Human bone marrow hematopoietic stem cells are increased in frequency and myeloid-biased with age

TLDR

Aging in humans is linked to reduced bone marrow cellularity, impaired adaptive immunity, and higher rates of anemia and hematologic malignancies, and while mouse studies implicate age‑related HSC changes, the corresponding alterations in human HSCs remain poorly defined. The study aimed to characterize how aged human bone marrow HSCs and progenitors differ from young counterparts to explain age‑related hematopoietic dysfunction. Researchers compared immunophenotypic HSC and progenitor populations from healthy young and elderly bone marrow samples, using flow cytometry and gene expression profiling. Aged human HSCs were more frequent, less quiescent, and myeloid‑biased, with transcriptional up‑regulation of cell‑cycle, myeloid‑lineage, and myeloid‑malignancy genes, mirroring mouse HSC changes and indicating conserved hematopoietic aging.

Abstract

In the human hematopoietic system, aging is associated with decreased bone marrow cellularity, decreased adaptive immune system function, and increased incidence of anemia and other hematological disorders and malignancies. Recent studies in mice suggest that changes within the hematopoietic stem cell (HSC) population during aging contribute significantly to the manifestation of these age-associated hematopoietic pathologies. Though the mouse HSC population has been shown to change both quantitatively and functionally with age, changes in the human HSC and progenitor cell populations during aging have been incompletely characterized. To elucidate the properties of an aged human hematopoietic system that may predispose to age-associated hematopoietic dysfunction, we evaluated immunophenotypic HSC and other hematopoietic progenitor populations from healthy, hematologically normal young and elderly human bone marrow samples. We found that aged immunophenotypic human HSC increase in frequency, are less quiescent, and exhibit myeloid-biased differentiation potential compared with young HSC. Gene expression profiling revealed that aged immunophenotypic human HSC transcriptionally up-regulate genes associated with cell cycle, myeloid lineage specification, and myeloid malignancies. These age-associated alterations in the frequency, developmental potential, and gene expression profile of human HSC are similar to those changes observed in mouse HSC, suggesting that hematopoietic aging is an evolutionarily conserved process.