A Cellular and Transcriptomic Atlas of the Aged Mouse Hematopoietic System

Area of Science:

• Hematology
• Immunology
• Gerontology

Background:

• Aging is a major risk factor for chronic diseases, characterized by tissue and organ functional decline.
• The aging hematopoietic system exhibits reduced regenerative capacity, DNA damage, and lineage skewing towards myeloid cells.

Purpose of the Study:

• To characterize the transcriptomic and cellular landscape of the aged C57Bl/6J mouse hematopoietic system.
• To identify age-related alterations in hematopoietic stem and progenitor cells (HSPCs) and immune cell populations.

Main Methods:

• Utilized bulk RNA sequencing and single-cell RNA sequencing (scRNAseq) on mouse peripheral blood mononuclear cells (PBMCs), lineage-depleted bone marrow cells (Lin-BM), and HSPCs (Lin- Sca1+ cKit+).
• Analyzed transcriptomic profiles and cell compositions across 39 hematopoietic cell types.

Main Results:

• Global transcriptional alterations and inflammatory process activation were observed in aged PBMCs and Lin-BM cells.
• HSPCs showed downregulation of cell cycle genes.
• Aged PBMCs exhibited decreased naive T cells and increased memory/exhausted T cells.
• Lin-BM cells displayed myeloid skewing in common myeloid progenitors and HSCs.
• A novel HSC population with increased Vwf, Wwtr1, and Clca3a1 expression was identified in aged mice.

Conclusions:

• Aging profoundly alters the hematopoietic system's transcriptional and cellular makeup.
• These findings provide a valuable resource for understanding age-related hematopoietic dysfunction.
• The identified unique aged HSC markers may offer therapeutic targets for age-related diseases.