Material properties of the cell dictate stress-induced spreading and differentiation in embryonic stem cells

Chowdhury, Farhan; Na, Sungsoo; Liu, Dong; Poh, Yeh Chuin; Tanaka, Tetsuya; Wang, Fei; Wang, Ning

doi:10.1038/nmat2563

Cited by 524 publications

(459 citation statements)

References 52 publications

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“…The expression profile of the enriched flexible SUM149 cell subpopulation shows underexpression of epithelial cytokeratins, actins, and lamins, as well as overexpression of vimentin. These properties could be indicators of greater flexibility and a less differentiated state (5)(6)(7)(8)35), providing support for the proposed mechanism of MS-chip separation.…”

Section: Resultsmentioning

confidence: 77%

“…Applications of these methods to stem cells have revealed the greater deformability of the cytoskeleton and nucleoskeleton in less differentiated cells, whereby deformability generally decreases during differentiation to mature cells (5)(6)(7)(8). Research on cancer cell deformability has also consistently revealed that increased deformability is correlated with increased metastatic potential (9)(10)(11)(12)(13)(14)(15).…”

mentioning

confidence: 99%

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Microfluidics separation reveals the stem-cell–like deformability of tumor-initiating cells

Zhang

Kai

Choi

et al. 2012

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

192

172

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Here we report a microfluidics method to enrich physically deformable cells by mechanical manipulation through artificial microbarriers. Driven by hydrodynamic forces, flexible cells or cells with high metastatic propensity change shape to pass through the microbarriers and exit the separation device, whereas stiff cells remain trapped. We demonstrate the separation of (i) a mixture of two breast cancer cell types (MDA-MB-436 and MCF-7) with distinct deformabilities and metastatic potentials, and (ii) a heterogeneous breast cancer cell line (SUM149), into enriched flexible and stiff subpopulations. We show that the flexible phenotype is associated with overexpression of multiple genes involved in cancer cell motility and metastasis, and greater mammosphere formation efficiency. Our observations support the relationship between tumor-initiating capacity and cell deformability, and demonstrate that tumor-initiating cells are less differentiated in terms of cell biomechanics.cell mechanics | cytoskeleton | genomic profiling C ell deformability is commonly measured using magnetic twisting cytometry, particle tracking rheometry, optical tweezers, micropipette aspiration, atomic force microscope, and other derivative cell stretching or poking methods (1-4). Applications of these methods to stem cells have revealed the greater deformability of the cytoskeleton and nucleoskeleton in less differentiated cells, whereby deformability generally decreases during differentiation to mature cells (5-8). Research on cancer cell deformability has also consistently revealed that increased deformability is correlated with increased metastatic potential (9-15).Despite the success achieved using cell deformability measurements, isolation of cells with differential deformabilities remains a great challenge (10, 16). Microfabrication-assisted technology, using microscale arrays of round or rectangular posts, channels, or other simple patterns, has the potential to solve this problem (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). Here, we focused on the mechanical properties of cancer cells in designing a unique cell purification system for the purpose of generating subpopulations enriched in highly deformable cells. We used microfabrication technology and obtained a subpopulation of SUM149 breast cancer cells with stem-cell-like deformability and mammosphere formation capability.The separation device, a mechanical separation chip (MS-chip), employs artificial microbarriers in combination with hydrodynamic force to separate deformable from stiff cells (Fig. 1A). Both the microbarrier structures and the fluidic parameters are essential to the cell-enrichment process. The most notable feature of the device is the precise placement of the microbarriers to impede the passage of stiff cells. Published in vivo observations suggest that the minimum crossable barrier for cancer cells is ∼8 μm or less (28,29). Here, we took those barrier dimensions into account in designing the MSchip to separate cells based on perfusion through constrictions. As...

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Section: Resultsmentioning

confidence: 77%

mentioning

confidence: 99%

Microfluidics separation reveals the stem-cell–like deformability of tumor-initiating cells

Zhang

Kai

Choi

et al. 2012

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

192

172

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“…As stated above, many cell types are responsive to the mechanical properties of their substrate, including towards their spreading behaviour 14,38 . Thus, as expected, hMSCs cultured on addition-only hydrogel substrates for 1 day spread in a manner that was dependent on the substrate stiffness ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Stiffening hydrogels to probe short- and long-term cellular responses to dynamic mechanics

2012

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Biological processes are dynamic in nature, and growing evidence suggests that matrix stiffening is particularly decisive during development, wound healing and disease; yet, nearly all in vitro models are static. Here we introduce a step-wise approach, addition then lightmediated crosslinking, to fabricate hydrogels that stiffen (for example, ~3-30 kPa) in the presence of cells, and investigated the short-term (minutes-to-hours) and long-term (daysto-weeks) cell response to dynamic stiffening. When substrates are stiffened, adhered human mesenchymal stem cells increase their area from ~500 to 3,000 µm 2 and exhibit greater traction from ~1 to 10 kPa over a timescale of hours. For longer cultures up to 14 days, human mesenchymal stem cells selectively differentiate based on the period of culture, before or after stiffening, such that adipogenic differentiation is favoured for later stiffening, whereas osteogenic differentiation is favoured for earlier stiffening.

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“…Studies on mESCs revealed that their pluripotency marker Oct3/4 expression is significantly reduced when a local stress is applied to undifferentiated mESCs using magnetic twisting cytometry. 80 Also, the spreading response in mESCs is greater than in airway smooth muscle cells or mESCderived cells. Based on these observations, it can be hypothesized that a threshold cell deformation is crucial for initiating a cell spreading response.…”

Section: Mechanical Stimulation Can Alter Hpsc Fatementioning

confidence: 99%

Mechanobiology of Human Pluripotent Stem Cells

Earls

Jin

2013

Tissue Engineering Part B: Reviews

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Human pluripotent stem cells (hPSCs) are self-renewing and have the potential to differentiate into any cell type in the body, making them attractive cell sources for applications in tissue engineering and regenerative medicine. However, in order for hPSCs to find use in the clinic, the mechanisms underlying their self-renewal and lineage commitment must be better understood. Many technologies that have been developed for the maintenance and directed differentiation of hPSCs involve the use of soluble growth factors, but recent studies suggest that other elements of the hPSC microenvironment also influence the growth and differentiation of hPSCs. This includes the influences of cell-cell interactions, substrate mechanics, cellular interactions with extracellular matrix, as well as the nanotopography of the substrate and physical forces such as shear stress, cyclic mechanical strain, and compression. In this review, we highlight the recent progress of this area of research and discuss ways in which the mechanical cues may be incorporated into hPSC culture regimes to improve methods for expanding and differentiating hPSCs.

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Material properties of the cell dictate stress-induced spreading and differentiation in embryonic stem cells

Cited by 524 publications

References 52 publications

Microfluidics separation reveals the stem-cell–like deformability of tumor-initiating cells

Microfluidics separation reveals the stem-cell–like deformability of tumor-initiating cells

Stiffening hydrogels to probe short- and long-term cellular responses to dynamic mechanics

Mechanobiology of Human Pluripotent Stem Cells

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