Proliferation Drives Aging-Related Functional Decline in a Subpopulation of the Hematopoietic Stem Cell Compartment

Kirschner, Kristina; Chandra, Tamir; Kiselev, Vladimir Yu; Cruz, David Flores-Santa; Macaulay, Iain C.; Park, Hyun Jun; Li, Juan; Kent, David G.; Kumar, Rupa; Pask, Dean C.; Hamilton, Tina L.; Hemberg, Martin; Reik, Wolf; Green, Anthony

doi:10.1016/j.celrep.2017.04.074

Cited by 80 publications

(101 citation statements)

References 35 publications

(62 reference statements)

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“…Beyond shifting cell state proportions, aging could promote the formation of novel cell states unseen in young animals. Previous studies have reported the emergence of novel cell states with age in the hematopoietic system (Kirschner et al 2017), and senescence phenotypes may be considered novel cell states from this perspective (Sousa-Victor et al 2014;Sharpless and Sherr 2015;Baker et al 2016). Here, we observed another example of a cell state that arises with age in spleen B cells.…”

Section: Aging Manifests Novel B Cell States In the Spleensupporting

confidence: 52%

Murine single-cell RNA-seq reveals cell-identity- and tissue-specific trajectories of aging

et al. 2019

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Aging is a pleiotropic process affecting many aspects of mammalian physiology. Mammals are composed of distinct cell type identities and tissue environments, but the influence of these cell identities and environments on the trajectory of aging in individual cells remains unclear. Here, we performed single-cell RNA-seq on >50,000 individual cells across three tissues in young and old mice to allow for direct comparison of aging phenotypes across cell types. We found transcriptional features of aging common across many cell types, as well as features of aging unique to each type. Leveraging matrix factorization and optimal transport methods, we found that both cell identities and tissue environments exert influence on the trajectory and magnitude of aging, with cell identity influence predominating. These results suggest that aging manifests with unique directionality and magnitude across the diverse cell identities in mammals. 2

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Section: Aging Manifests Novel B Cell States In the Spleensupporting

confidence: 52%

Murine single-cell RNA-seq reveals cell-identity- and tissue-specific trajectories of aging

et al. 2019

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“…The JAK/STAT signaling pathway is a conserved metazoan signaling system that plays an important role in the immune response, homeostasis, and regenerative processes [47]. Recently, a study using single-cell transcriptomics revealed JAK/STAT signaling functions in stem cell exhaustion during aging [48]. Kirschner et al showed that approximately 25% of p53-activated old HSCs coexpressed cell cycle inhibitory and proliferative transcripts from JAK/STAT signaling, partially explaining the prolonged cell proliferation, myeloid skewing, and stem cell exhaustion [48].…”

Section: Dna Damaging Pathwaysmentioning

confidence: 99%

Mechanisms and rejuvenation strategies for aged hematopoietic stem cells

Zhang

et al. 2020

J Hematol Oncol

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Hematopoietic stem cell (HSC) aging, which is accompanied by reduced self-renewal ability, impaired homing, myeloid-biased differentiation, and other defects in hematopoietic reconstitution function, is a hot topic in stem cell research. Although the number of HSCs increases with age in both mice and humans, the increase cannot compensate for the defects of aged HSCs. Many studies have been performed from various perspectives to illustrate the potential mechanisms of HSC aging; however, the detailed molecular mechanisms remain unclear, blocking further exploration of aged HSC rejuvenation. To determine how aged HSC defects occur, we provide an overview of differences in the hallmarks, signaling pathways, and epigenetics of young and aged HSCs as well as of the bone marrow niche wherein HSCs reside. Notably, we summarize the very recent studies which dissect HSC aging at the single-cell level. Furthermore, we review the promising strategies for rejuvenating aged HSC functions. Considering that the incidence of many hematological malignancies is strongly associated with age, our HSC aging review delineates the association between functional changes and molecular mechanisms and may have significant clinical relevance.

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“…Smart‐seq/Smart‐seq2, which enables full‐length amplification of single‐cell cDNA can readily be applied to FACS isolated cells in multi‐well plates or cells isolated on Fluidigm's C1 microfluidic instrument . By combining full‐length, PCR‐based cDNA amplification with tagmentation‐based NGS library preparation, it is possible to enumerate transcript abundance within the cell, but also to explore sequence variation (SNVs, UTRs, and alternative splicing) within the transcriptome.…”

Section: Concepts and Methods For Single‐cell Isolation And Profilingmentioning

confidence: 99%

Defining Cell Identity with Single‐Cell Omics

et al. 2018

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Cells are a fundamental unit of life, and the ability to study the phenotypes and behaviors of individual cells is crucial to understanding the workings of complex biological systems. Cell phenotypes (epigenomic, transcriptomic, proteomic, and metabolomic) exhibit dramatic heterogeneity between and within the different cell types and states underlying cellular functional diversity. Cell genotypes can also display heterogeneity throughout an organism, in the form of somatic genetic variation—most notably in the emergence and evolution of tumors. Recent technical advances in single‐cell isolation and the development of omics approaches sensitive enough to reveal these aspects of cell identity have enabled a revolution in the study of multicellular systems. In this review, we discuss the technologies available to resolve the genomes, epigenomes, transcriptomes, proteomes, and metabolomes of single cells from a wide variety of living systems.

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Proliferation Drives Aging-Related Functional Decline in a Subpopulation of the Hematopoietic Stem Cell Compartment

Cited by 80 publications

References 35 publications

Murine single-cell RNA-seq reveals cell-identity- and tissue-specific trajectories of aging

Murine single-cell RNA-seq reveals cell-identity- and tissue-specific trajectories of aging

Mechanisms and rejuvenation strategies for aged hematopoietic stem cells

Defining Cell Identity with Single‐Cell Omics

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