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Alteration of long- and short-term hematopoietic stem cell ratio causes myeloid-biased hematopoiesis.

Katsuyuki Nishi | Taro Sakamaki | Akiomi Nagasaka | Kevin Shuolong Kao | Kay Sadaoka | Masahide Asano | Nobuyuki Yamamoto | Akifumi Takaori-Kondo | Masanori Miyanishi
eLife | 2025

Myeloid-biased hematopoiesis is a well-known age-related alteration. Several possibilities, including myeloid-biased hematopoietic stem cell (HSC) clones, may explain this. However, the precise mechanisms remain controversial. Utilizing the Hoxb5 reporter system to prospectively isolate long-term HSCs (LT-HSCs) and short-term HSCs (ST-HSCs), we found that young and aged LT-HSCs co-transplanted into the same recipients demonstrated nearly equivalent myeloid lineage output, contrary to the theory of myeloid-biased HSC clones. Transcriptomics indicated no significant myeloid gene enrichment in aged LT-HSCs compared to their young counterparts. Instead, transplanting reconstituted young HSCs with the ratio of LT/ST-HSCs seen in aged mice can significantly skew the lineage output to myeloid cells. In addition, while the niche environment in the bone marrow minimally affects myeloid-biased hematopoiesis, aged thymi and spleens substantially hinder lymphoid hematopoiesis, resulting in further myeloid domination. Thus, we demonstrate that myeloid-biased hematopoiesis in aged mice originates due to alteration of the ratio between LT-HSCs and ST-HSCs rather than in heterogeneous HSC clones with various cell fates.

Pubmed ID: 40864176

Associated grants

  • Agency: Japan Society for the Promotion of Science,
    Id: JP17K07407
  • Agency: Japan Agency for Medical Research and Development,
    Id: JP18gm6110020
  • Agency: Japan Society for the Promotion of Science,
    Id: JP21K20669
  • Agency: Japan Society for the Promotion of Science,
    Id: 23K15326
  • Agency: RIKEN,
    Id: Junior Research Associate Program
  • Agency: Japan Society for the Promotion of Science,
    Id: JP20H03268
  • Agency: Japan Society for the Promotion of Science,
    Id: The JSPS Core to Core program
  • Agency: Japan Society for the Promotion of Science,
    Id: JP22K16334
  • Agency: Japan Society for the Promotion of Science,
    Id: JP18J13408

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