Foundation for Biomedical Research and Innovation at Kobe
• Principal Investigator: Hayashi Yasutaka 公益財団法人神戸医療産業都市推進機構, その他部局等, 研究員 (10854664)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 骨髄微小環境 / 間葉系幹細胞 / 骨髄異形成症候群

Outline of Final Research Achievements

In Myelodysplastic syndrome (MDS), MDS cells remodel bone marrow mesenchymal stem/stromal cells (MSC) to construct a favorable environment for themselves. In this study, we explored subpopulations that played a crucial role in the pathogenesis of MDS through single-cell analysis of MSCs. Our single-cell RNA-seq data showed remarkable downregulation of niche factors in the Leptin receptor high subpopulation (LepR-high MSCs). We also found suppressed osteoblastic differentiation in LepR-high MSCs derived from MDS, which led to a reduction of osteoblastic subpopulation in MDS. Furthermore, we identified a decreased activity in the enhancer region of the niche factor gene in LepR-high MSCs from MDS. We confirmed the presence of motif sequences for transcription factors that regulate osteoblastic differentiation in this region. These findings suggest that hematopoietic failure in MDS occurs via transcription factors that regulate osteoblastic differentiation.

Free Research Field

骨髄微小環境

Academic Significance and Societal Importance of the Research Achievements

本研究は、骨髄異形成症候群(MDS)では骨髄間葉系幹細胞(MSC)の骨芽細胞系列への分化障害を介して造血不全を惹起することを明らかにした。またLeptin受容体遺伝子高発現MSC亜集団はMDSの病態に鍵となる役割を果たし、同亜集団においてニッチ因子の新規エンハンサー領域が疾患による分化抑制に伴い顕著に変動することを見出した。これらの知見はMDSにおけるMSC機能異常を司るマスターレギュレーターを明らかにし、改変MSCを対象とする治療応用につながると期待される。