Compliant substratum guides endothelial commitment from human pluripotent stem cells

Smith, Quinton; Chan, Xin Yi; Carmo, Ana Maria do; Trempel, M.; Saunders, Michael N; Gerecht, Sharon

doi:10.1126/sciadv.1602883

Cited by 49 publications

(51 citation statements)

References 43 publications

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“…5D): In this system, we observed four different types of domains; an edge of a pattern (black); the region of increased density toward the edge of a pattern-an annulus in the case of a circle (purple), the center of a pattern (yellow), and a region of increased density toward the edge of patterns with corners-and thus two neighboring edges-subjected to higher tension deeper into the center of the pattern (red). In a previous study, we tracked other mesodermal markers along our differentiation scheme, showing the temporal expression of markers including KDR, GATA-2, MESP-1, and SNAIL (26). We view the current study as a robust computational foundation to explore the temporal/spatial expression of these markers in the context of cytoskeletal tension, allowing more insight into mechanical regulation of vascular specification.…”

Section: Svm Learning Elucidates the Roles Of Cytoskeletal Tension Anmentioning

confidence: 87%

“…After 48 h of culture, cells were fixed for immunofluorescence staining. To induce EVC specification, seeded micropatterns were cultured in Diff Media that on day 6 was switched to EC Diff Media (15,22,23,26). Cells cultured on micropatterned surfaces were fixed and stained (SI Appendix, Table S2).…”

Section: Methodsmentioning

confidence: 99%

“…Early Mesoderm Patterning Predicts Vascular Specification. To investigate the effect of early mesoderm specification, evidenced by T expression on the micropattern domains, we extended differentiation on the micropatterns toward early vascular cell (EVC) populations based on our previous work (22,23,26). Briefly, cells were differentiated with and without temporary RhoA/ROCK inhibition for 48 h. After 2 d in the respective conditions, media was replaced for an additional 4 d without Y-27632.…”

Section: Svm Learning Elucidates the Roles Of Cytoskeletal Tension Anmentioning

confidence: 99%

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Cytoskeletal tension regulates mesodermal spatial organization and subsequent vascular fate

Smith

Rochman

Carmo

et al. 2018

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

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Morphogenesis during human development relies on the interplay between physiochemical cues that are mediated in part by cellular density and cytoskeletal tension. Here, we interrogated these factors on vascular lineage specification during human-induced pluripotent stem-cell (hiPSC) fate decision. We found that independent of chemical cues, spatially presented physical cues induce the self-organization of Brachyury-positive mesodermal cells, in a RhoA/Rho-associated kinase (ROCK)-dependent manner. Using unbiased support vector machine (SVM) learning, we found that density alone is sufficient to predict mesodermal fate. Furthermore, the long-withstanding presentation of spatial confinement during hiPSC differentiation led to an organized vascular tissue, reminiscent of native blood vessels, a process dependent on cell density as found by SVM analysis. Collectively, these results show how tension and density relate to vascular identity mirroring early morphogenesis. We propose that such a system can be applied to study other aspects of the stem-cell niche and its role in embryonic patterning.

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Section: Svm Learning Elucidates the Roles Of Cytoskeletal Tension Anmentioning

confidence: 87%

Section: Methodsmentioning

confidence: 99%

Section: Svm Learning Elucidates the Roles Of Cytoskeletal Tension Anmentioning

confidence: 99%

See 1 more Smart Citation

Cytoskeletal tension regulates mesodermal spatial organization and subsequent vascular fate

Smith

Rochman

Carmo

et al. 2018

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

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“…As a scaffold material, PDMS can be modified to contain chemical cues, including sites for cell adhesion. The mechanical properties of PDMS are easily manipulated and thus these scaffolds have been used to determine how mechanical properties of the microenvironment influence stem cell differentiation [200,253]. Another interesting tissue engineering application requires the incorporation of PDMS microspheres in stem cell aggregates.…”

Section: Polydimethylsiloxane (Pdms)mentioning

confidence: 99%

Combining Stem Cells and Biomaterial Scaffolds for Constructing Tissues and Cell Delivery

Willerth

Sakiyama‐Elbert

2019

STJ

111

113

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Combining stem cells with biomaterial scaffolds serves as a promising strategy for engineering tissues for both in vitro and in vivo applications. This updated review details commonly used biomaterial scaffolds for engineering tissues from stem cells. We first define the different types of stem cells and their relevant properties and commonly used scaffold formulations. Next, we discuss natural and synthetic scaffold materials typically used when engineering tissues, along with their associated advantages and drawbacks and gives examples of target applications. New approaches to engineering tissues, such as 3D bioprinting, are described as they provide exciting opportunities for future work along with current challenges that must be addressed. Thus, this review provides an overview of the available biomaterials for directing stem cell differentiation as a means of producing replacements for diseased or damaged tissues.

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“…It is also known that hydrodynamic shear stress promotes the conversion of primary patient epithelial tumor cells into specific cancer stem-like cells [34]. Smith et al found that the mechanical context of the differentiation niche can drive endothelial cell identity from human-induced pluripotent stem cells, showing that stiffness drives mesodermal differentiation, leading to endothelial commitment [35]. Thus, microenvironments help specify stem cell lineages, although it may be difficult to decouple the influence of mechanical interactions and surface topography and stiffness from biochemical effects [12,35].…”

Section: Introductionmentioning

confidence: 99%

Understanding the Influence of Substrate When Growing Tumorspheres

Benítez

Barberis

Vellón

et al. 2020

Preprint

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Background: Cancer stem cells are important for the development of many solid tumors. These cells receive promoting and inhibitory signals that depend on the nature of their environment (their niche) and determine cell dynamics. Mechanical stresses are crucial to the initiation and interpretation of these signals. Methods: A two-population mathematical model of tumorsphere growth is used to interpret the results of a series of experiments recently carried out in Tianjin, China, and extract information about the intraspecific and interspecific interactions between cancer stem cell and differentiated cancer cell populations. Results: The model allows us to reconstruct the time evolution of the cancer stem cell fraction, which was not directly measured. We find that, in the presence of stem cell growth factors, the interspecific cooperation between cancer stem cells and differentiated cancer cells induces a positive feedback loop that determines growth, independently of substrate hardness. In a frustrated attempt to reconstitute the stem cell niche, the number of cancer stem cells increases continuously with a reproduction rate that is enhanced by a hard substrate. For growth on soft agar, intraspecific interactions are always inhibitory, but on hard agar the interactions between stem cells are collaborative while those between differentiated cells are strongly inhibitory. Evidence also suggests that a hard substrate brings about a large fraction of asymmetric stem cell divisions. In the absence of stem cell growth factors, the barrier to differentiation is broken and overall growth is faster, even if the stem cell number is conserved. Conclusions: Our interpretation of the experimental results validates the centrality of the concept of stem cell niche when tumor growth is fueled by cancer stem cells. Niche memory is found to be responsible for the characteristic population dynamics observed in tumorspheres. A specific condition for the growth of the cancer stem cell number is also obtained.

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Compliant substratum guides endothelial commitment from human pluripotent stem cells

Abstract: Surface stiffness during the early stages of stem cell differentiation affects vascular fate under chemically defined conditions.

Cited by 49 publications

References 43 publications

Cytoskeletal tension regulates mesodermal spatial organization and subsequent vascular fate

Cytoskeletal tension regulates mesodermal spatial organization and subsequent vascular fate

Combining Stem Cells and Biomaterial Scaffolds for Constructing Tissues and Cell Delivery

Understanding the Influence of Substrate When Growing Tumorspheres

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