More Like this

1. Metabolic alterations caused by the mutation and overexpression of the Tmem135 gene

   https://doi.org/10.1177/1535370220932856  

   Lee, Wei-Hua ; Bhute, Vijesh J ; Higuchi, Hitoshi ; Ikeda, Sakae ; Palecek, Sean P ; Ikeda, Akihiro ( November 2020 , Experimental Biology and Medicine)

   null (Ed.)

   Mitochondria are dynamic organelles that undergo fission and fusion. While they are essential for cellular metabolism, the effect of dysregulated mitochondrial dynamics on cellular metabolism is not fully understood. We previously found that transmembrane protein 135 ( Tmem135) plays a role in the regulation of mitochondrial dynamics in mice. Mice homozygous for a Tmem135 mutation ( Tmem135 FUN025/FUN025 ) display accelerated aging and age-related disease pathologies in the retina including the retinal pigment epithelium (RPE). We also generated a transgenic mouse line globally overexpressing the Tmem135 gene ( Tmem135 TG). In several tissues and cells that we studied such as the retina, heart, and fibroblast cells, we observed that the Tmem135 mutation causes elongated mitochondria, while overexpression of Tmem135 results in fragmented mitochondria. To investigate how abnormal mitochondrial dynamics affect metabolic signatures of tissues and cells, we identified metabolic changes in primary RPE cell cultures as well as heart, cerebellum, and hippocampus isolated from Tmem135 FUN025/FUN025 mice (fusion > fission) and Tmem135 TG mice (fusion < fission) using nuclear magnetic resonance spectroscopy. Metabolomics analysis revealed a tissue-dependent response to Tmem135 alterations, whereby significant metabolic changes were observed in the heart of both Tmem135 mutant and TG mice as compared to wild-type, while negligible effects were observed in the cerebellum and hippocampus. We also observed changes in Tmem135 FUN025/FUN025 and Tmem135 TG RPE cells associated with osmosis and glucose and phospholipid metabolism. We observed depletion of NAD + in both Tmem135 FUN025/FUN025 and Tmem135 TG RPE cells, indicating that imbalance in mitochondrial dynamics to both directions lowers the cellular NAD + level. Metabolic changes identified in this study might be associated with imbalanced mitochondrial dynamics in heart tissue and RPE cells which can likely lead to functional abnormalities. Impact statement Mitochondria are dynamic organelles undergoing fission and fusion. Proper regulation of this process is important for healthy aging process, as aberrant mitochondrial dynamics are associated with several age-related diseases/pathologies. However, it is not well understood how imbalanced mitochondrial dynamics may lead to those diseases and pathologies. Here, we aimed to determine metabolic alterations in tissues and cells from mouse models with over-fused (fusion > fission) and over-fragmented (fusion < fission) mitochondria that display age-related disease pathologies. Our results indicated tissue-dependent sensitivity to these mitochondrial changes, and metabolic pathways likely affected by aberrant mitochondrial dynamics. This study provides new insights into how dysregulated mitochondrial dynamics could lead to functional abnormalities of tissues and cells. 

   more » « less
2. Mechanotransduction and cell biomechanics of the intervertebral disc

   https://doi.org/10.1002/jsp2.1026  

   Fearing, Bailey V. ; Hernandez, Paula A. ; Setton, Lori A. ; Chahine, Nadeen O. ( July 2018 , JOR SPINE)

   Mechanical loading of the intervertebral disc (IVD) initiates cell‐mediated remodeling events that contribute to disc degeneration. Cells of the IVD, nucleus pulposus (NP) and anulus fibrosus (AF), will exhibit various responses to different mechanical stimuli which appear to be highly dependent on loading type, magnitude, duration, and anatomic zone of cell origin. Cells of the NP, the innermost region of the disc, exhibit an anabolic response to low‐moderate magnitudes of static compression, osmotic pressure, or hydrostatic pressure, while higher magnitudes promote a catabolic response marked by increased protease expression and activity. Cells of the outer AF are responsive to physical forces in a manner that depends on frequency and magnitude, as are cells of the NP, though they experience different forces, deformations, pressure, and osmotic pressure in vivo. Much remains to be understood of the mechanotransduction pathways that regulate IVD cell responses to loading, including responses to specific stimuli and also differences among cell types. There is evidence that cytoskeletal remodeling and receptor‐mediated signaling are important mechanotransduction events that can regulate downstream effects like gene expression and posttranslational biosynthesis, all of which may influence phenotype and bioactivity. These and other mechanotransduction events will be regulated by known and to‐be‐discovered cell‐matrix and cell‐cell interactions, and depend on composition of extracellular matrix ligands for cell interaction, matrix stiffness, and the phenotype of the cells themselves. Here, we present a review of the current knowledge of the role of mechanical stimuli and the impact upon the cellular response to loading and changes that occur with aging and degeneration of the IVD.

    

   more » « less
3. Dynamic mechanobiology of cardiac cells and tissues: Current status and future perspective

   https://doi.org/10.1063/5.0141269  

   Wang, Chenyan ; Ramahdita, Ghiska ; Genin, Guy ; Huebsch, Nathaniel ; Ma, Zhen ( March 2023 , Biophysics Reviews)

   Mechanical forces impact cardiac cells and tissues over their entire lifespan, from development to growth and eventually to pathophysiology. However, the mechanobiological pathways that drive cell and tissue responses to mechanical forces are only now beginning to be understood, due in part to the challenges in replicating the evolving dynamic microenvironments of cardiac cells and tissues in a laboratory setting. Although many in vitro cardiac models have been established to provide specific stiffness, topography, or viscoelasticity to cardiac cells and tissues via biomaterial scaffolds or external stimuli, technologies for presenting time-evolving mechanical microenvironments have only recently been developed. In this review, we summarize the range of in vitro platforms that have been used for cardiac mechanobiological studies. We provide a comprehensive review on phenotypic and molecular changes of cardiomyocytes in response to these environments, with a focus on how dynamic mechanical cues are transduced and deciphered. We conclude with our vision of how these findings will help to define the baseline of heart pathology and of how these in vitro systems will potentially serve to improve the development of therapies for heart diseases. 

   more » « less
4. Image‐Based Elastography of Heterochromatin and Euchromatin Domains in the Deforming Cell Nucleus

   https://doi.org/10.1002/smll.202006109  

   Ghosh, Soham ; Cuevas, Victor Crespo ; Seelbinder, Benjamin ; Neu, Corey P. ( January 2021 , Small)

   Chromatin of the eukaryotic cell nucleus comprises microscopically dense heterochromatin and loose euchromatin domains, each with distinct transcriptional ability and roles in cellular mechanotransduction. While recent methods are developed to characterize the mechanics of nucleus, measurement of intranuclear mechanics remains largely unknown. Here, the development of “nuclear elastography,” which combines microscopic imaging and computational modeling to quantify the relative elasticity of the heterochromatin and euchromatin domains, is described. Using contracting murine embryonic cardiomyocytes, nuclear elastography reveals that the heterochromatin is almost four times stiffer than the euchromatin at peak deformation. The relative elasticity between the two domains changes rapidly during the active deformation of the cardiomyocyte in the normal physiological condition but progresses more slowly in cells cultured in a mechanically stiff environment, although the relative stiffness at peak deformation does not change. Further, it is found that the disruption of the Klarsicht, ANC‐1, Syne Homology domain of the Linker of Nucleoskeleton and Cytoskeleton complex compromises the intranuclear elasticity distribution resulting in elastically similar heterochromatin and euchromatin. These results provide insight into the elastography dynamics of heterochromatin and euchromatin domains and provide a noninvasive framework to further investigate the mechanobiological function of subcellular and subnuclear domains limited only by the spatiotemporal resolution of the acquired images.

    

   more » « less
5. Mimicking the neural stem cell niche: An engineer’s view of cell: material interactions

   https://doi.org/10.3389/fceng.2022.1086099  

   Yazdani, Narges ; Willits, Rebecca Kuntz ( January 2023 , Frontiers in Chemical Engineering)

   Neural stem cells have attracted attention in recent years to treat neurodegeneration. There are two neurogenic regions in the brain where neural stem cells reside, one of which is called the subventricular zone (SVZ). The SVZ niche is a complicated microenvironment providing cues to regulate self-renewal and differentiation while maintaining the neural stem cell’s pool. Many scientists have spent years understanding the cellular and structural characteristics of the SVZ niche, both in homeostasis and pathological conditions. On the other hand, engineers focus primarily on designing platforms using the knowledge they acquire to understand the effect of individual factors on neural stem cell fate decisions. This review provides a general overview of what we know about the components of the SVZ niche, including the residing cells, extracellular matrix (ECM), growth factors, their interactions, and SVZ niche changes during aging and neurodegenerative diseases. Furthermore, an overview will be given on the biomaterials used to mimic neurogenic niche microenvironments and the design considerations applied to add bioactivity while meeting the structural requirements. Finally, it will discuss the potential gaps in mimicking the microenvironment. 

   more » « less