Aged Hematopoietic Stem Cells Drive Aging-Associated Immune Remodeling
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE107007 | GEO | 2018/06/12
REPOSITORIES: GEO
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Project description:Studies in model organisms suggest that aged cells can be functionally rejuvenated, but whether this concept applies to human skin is unclear. Here we apply deep sequencing of RNA 3' ends ("3-seq") to discover the gene expression program associated with human photoaging and intrinsic skin aging (collectively termed "skin aging") and the impact of broadband light (BBL) treatment. We find that skin aging was associated with the significantly altered expression level of 2,265 coding and noncoding RNAs, of which 1,293 became "rejuvenated" after BBL treatment, i.e. more similar in expression level of youthful skin. Rejuvenated genes (RGs) included several known key regulators of organismal longevity and their proximal long non-coding RNAs. Skin aging is not associated with systematic changes in 3' end mRNA processing. Hence, BBL treatment can restore the gene expression pattern of photoaged and intrinsically aged human skin to resemble young skin. In addition, our data reveals a novel set of targets that may lead to new insights into the human skin aging process. Examination of broadband light treated and untreated human skin transcriptomes of 5 women aged 50 years or more. They were compared to the skin transcriptomes of 5 young women aged 30 years or less.
2012-07-30 | E-GEOD-39170 | biostudies-arrayexpress
Project description:Studies in model organisms suggest that aged cells can be functionally rejuvenated, but whether this concept applies to human skin is unclear. Here we apply deep sequencing of RNA 3' ends ("3-seq") to discover the gene expression program associated with human photoaging and intrinsic skin aging (collectively termed "skin aging") and the impact of broadband light (BBL) treatment. We find that skin aging was associated with the significantly altered expression level of 2,265 coding and noncoding RNAs, of which 1,293 became "rejuvenated" after BBL treatment, i.e. more similar in expression level of youthful skin. Rejuvenated genes (RGs) included several known key regulators of organismal longevity and their proximal long non-coding RNAs. Skin aging is not associated with systematic changes in 3' end mRNA processing. Hence, BBL treatment can restore the gene expression pattern of photoaged and intrinsically aged human skin to resemble young skin. In addition, our data reveals a novel set of targets that may lead to new insights into the human skin aging process.
2012-07-30 | GSE39170 | GEO
Project description:Biomechanical alterations contribute to the decreased regenerative capacity of hematopoietic stem cells (HSCs) upon aging. RhoA is a key regulator of mechano-signaling but its role for mechanotransduction in stem cell aging has not been investigated yet. Here, we show that murine HSCs respond to increased nuclear envelope (NE) tension by inducing NE translocation of P-cPLA2, which cell intrinsically activates RhoA. Interestingly, aged HSCs experience physiologically higher intrinsic NE tension, associated with increased NE P-cPLA2 and RhoA activity. Reducing RhoA activity lowers NE tension in aged HSCs. Feature image analysis of HSC nuclei reveals that chromatin remodeling is associated to RhoA inhibition, which includes the restoration of youthful levels of the heterochromatin marker H3K9me2 and a decrease in chromatin accessibility and transcription at retrotransposons. Eventually, we demonstrate that RhoA inhibition upregulates Klf4 expression and transcriptional activity, improving aged HSCs regenerative capacity and lympho/myeloid skewing in vivo. Overall, our data support that an intrinsic mechano-signaling axis dependent on RhoA can be pharmacologically targeted to rejuvenate stem cell function upon aging.
2025-08-29 | GSE269953 | GEO
Project description:Biomechanical alterations contribute to the decreased regenerative capacity of hematopoietic stem cells (HSCs) upon aging. RhoA is a key regulator of mechano-signaling but its role for mechanotransduction in stem cell aging has not been investigated yet. Here, we show that murine HSCs respond to increased nuclear envelope (NE) tension by inducing NE translocation of P-cPLA2, which cell intrinsically activates RhoA. Interestingly, aged HSCs experience physiologically higher intrinsic NE tension, associated with increased NE P-cPLA2 and RhoA activity. Reducing RhoA activity lowers NE tension in aged HSCs. Feature image analysis of HSC nuclei reveals that chromatin remodeling is associated to RhoA inhibition, which includes the restoration of youthful levels of the heterochromatin marker H3K9me2 and a decrease in chromatin accessibility and transcription at retrotransposons. Eventually, we demonstrate that RhoA inhibition upregulates Klf4 expression and transcriptional activity, improving aged HSCs regenerative capacity and lympho/myeloid skewing in vivo. Overall, our data support that an intrinsic mechano-signaling axis dependent on RhoA can be pharmacologically targeted to rejuvenate stem cell function upon aging.
2025-08-29 | GSE233986 | GEO
Project description:Biomechanical alterations contribute to the decreased regenerative capacity of hematopoietic stem cells (HSCs) upon aging. RhoA is a key regulator of mechano-signaling but its role for mechanotransduction in stem cell aging has not been investigated yet. Here, we show that murine HSCs respond to increased nuclear envelope (NE) tension by inducing NE translocation of P-cPLA2, which cell intrinsically activates RhoA. Interestingly, aged HSCs experience physiologically higher intrinsic NE tension, associated with increased NE P-cPLA2 and RhoA activity. Reducing RhoA activity lowers NE tension in aged HSCs. Feature image analysis of HSC nuclei reveals that chromatin remodeling is associated to RhoA inhibition, which includes the restoration of youthful levels of the heterochromatin marker H3K9me2 and a decrease in chromatin accessibility and transcription at retrotransposons. Eventually, we demonstrate that RhoA inhibition upregulates Klf4 expression and transcriptional activity, improving aged HSCs regenerative capacity and lympho/myeloid skewing in vivo. Overall, our data support that an intrinsic mechano-signaling axis dependent on RhoA can be pharmacologically targeted to rejuvenate stem cell function upon aging.
2025-08-29 | GSE233985 | GEO
Project description:Biomechanical alterations contribute to the decreased regenerative capacity of hematopoietic stem cells (HSCs) upon aging. RhoA is a key regulator of mechano-signaling but its role for mechanotransduction in stem cell aging has not been investigated yet. Here, we show that murine HSCs respond to increased nuclear envelope (NE) tension by inducing NE translocation of P-cPLA2, which cell intrinsically activates RhoA. Interestingly, aged HSCs experience physiologically higher intrinsic NE tension, associated with increased NE P-cPLA2 and RhoA activity. Reducing RhoA activity lowers NE tension in aged HSCs. Feature image analysis of HSC nuclei reveals that chromatin remodeling is associated to RhoA inhibition, which includes the restoration of youthful levels of the heterochromatin marker H3K9me2 and a decrease in chromatin accessibility and transcription at retrotransposons. Eventually, we demonstrate that RhoA inhibition upregulates Klf4 expression and transcriptional activity, improving aged HSCs regenerative capacity and lympho/myeloid skewing in vivo. Overall, our data support that an intrinsic mechano-signaling axis dependent on RhoA can be pharmacologically targeted to rejuvenate stem cell function upon aging.
2025-08-29 | GSE269396 | GEO
Project description:Aged Hematopoietic Stem Cells Drive Aging-Associated Immune Remodeling
| PRJNA418778 | ENA
Project description:One goal of regenerative medicine is to rejuvenate tissues and extend lifespan by restoring the function of endogenous aged stem cells. However, evidence that somatic stem cells can be targeted in vivo to extend lifespan is still lacking. Here, we demonstrate that after a short systemic treatment with a specific inhibitor of the small RhoGTPase Cdc42 (CASIN), transplanting aged hematopoietic stem cells (HSCs) from treated mice is sufficient to extend the healthspan and lifespan of aged immunocompromised mice without additional treatment. In detail, we show that systemic CASIN treatment improves strength and endurance of aged mice by increasing the myogenic regenerative potential of aged skeletal muscle stem cells. Further, we show that CASIN modifies niche localization and H4K16ac polarity of HSCs in vivo. Single cell profiling reveals changes in HSC transcriptome, which underlie enhanced lymphoid and regenerative capacity in serial transplantation assays. Overall, we provide proof-of-concept evidence that a short systemic treatment to decrease Cdc42 activity improves the regenerative capacity of different endogenous aged stem cells in vivo, and that rejuvenated HSCs exert a broad systemic effect sufficient to extend murine health- and lifespan.
2022-12-01 | GSE197070 | GEO
Project description:Skeletal aging and disease are associated with a misbalance in the opposing actions of osteoblasts and osteoclasts that are responsible for maintaining the integrity of bone tissues. Here, we show through detailed functional and single-cell genomic studies that intrinsic aging of bona fide mouse skeletal stem cells (SSCs) alters bone marrow niche signaling and skews bone and blood lineage differentiation leading to fragile bones that regenerate poorly. Aged SSCs have diminished bone and cartilage forming potential but produce higher frequencies of stromal lineages that express high levels of pro-inflammatory and pro-resorptive cytokines. Single-cell transcriptomic studies reveal a distinct population of SSCs in aged mice that gradually outcompete their younger counterparts in the bone marrow niche. While systemic exposure to a youthful circulation through heterochronic parabiosis reduced local expression of inflammatory cytokines, it did not reverse the diminished osteochondrogenic activity of aged SSCs and was insufficient to improve bone mass and skeletal-healing parameters in aged mice. Hematopoietic reconstitution of aged mice with young hematopoietic stem cells (HSC) also did not improve bone integrity and repair. We find that deficient bone regeneration in aged mice could only be reversed by the local application of a combinatorial treatment that re-activates aged SSCs and simultaneously abates crosstalk to hematopoietic cells favoring an inflammatory milieu. This treatment expanded aged SSC pools, reduced osteoclast activity, and enhanced bone healing to youthful levels. Our findings provide mechanistic insight into the complex, multifactorial mechanisms underlying skeletal aging and offer new prospects for rejuvenating the aged skeletal system.
2021-06-11 | GSE166441 | GEO
Project description:We show that platelet factors transfer rejuvenating effects of young plasma to the aging brain. Proteomic analysis of plasma from young and aged mice identified age-related changes in platelets. Systemic exposure of aged animals to the platelet fraction of young plasma decreased hippocampal neuroinflammation at a transcriptional and cellular level and ameliorated cognitive impairments. We identified the platelet-derived chemokine CXCL4/Platelet Factor-4 (PF4) as a pro-youthful circulating factor. Systemic PF4 administration decreased age-related neuroinflammation, restored the aging peripheral immune system to a more youthful state, and improved hippocampal-dependent learning and memory in aged mice.
2023-06-20 | GSE173254 | GEO