Nuclear morphology is a deep learning biomarker of cellular senescence

Heckenbach, Indra; Mkrtchyan, Garik; Ezra, Michael Ben; Bakula, Daniela; Madsen, Jakob Sture; Nielsen, Malte Hasle; Oró, Denise; Osborne, Brenna; Covarrubias, Anthony J.; Idda, Maria Laura; Gorospe, Myriam; Mortensen, Laust Hvas; Verdin, Eric; Westendorp, Rudi G.J.; Scheibye‐Knudsen, Morten

doi:10.1038/s43587-022-00263-3

Cited by 120 publications

(84 citation statements)

References 55 publications

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“…Previous studies have shown that cellular senescence affects nuclear morphology ( Pathak et al, 2021 ; Heckenbach et al, 2022 ). We therefore sought to characterize nuclear morphology during aging.…”

Section: Resultsmentioning

confidence: 99%

Region-specific heterogeneity in neuronal nuclear morphology in young, aged and in Alzheimer’s disease mouse brains

Ramanan

2023

Front. Cell Dev. Biol.

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Neurons in the mammalian brain exhibit enormous structural and functional diversity across different brain regions. Compared to our understanding of the morphological diversity of neurons, very little is known about the heterogeneity of neuronal nuclear morphology and how nuclear size changes in aging and diseased brains. Here, we report that the neuronal cell nucleus displays differences in area, perimeter, and circularity across different anatomical regions in the mouse brain. The pyramidal neurons of the hippocampal CA3 region exhibited the largest area whereas the striatal neuronal nuclei were the smallest. These nuclear size parameters also exhibited dichotomous changes with age across brain regions–while the neocortical and striatal neurons showed a decrease in nuclear area and perimeter, the CA3 neurons showed an increase with age. The nucleus of parvalbumin- and calbindin-positive interneurons had comparable morphological features but exhibited differences between brain regions. In the context of activity-dependent transcription in response to a novel environment, there was a decrease in nuclear size and circularity in c-Fos expressing neurons in the somatosensory cortex and hippocampal CA1 and CA3. In an APP/PS1 mutant mouse model of Alzheimer’s disease (AD), the neuronal nuclear morphology varies with plaque size and with increasing distance from the plaque. The neuronal nuclear morphology in the immediate vicinity of the plaque was independent of the plaque size and the morphology tends to change away from the plaque. These changes in the neuronal nuclear size and shape at different ages and in AD may be attributed to changes in transcriptional activity. This study provides a detailed report on the differences that exist between neurons in nuclear morphology and can serve as a basis for future studies.

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Section: Resultsmentioning

confidence: 99%

Region-specific heterogeneity in neuronal nuclear morphology in young, aged and in Alzheimer’s disease mouse brains

Ramanan

2023

Front. Cell Dev. Biol.

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“…Nuclear area has been demonstrated to expand during senescence [ 10 ]. Our quantitative analysis has indicated that the population of cobalamin-deficient astrocytes differs from the control culture in terms of cell nuclei area, as presented in Figure 4 .…”

Section: Resultsmentioning

confidence: 99%

“…Recently, Heckenbach et al [ 10 ] examined the morphology of cell nuclei in senescent dermal fibroblasts. They provided strong evidence that there is a significant difference in nuclear area between non-senescent and senescent cells.…”

Section: Discussionmentioning

confidence: 99%

“…It has been shown that β-galactosidase activity is significantly higher in senescent cells than in pre-senescent cells. Senescent cells are also characterized by enlarged and flat cell morphology, increased p16 INK4A and p21 Waf1/Cip1 protein expression [ 8 , 9 ], and an expanded nuclear area [ 10 ]. Moreover, some senescent cells could show an altered reaction to apoptotic stimuli [ 11 ]; however, this is not a general feature of senescent cells and the interplay between senescence and apoptosis is cell-type-specific [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

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Cobalamin Deficiency May Induce Astrosenescence—An In Vitro Study

Rzepka

Rok

Kowalska

et al. 2022

Cells

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Cobalamin (vitamin B12) deficiency is one of the major factors causing degenerative changes in the nervous system and, thus, various neurological and psychiatric symptoms. The underlying cellular mechanism of this phenomenon is not yet fully understood. An accumulation of senescent astrocytes has been shown to contribute to a wide range of pathologies of the nervous system, including neurodegenerative disorders. This study aimed to investigate whether cobalamin deficiency triggers astrosenescence. After inducing cobalamin deficiency in normal human astrocytes in vitro, we examined biomarkers of cellular senescence: SA-β-gal, p16INK4A, and p21Waf1/Cip1 and performed cell nuclei measurements. The obtained results may contribute to an increase in the knowledge of the cellular effects of cobalamin deficiency in the context of astrocytes. In addition, the presented data suggest a potential causative agent of astrosenescence that has not been proven to date.

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“…Among several hallmarks of the aging process, abnormalities of nuclear properties are common features of naturally aged and senescent cells in nonneural tissues [4][5][6] . In neural tissues, the abnormal nuclear shape is observed in aging-associated neurodegenerative diseases.…”

Section: Introductionmentioning

confidence: 99%

Age-associated reduction of nuclear shape dynamics in excitatory neurons of the visual cortex

Frey

Murakami

Ohki

et al. 2022

Preprint

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External stimuli contribute to the neuronal properties partly through regulating gene expression. Previous works have shown nuclear infolding induced by external stimuli and pathological conditions in neurons. However, the dynamics and reversibility of the changes in nuclear shape upon external stimuli have been unknown. In this study, we found that the nuclear shape of excitatory neurons in the visual cortex altered and undergo invagination upon visual stimuli. Subsequently, we performed time-lapse imaging of the nuclear shape of excitatory neurons in the visual cortex using Nex-Cre;SUN1-GFP mice, labeling the nuclear membrane of excitatory neurons with GFP. We found that nuclear infolding can be observed within the first 15 minutes of light exposure. Depletion of the stimuli by finishing the light exposure or injection of MK-801, an inhibitor of NMDA receptor, restored the nucleus to a spherical shape and reduced the dynamic behavior, suggesting that nuclear infolding in neurons is reversible process. Then, as brain function declines naturally over age, we also examine the nuclear shapes of neurons in aged mice. In contrast to young mice, the nuclear shape in aged mice showed less dynamic change upon light stimulation. In conclusion, our data highlights the changes of the nuclear shape upon visual stimulation and its potential role in the response towards external stimuli and the dysfunction of the aged brain.

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Nuclear morphology is a deep learning biomarker of cellular senescence

Cited by 120 publications

References 55 publications

Region-specific heterogeneity in neuronal nuclear morphology in young, aged and in Alzheimer’s disease mouse brains

Region-specific heterogeneity in neuronal nuclear morphology in young, aged and in Alzheimer’s disease mouse brains

Cobalamin Deficiency May Induce Astrosenescence—An In Vitro Study

Age-associated reduction of nuclear shape dynamics in excitatory neurons of the visual cortex

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