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Inflammatory exposure drives permanent impairment of hematopoietic stem cell self-renewal activity and accelerated aging

ABSTRACT: Hematopoietic stem cells (HSCs) mediate regeneration of the hematopoietic system following injury, as exemplified by the transient activation of HSCs out of dormancy upon exposure to infection or inflammation. Such challenges have been documented to impair HSC function. However, whether this functional impairment extends beyond the duration of inflammatory exposure is unknown. To assess the effects of repeated inflammatory challenge, wild-type C57BL/6J mice were subjected to a dose escalation regimen of polyinosinic:polycytidylic acid (pI:pC) treatment mimicking viral infection. Unexpectedly, we observed an irreversible depletion of functional HSCs and hallmarks of accelerated aging in LT-HSCs. In an effort to conclusively assess whether there was molecular evidence of accelerated aging of LT-HSC after sterile inflammation, we performed whole genome bisulfite sequencing and calculated the biological age by applying a multi-tissue DNA methylome clock. LT-HSCs from mice subject to inflammation demonstrated multiple cellular and molecular features of accelerated aging, including increased biological age.

ORGANISM(S): Mus musculus

PROVIDER: GSE200337 | GEO | 2022/07/19

REPOSITORIES: GEO

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Inflammatory exposure drives permanent impairment of hematopoietic stem cell self-renewal activity and accelerated aging.

Project description:Hematopoietic stem cells (HSCs) mediate regeneration of the hematopoietic system following injury, as exemplified by the transient activation of HSCs out of dormancy upon exposure to infection or inflammation. Such challenges have been documented to impair HSC function. However, whether this functional impairment extends beyond the duration of inflammatory exposure is unknown. To assess the effects of repeated inflammatory challenge, wild-type C57BL/6J mice were subjected to a dose escalation regimen of polyinosinic:polycytidylic acid (pI:pC) treatment mimicking viral infection. Unexpectedly, we observed an irreversible depletion of functional HSCs and hallmarks of accelerated aging in LT-HSCs.

2022-07-19 | GSE200979 | GEO

Expression data from control and LRF (leukemia/lymphoma related factor)-deficient mouse LT-HSCs

Project description:LRF, which is encoded by the ZBTB7A gene and formerly known as POKEMON (POK erythroid myeloid ontogenic factor), was originally identified as a PLZF (promyelocytic leukemia zinc finger) homologue interacting with BCL6 (B-cell lymphoma 6). LRF is a transcription factor that is broadly expressed in hematopoietic lineage cells, but its expression is particularly high in erythroblasts and germinal center (GC) B-cells. The goal of this study is to assess the effect of LRF loss on the LT-HSC transcriptome. Nine days after injection of adult mice with polyinosinic polycytidylic acid (pIpc) to activate Cre, total RNAs were isolated from double-sorted LT-HSCs from LRF Flox/+ Mx1-Cre+ and LRF Flox/Flox Mx1-Cre+ mice and processed for microarray analysis. We performed gene expression microarray analysis of FACS-sorted LT-HSCs (LSK IL7Ra-Flt3-CD150+CD48-) to assess the effect of Lrf loss on the LT-HSC transcriptome. Zbtb7a Flox/+ Mx1-Cre+ mice were used as a control to normalize the potential effects of Cre recombinase. LT-HSCs were FACS-sorted from three Lrf knockout (Zbtb7a Flox/Flox Mx1-Cre+) and two control (Zbtb7a Flox/+ Mx1-Cre+) mice, nine days after the first pIpC injection.

2012-10-26 | E-GEOD-41839 | biostudies-arrayexpress

LT-HSC from young and middle-age mice stimulated with IGF1 RNA-seq

Project description:Long-term hematopoietic stem cells (LT-HSCs) are responsible for lifelong maintenance and regeneration of the blood system. Loss of LT-HSC function is a major contributor to decline in hematopoietic function with aging, leading to increased rate of infection, poor vaccination response, and increased risk of hematologic malignancies. While cellular and molecular hallmarks of LT-HSC aging have been defined1-3, a barrier to achieving the goal of extending healthy hematopoietic function into older age is the lack of understanding of the nature and timing of the initiating events that cause LT-HSC aging. Here we show that hallmarks of LT-HSC aging and decline in hematopoietic function accumulate by middle age in mice, and that the hematopoietic cell-extrinsic bone marrow (BM) microenvironment at middle age is necessary and sufficient to cause LT-HSC aging. Using unbiased transcriptome-based approaches, we identify decreased production of IGF1 by mesenchymal stromal cells (MSC) in the local middle-aged BM microenvironment as a factor causing LT-HSC aging and show that direct stimulation of middle-aged LT-HSCs with IGF1 rescues hallmarks of aging. Together, our study demonstrates that the initiating events causing LT-HSC and hematopoietic aging emerge by middle age and are caused by hematopoietic cell-extrinsic changes in the BM microenvironment. Declining IGF1 in the BM microenvironment at middle age represents a compelling target for intervention using prophylactic therapies to effectively extend healthspan and prevent decline in hematopoietic function during aging.

2020-02-08 | GSE144934 | GEO

LT-HSC from middle-age mice stimulated with IGF1 ATAC-seq

Project description:Long-term hematopoietic stem cells (LT-HSCs) are responsible for lifelong maintenance and regeneration of the blood system. Loss of LT-HSC function is a major contributor to decline in hematopoietic function with aging, leading to increased rate of infection, poor vaccination response, and increased risk of hematologic malignancies. While cellular and molecular hallmarks of LT-HSC aging have been defined, a barrier to achieving the goal of extending healthy hematopoietic function into older age is the lack of understanding of the nature and timing of the initiating events that cause LT-HSC aging. Here we show that hallmarks of LT-HSC aging and decline in hematopoietic function accumulate by middle age in mice, and that the hematopoietic cell-extrinsic bone marrow (BM) microenvironment at middle age is necessary and sufficient to cause LT-HSC aging. Using unbiased transcriptome-based approaches, we identify decreased production of IGF1 by mesenchymal stromal cells (MSC) in the local middle-aged BM microenvironment as a factor causing LT-HSC aging and show that direct stimulation of middle-aged LT-HSCs with IGF1 rescues hallmarks of aging. Together, our study demonstrates that the initiating events causing LT-HSC and hematopoietic aging emerge by middle age and are caused by hematopoietic cell-extrinsic changes in the BM microenvironment. Declining IGF1 in the BM microenvironment at middle age represents a compelling target for intervention using prophylactic therapies to effectively extend healthspan and prevent decline in hematopoietic function during aging.

2021-01-12 | GSE164609 | GEO

LT-HSC from young (2mo), middle-age (12mo) and old (22mo) mice for RNA-seq

2020-07-01 | GSE151333 | GEO

LT-HSC re-isolated from tranplants altering the age (young and middle age) of the donor LT-HSC, support cells and recipient mice

2020-02-08 | GSE144933 | GEO

Transcription profiling of hematopoietic stem cell aging

Project description:Loss of immune function and an increased incidence of myeloid leukemia are two of the most clinically significant consequences of aging of the hematopoietic system. To better understand the mechanisms underlying hematopoietic aging, we evaluated the cell intrinsic functional and molecular properties of highly purified long-term hematopoietic stem cells (LT-HSCs) from young and old mice. We found that LT-HSC aging was accompanied by cell autonomous changes, including increased stem cell self-renewal, differential capacity to generate committed myeloid and lymphoid progenitors, and diminished lymphoid potential. Expression profiling revealed that LT-HSC aging was accompanied by the systemic down-regulation of genes mediating lymphoid specification and function and up-regulation of genes involved in specifying myeloid fate and function. Moreover, LT-HSCs from old mice expressed elevated levels of many genes involved in leukemic transformation. These data support a model in which age-dependent alterations in gene expression at the stem cell level presage downstream developmental potential and thereby contribute to age-dependent immune decline, and perhaps also to the increased incidence of leukemia in the elderly.

2005-08-16 | E-SMDB-3450 | biostudies-arrayexpress

Transcription profiling of long-term hematopoietic stem cells from old and young mice to investigate the mechanisms of hematopoietic aging

2007-12-19 | E-GEOD-4332 | biostudies-arrayexpress

Regulatory Role of S100A6 in Hematopoetic Stem Cells

Project description:The fate options of hematopoietic stem cells (HSCs) include self-renewal, differentiation, migration and apoptosis, but the interaction between intracellular Ca2+ and cytoplasmic chaperon protein in regulating fate options of long term-HSCs (LT-HSC) is unknown. We created a S100A6 conditional knockout mouse model in the hematopoietic system and our studies showed that in S100A6KO, the number of LT-HSCs was significantly reduced and HSCs engrafted poorly. After 5FU challenge, the frequency of S100A6KO HSCs remained significantly low. Our data showed that S100A6 failed to self-renew through Akt pathway in an intracellular calcium (Cai2+)-dependent manner. Expression profiling of S100A6KO obtained from gene signatures revealed that cytosolic calcium level and proteins translocation to mitochondria were decreased. Mitochondrial oxidative phosphorylation was impaired in S100A6KO. Proteomic data indicated Hsp90 protein and chaperonin family were reduced. Our findings demonstrated that S100A6 regulates fate options of HSCs self-renewal through integrating Akt signaling, specifically governing mitochondria metabolic function and protein quality.

2020-06-22 | PXD015854 | Pride

Expression data from control and LRF (leukemia/lymphoma related factor)-deficient mouse LT-HSCs

2012-10-26 | GSE41839 | GEO

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