Materials Stiffness‐Dependent Redox Metabolic Reprogramming of Mesenchymal Stem Cells for Secretome‐Based Therapeutic Angiogenesis

Yang, Hai‐Bo; Cheam, Nicole Mein Ji; Cao, Huấn; Lee, Melissa Kao Hui; Sze, Siu Kwan; Tan, Nguan Soon; Tay, Chor Yong

doi:10.1002/adhm.201900929

Cited by 55 publications

(36 citation statements)

References 38 publications

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“…When ADSCs reached 60%-80% confluency on Cyto-MCs, differentiation process was initiated as previously described. [49][50][51] As shown in the nucleus-stained (DAPI) images of Cyto-MCs (Figure 6C), cell proliferated slower during differentiation as cell densities on Cyto-MCs cultured in DMEM were higher than in adipogenic medium (AM) and osteogenic medium (OM). By Day 6, some non-differentiated cells in DMEM began to detach due to over confluence.…”

Section: Impedance-based Monitoring Of Stem Cell Differentiation On Cytodex Microcarriersmentioning

confidence: 90%

Direct and Label‐Free Cell Status Monitoring of Spheroids and Microcarriers Using Microfluidic Impedance Cytometry

Gong

Petchakup

Shi

et al. 2021

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cytotoxicity assessment due to close resemblance of intercellular and cellmatrix complexities in vivo. [1][2][3] Microcarriers are bead-based 3D matrix scaffolds (≈100-400 µm in diameter) used to upscale cell culture processes in tissue engineering [4,5] and cell therapies. [6,7] As these cultures may last from several days to months, [8] real-time monitoring of spheroid/microcarrier status in a label-free and non-invasive manner is of great significance in many bioprocesses. Conventional sensors for bioreactors probe changes in culture media properties (pH, dissolved oxygen, temperature etc.) that are affected by biomass. As quantification of cell metabolites in culture media indirectly indicates cell/spheroid growth, it is not suitable for real-time monitoring due to a delay between metabolites change and the cell state. [9] Unlike single cells, an inherent problem for optical imaging of 3D spheroids/microcarriers is their large sizes which limit light penetration and fluorescent staining. [10] Typically, cellular aggregates are dissociated into single cells and stained to determine viability as endpoint measurements. [11,12] Electrical impedance spectroscopy is a label-free approach for characterization of material dielectric properties in a static (non-flow) manner, [13] and has been recently applied in microfluidic systems to monitor 3D 3D cellular spheroids/microcarriers (100 µm-1 mm) are widely used in biomanufacturing, and non-invasive biosensors are useful to monitor cell quality in bioprocesses. In this work, a novel microfluidic approach for label-free and continuous-flow monitoring of single spheroid/microcarrier (hydrogel and Cytodex) based on electrical impedance spectroscopy using co-planar Field's metal electrodes is reported. Through numerical simulation and experimental validation, two unique impedance signatures (|Z LF | (60 kHz), |Z HF | (1 MHz)) which are optimal for spheroid growth and viability monitoring are identified. Using a closed-loop recirculation system, it is demonstrated that |Z LF | increases with breast cancer (MCF-7) spheroid biomass, while higher opacity (impedance ratio |Z HF |/|Z LF |) indicates cell death due to compromised cell membrane. Anti-cancer drug (paclitaxel)-treated spheroids also exhibit lower |Z LF | with increased cell dissociation. Interestingly, impedance characterization of adipose-derived mesenchymal stem cell differentiation on Cytodex microcarriers reveals that adipogenic cells (higher intracellular lipid content) exhibit higher impedance than osteogenic cells (more conductive due to calcium ions) for both microcarriers and single cell level. Taken together, the developed platform offers great versatility for multi-parametric analysis of spheroids/microcarriers at high throughput (≈1 particle/s), and can be readily integrated into bioreactors for long-term and remote monitoring of biomass and cell quality.

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Section: Impedance-based Monitoring Of Stem Cell Differentiation On Cytodex Microcarriersmentioning

confidence: 90%

Direct and Label‐Free Cell Status Monitoring of Spheroids and Microcarriers Using Microfluidic Impedance Cytometry

Gong

Petchakup

Shi

et al. 2021

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“…In this context, a potential association of material stiffness with trophic activities has generally not yet received much attention. However, recent evidence suggests that material stiffness modulates the paracrine signaling of a few cell types [ 205 , 206 , 207 , 208 ] and even the intracellular reactive oxygen species (ROS) level in human adipose-derived MSCs (ADMSCs) [ 209 ]. One study varied either poly(ethylene)glycol diacrylate (PEGDA) hydrogel stiffness but kept the cell adhesive sites constant or varied the concentration of the cell adhesive sites.…”

Section: Immuno-modulative and Angiogenic Role Of Materials Stiffnmentioning

confidence: 99%

Mechanotransduction and Stiffness-Sensing: Mechanisms and Opportunities to Control Multiple Molecular Aspects of Cell Phenotype as a Design Cornerstone of Cell-Instructive Biomaterials for Articular Cartilage Repair

Selig

Lauer

Hart

et al. 2020

IJMS

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Since material stiffness controls many cell functions, we reviewed the currently available knowledge on stiffness sensing and elucidated what is known in the context of clinical and experimental articular cartilage (AC) repair. Remarkably, no stiffness information on the various biomaterials for clinical AC repair was accessible. Using mRNA expression profiles and morphology as surrogate markers of stiffness-related effects, we deduced that the various clinically available biomaterials control chondrocyte (CH) phenotype well, but not to equal extents, and only in non-degenerative settings. Ample evidence demonstrates that multiple molecular aspects of CH and mesenchymal stromal cell (MSC) phenotype are susceptible to material stiffness, because proliferation, migration, lineage determination, shape, cytoskeletal properties, expression profiles, cell surface receptor composition, integrin subunit expression, and nuclear shape and composition of CHs and/or MSCs are stiffness-regulated. Moreover, material stiffness modulates MSC immuno-modulatory and angiogenic properties, transforming growth factor beta 1 (TGF-β1)-induced lineage determination, and CH re-differentiation/de-differentiation, collagen type II fragment production, and TGF-β1- and interleukin 1 beta (IL-1β)-induced changes in cell stiffness and traction force. We then integrated the available molecular signaling data into a stiffness-regulated CH phenotype model. Overall, we recommend using material stiffness for controlling cell phenotype, as this would be a promising design cornerstone for novel future-oriented, cell-instructive biomaterials for clinical high-quality AC repair tissue.

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“…Human adipose-derived mesenchymal stem cells on mechanically tunable fibronectin-conjugated polyacrylamide (FN-PAAm) hydrogel substrates have been studied and it has been found that the intranuclear Nrf2 level of the cells grown on the soft 0.15 kPa FN-PAAm hydrogel was about three times higher compared with intranuclear Nrf2 level in the cells cultured on the hard glass surfaces. Upregulation of downstream target of Nrf2 heme oxygenase-1 was also reported [96]. So, the decrease in substrate stiffness activated Nrf2.…”

Section: Nf-κb Activationmentioning

confidence: 72%

Tissue Integrity and COVID-19

Kerch

2021

Encyclopedia

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Tissue integrity depends on biological tissue stiffness. Tissue integrity can protect both against age-related diseases and against severity of COVID-19. The disruption of tight junctions and increase of tissue permeability with advancing age can be related with age-related diseases as well as with age-dependent COVID-19. Release of tightly bound water from collagen fibrils leads to the increase of extracellular matrix stiffness and to the associated with matrix stiffness increased tissue permeability. The link between arterial stiffness and oxidative stress has been reported and is expected to be studied in more detail in the future. Trehalose can be suggested for retardation of tightly bound water release and subsequent extracellular matrix crosslinking by advanced glycation end products. Increase in tissue permeability can be blocked by polyphenols that inhibit ICAM-1 expression and mitigate cytoskeleton reorganization. NF-κB activation as a result of increased stiffness and cytoskeleton reorganization can cause both cardiovascular pathologies and COVID-19. Increased cholesterol content in cell membrane leads to increased virus entry into cell and increase of cholesterol is linked with cardiovascular diseases. Statins and chitosan are known as cholesterol-lowering substances. Nrf2 inhibits NF-κB activation and NF-κB inhibits Nrf2 pathway.

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Materials Stiffness‐Dependent Redox Metabolic Reprogramming of Mesenchymal Stem Cells for Secretome‐Based Therapeutic Angiogenesis

Cited by 55 publications

References 38 publications

Direct and Label‐Free Cell Status Monitoring of Spheroids and Microcarriers Using Microfluidic Impedance Cytometry

Direct and Label‐Free Cell Status Monitoring of Spheroids and Microcarriers Using Microfluidic Impedance Cytometry

Mechanotransduction and Stiffness-Sensing: Mechanisms and Opportunities to Control Multiple Molecular Aspects of Cell Phenotype as a Design Cornerstone of Cell-Instructive Biomaterials for Articular Cartilage Repair

Tissue Integrity and COVID-19

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