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Cellular senescence has beneficial impact on cell mechanics in tissue regeneration

New insights into how senescent cells play a role in wound healing not only through its secretory action but also by impacting on cell mechanics have been provided by a study performed at Charité Universitätsmedizin Berlin and published in Aging Cell. Led by Uwe Kornak, professor at the Institute of Human Genetics Göttingen, and Ansgar Petersen, professor at Julius Wolff Institute of Charité, a team of scientists has revealed that cellular senescence beneficially influences tissue formation by modulating cell mechanics and extracellular matrix (ECM) synthesis and composition.

Senescence is a multistep process in which cells, in response to different stresses and damage, go from a transient cell cycle inhibition to an irreversible state in which they no longer divide. Senescent cells do not die but remain metabolically active, secreting a characteristic combination of proteins and factors that can affect the cell’s surrounding environment, the extracellular matrix, and neighboring cells. Accumulation of senescent cells is a hallmark of ageing and a factor in the development of ageing-associated pathologies. These detrimental effects are also investigated intensively at the Institute of Human Genetics. There is, however, also a positive aspect of cellular senescence: Short-term presence of senescent cells promotes wound healing and contributes to scar development. However, it has so far not been known that senescence has also a direct role in tissue formation beyond its paracrine signaling.

The researchers used a specific in vitro wound healing model of primary human skin fibroblasts in which they induced cellular senescence by two different mechanisms (either by DNA damage or by overexpression of cell cycle inhibitors). They investigated the effects of both types of senescence on cell migration, morphology and adhesion. Their investigations showed that cellular senescence modulated size and composition of focal adhesions. These multiprotein structures anchor cells to the extracellular matrix and are responsible for transferring cellular forces. In all senescent cells, increased single cell forces were observed. However, in DNA damage-mediated senescence, contrary to senescence induced by cell cycle inhibitors, degenerative changes in ECM acted against contraction in 3D cell cultures. Thus, depending on the type, senescence showed different and partly conversing effects on tissue formation, contraction and tensioning. In addition to mechanical effects, the study also revealed altered expression profiles for genes encoding ECM-related proteins including collagens, lysyl oxidases and matrix metalloproteinases.

Contact: Prof. Dr. med. Uwe Kornak, uwe.kornak@med.uni-goettingen.de

Ozen A, Brauer E, Lange T, Keller D, Görlitz S, Cho S, Keye J, Gossen M, Petersen A, Kornak U. Dissecting the influence of cellular senescence on cell mechanics and extracellular matrix formation in vitro. Aging Cell. 2022 Dec 13:e13744. doi: 10.1111/acel.13744. Epub ahead of print.

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First pathogenic mosaic variant in STAG2 identified: New insights into an associated rare disorder

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Somatic mosaicism in STAG2-associated cohesinopathies: Expansion of the genotypic and phenotypic spectrum
Schmidt J, Dreha-Kulaczewski S, Zafeiriou M-P, Schreiber M-K, Wilken B, Funke R, Neuhofer CM, Altmüller J, Thiele H, Nürnberg P, Biskup S, Li Y, Zimmermann WH, Kaulfuß S, Yigit G and Wollnik B.
Front. Cell Dev. Biol.. 2022 10:1025332. doi: 10.3389/fcell.2022.1025332.

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Biallelic WARS1 variants identified as genetic cause of neurodevelopmental syndrome

WARS1 is one of many key enzymes required for protein synthesis. Genetic variants in WARS1 are rare, with extremely limited evidence implicating it in a clinically heterogeneous autosomal recessive disorder. A study led by PD Dr Barbara Vona, researcher at the Institute of Human Genetics and the Institute of Auditory Neuroscience at the University Medical Center Göttingen, identified two families with different homozygous variants in WARS1 that show varying severities of intellectual disability and developmental delay. The researchers also observed several variable clinical features including hearing impairment. In further studies in a knockout zebrafish model, they investigated the functional effects of WARS1 variants and found that one part of the gene may be especially important in the auditory system. While this study, published in Human Mutation, only scratches the surface of the biology and function of WARS1, it provided further genetic evidence to implicate it in an autosomal recessive neurodevelopmental syndrome.

Biallelic variants in WARS1 cause a highly variable neurodevelopmental syndrome and implicate a critical exon for normal auditory function
Lin SJ, Vona B, Porter HM, Izadi M, Huang K, Lacassie Y, Rosenfeld JA, Khan S, Petree C, Ali TA, Muhammad N, Khan SA, Muhammad N, Liu P, Haymon ML, Rüschendorf F, Kong IK, Schnapp L, Shur N, Chorich L, Layman L, Haaf T, Pourkarimi E, Kim HG, Varshney GK.
Hum Mutat. 2022 Jul 11. doi: 10.1002/humu.24435. Epub ahead of print.

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Identified biallelic variants in tRNA synthetases reveal an emerging associated disease spectrum

Visual Bögershausen et al, Human Mutat 2022

WARS1 and SARS1: two tRNA synthetases implicated in autosomal recessive microcephaly.
Bögershausen N, Krawczyk HE, Jamra RA, Lin SJ, Yigit G, Hüning I, Polo AM, Vona B, Huang K, Schmidt J, Altmüller J, Luppe J, Platzer K, Dörgeloh BB, Busche A, Biskup S, Mendes MI, Smith DEC, Salomons GS, Zibat A, Bültmann E, Nürnberg P, Spielmann M, Lemke JR, Li Y, Zenker M, Varshney GK, Hillen HS, Kratz CP, Wollnik B.
Hum Mutat. 2022 Jul 5. doi: 10.1002/humu.24430. Epub ahead of print.

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Molecular diagnosis of very rare Proteus syndrome expands phenotype

In a young patient referred to the Institute of Human Genetics at the University Medical Center Göttingen, the clinical suspicion of Proteus syndrome was made and confirmed by molecular genetic diagnostics. The patient presented with a progressively protruding frontal bone due to an intraosseus lipoma (a benign tumor of fat tissue) and, additionally, mild developmental delay, unilateral hearing impairment, strabism and a dermoid of the eye. DNA analysis performed on a tissue sample yielded from the lipoma showed that the patient carries a specific heterozygous variant of the AKT1 gene that is known to cause Proteus syndrome. This variant is present in a mosaic state, i.e. it occurred spontaneously as a de novo mutation after fertilization at some point in embryonic development. Therefore, it is not present in every cell of the body. Mosaic genetic variants are more difficult to detect in molecular diagnostics. In such cases, a clinical suspicion of an underlying mosaic disorder and selection of an appropriate sample for genetic testing are crucially important, because analysis of standard blood samples will usually not reveal the causative variant.

Proteus syndrome is a very rare disorder and only occurs in a mosaic form. Its clinical manifestations vary considerably, depending on which cells and tissues are affected by the genetic defect. The syndrome is characterized by disproportionate and asymmetric overgrowth affecting some parts of the patient’s body and by specific skin anomalies. As the researchers report in Clinical Genetics, their patient is the first case of a molecularly confirmed Proteus syndrome with a progressive intraosseous lipoma of the frontal bone but without other, characteristic features – in particular without any suggestive skin anomalies. For the patient, the correct molecular diagnosis may also have implications for novel treatment options, because AKT1-inhibiting substances are available and are already applied in clinical studies.

Schmidt J, Bremmer F, Brockmann K, Kaulfuß S, Wollnik B. Progressive frontal intraosseous lipoma: Detection of the mosaic AKT1 variant discloses Proteus syndrome. Clin Genet. 2022 Jun 7. doi: 10.1111/cge.14174. Epub ahead of print.

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