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

Author:

Nishi Katsuyuki12,Sakamaki Taro12,Nagasaka Akiomi12,Kao Kevin S.3,Sadaoka Kay12,Asano Masahide4,Yamamoto Nobuyuki5ORCID,Takaori-Kondo Akifumi6ORCID,Miyanishi Masanori12

Affiliation:

1. Hematopoietic Stem Cell Biology and Medical Innovation (HSCBMI), Department of Pediatrics, Kobe University Graduate School of Medicine

2. RIKEN Center for Biosystems Dynamics Research

3. Weill Cornell, Rockefeller, Sloan-Kettering, Tri-Institutional MD-PhD Program

4. Institute of Laboratory Animals, Kyoto University Graduate School of Medicine

5. Department of Pediatrics, Kobe University Graduate School of Medicine

6. Department of Hematology and Oncology, Kyoto University Graduate School of Medicine

Abstract

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 organisms originates due to alteration of the ratio between LT-HSCs and ST-HSCs rather than in heterogeneous HSC clones with various cell fates.

Publisher

eLife Sciences Publications, Ltd

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