A Notch trans-activation to cis-inhibition switch underlies hematopoietic stem cell aging.

Proliferation-Dependent Alterations of the DNA Methylation Landscape Underlie Hematopoietic Stem Cell Aging

Dysfunctional Clusterin-Positive Hematopoietic Stem Cells Expand with Aging

Aging is associated with reduced fitness and increased myeloid bias of the hematopoietic stem cell (HSC) compartment, causing increased risk of immune compromise, anemia, and malignancy. We show that mitochondrial membrane potential (MMP) can be used to prospectively isolate chronologically old HSCs with transcriptional features and functional attributes characteristic of young HSCs, including a high rate of transcription and balanced lineage-affiliated programs. Strikingly, MMP is a stronger determinant of the quantitative and qualitative transcriptional state of HSCs than chronological age, and transcriptional consequences of manipulation of MMP in HSCs within their native niche suggest a causal relationship. Accordingly, we show that pharmacological enhancement of MMP in old HSCs invivo increases engraftment potential upon transplantation and reverses myeloid-biased peripheral blood output at steady state. Our results demonstrate that MMP is a source of heterogeneity in old HSCs, and its pharmacological manipulation can alter transcriptional programs with beneficial consequences for function.

Heterogeneity and hierarchy of hematopoietic stem cells

Histone Alterations Are Associated with Hematopoietic Stem Cell (HSC) Differentiation and Aging

Clonality and Mixed Mutational Signature in Aged Hematopoietic Stem Cells Via Single Cell Variant Analysis

Platelet Factor 4 (PF4) Regulates Hematopoietic Stem Cell Aging

Changes in the frequencies of human hematopoietic stem and progenitor cells with age and site

Unraveling Heterogeneity of Aged Hematopoietic Stem Cells By Single-Cell RNA Sequence Analysis

Functional and Molecular Heterogeneity of Aging Hematopoietic Stem Cells

HSC Aging Epigenome: Widespread Alterations in DNA Methylation and Transcription.

NOTCH-mediated exvivo expansion of human hematopoietic stem and progenitor cells by culture under hypoxia.

Endothelial mTOR Preserves Hematopoietic Stem Cell Fitness By Suppressing Thrombospondin1

Age-Related Changes in Hematopoietic Stem Cell Proteostasis Promote the Emergence of Clonal Hematopoiesis and Leukemia in Older Adults

Aging of the Hematopoietic Stem Cell Niche: An Unnerving Matter.