Age-Related Gene Expression Signature in Rats Demonstrate Early, Late, and Linear Transcriptional Changes from Multiple Tissues

Shavlakadze, Tea; Morris, Melody K.; Fang, Jian; Wang, Sharon X.; Zhu, Jiang; Zhou, Weihua; Tse, Herman W.; Mondragón-González, Ricardo; Roma, Guglielmo; Glass, David J.

doi:10.1016/j.celrep.2019.08.043

Cited by 129 publications

(124 citation statements)

References 41 publications

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“…We observe this signature even at 7 days in the OL, but it becomes stronger by 21 days. This is consistent with other studies that report that signatures of ageing appear gradually over the course of an organism's lifespan and not abruptly at later chronological ages [90][91][92] . We do not know whether the increased DNA damage signature we observe in the OLs is because the OLs intrinsically sustain higher levels of DNA damage or whether other parts of the brain better equipped to resolve DNA lesions.…”

Section: Dna Damage Accumulates In the Ol With Agesupporting

confidence: 93%

Polyploidy in the adultDrosophilabrain

Nandakumar

Grushko

Buttitta

2019

Preprint

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Long-lived cells such as terminally differentiated postmitotic neurons and glia must cope with the accumulation of damage over the course of an animal's lifespan. How long-lived cells deal with ageing-related damage is poorly understood. Here we show that polyploid cells accumulate in the ageing adult fly brain and that polyploidy protects against DNA damage-induced cell death. Multiple types of neurons and glia that are diploid at eclosion, become polyploid with age in the adult Drosophila brain. The optic lobes exhibit the highest levels of polyploidy, associated with an elevated DNA damage response in this brain region with age. Inducing oxidative stress or exogenous DNA damage leads to an earlier onset of polyploidy, and polyploid cells in the adult brain are more resistant to DNA damage-induced cell death than diploid cells. Our results suggest polyploidy may serve a protective role for neurons and glia in ageing Drosophila melanogaster brains. for providing fly stocks, particularly the labs of Cheng-

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Section: Dna Damage Accumulates In the Ol With Agesupporting

confidence: 93%

Polyploidy in the adultDrosophilabrain

Nandakumar

Grushko

Buttitta

2019

Preprint

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“…The proportion of FR-PTC also increased with age in rat kidneys, increasing from ~5% at six months to ~12% at 27 months ( Fig. S5C) (16).…”

Section: Proximal Tubule Responses To Acute Injurymentioning

confidence: 83%

Cell profiling of mouse acute kidney injury reveals conserved cellular responses to injury

Kirita

Uchimura

et al. 2020

Preprint

176

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After acute kidney injury (AKI), patients either recover or alternatively develop fibrosis and chronic kidney disease. Interactions between injured epithelia, stroma and inflammatory cells determine whether kidneys repair or undergo fibrosis, but the molecular events that drive these processes are poorly understood. Here, we use single nucleus RNA sequencing of a mouse model of AKI to characterize cell states during repair from acute injury. We identify a distinct proinflammatory and profibrotic proximal tubule cell state that fails to repair. Deconvolution of bulk RNA-seq datasets indicates that this "failed-repair proximal tubule cell" or FR-PTC, state can be detected in other models of kidney injury, increasing in the aging rat kidney and over time in human kidney allografts. We also describe dynamic intercellular communication networks and discern transcriptional pathways driving successful vs. failed repair. Our study provides a detailed description of cellular responses after injury and suggests that the FR-PTC state may represent a therapeutic target to improve repair. Significance StatementSingle nucleus RNA sequencing revealed gene expression changes during repair after acute kidney injury. We describe a small population of proximal tubule cells that fail to repair (FR-PTC). Since this subpopulation expresses abundant pro-inflammatory and profibrotic genes, it may represent a new therapeutic target to improve repair and reduce fibrosis after AKI.

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“…The proportion of FR-PTCs also increased with age in rat kidneys, increasing from ∼5% at 6 mo to ∼12% at 27 mo ( SI Appendix , Fig. S5 C ) ( 16 ).…”

Section: Resultsmentioning

confidence: 99%

Cell profiling of mouse acute kidney injury reveals conserved cellular responses to injury

Kirita

Uchimura

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

338

392

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After acute kidney injury (AKI), patients either recover or alternatively develop fibrosis and chronic kidney disease. Interactions between injured epithelia, stroma, and inflammatory cells determine whether kidneys repair or undergo fibrosis, but the molecular events that drive these processes are poorly understood. Here, we use single nucleus RNA sequencing of a mouse model of AKI to characterize cell states during repair from acute injury. We identify a distinct proinflammatory and profibrotic proximal tubule cell state that fails to repair. Deconvolution of bulk RNA-seq datasets indicates that this failed-repair proximal tubule cell (FR-PTC) state can be detected in other models of kidney injury, increasing during aging in rat kidney and over time in human kidney allografts. We also describe dynamic intercellular communication networks and discern transcriptional pathways driving successful vs. failed repair. Our study provides a detailed description of cellular responses after injury and suggests that the FR-PTC state may represent a therapeutic target to improve repair.

show abstract

Age-Related Gene Expression Signature in Rats Demonstrate Early, Late, and Linear Transcriptional Changes from Multiple Tissues

Cited by 129 publications

References 41 publications

Polyploidy in the adultDrosophilabrain

Polyploidy in the adultDrosophilabrain

Cell profiling of mouse acute kidney injury reveals conserved cellular responses to injury

Cell profiling of mouse acute kidney injury reveals conserved cellular responses to injury

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