Effect of M1–M2 Polarization on the Motility and Traction Stresses of Primary Human Macrophages

Hind, Laurel E.; Lurier, Emily; Dembo, Micah; Spiller, Kara L.; Hammer, Daniel A.

doi:10.1007/s12195-016-0435-x

Cited by 57 publications

(49 citation statements)

References 26 publications

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“…We found that, consistent with previous reports ( Zhang et al. , 2013a ; Hind et al. , 2016 ), IL4-treated M2 macrophages have higher migration total speed and directedness compared with control (no treatment, naïve, M0 macrophages) and LPS-treated M1 macrophages.…”

Section: Resultssupporting

confidence: 93%

Interstitial flow promotes macrophage polarization toward an M2 phenotype

Serrano

Xing

et al. 2018

MBoC

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Tumor tissues are characterized by an elevated interstitial fluid flow from the tumor to the surrounding stroma. Macrophages in the tumor microenvironment are key contributors to tumor progression. While it is well established that chemical stimuli within the tumor tissues can alter macrophage behaviors, the effects of mechanical stimuli, especially the flow of interstitial fluid in the tumor microenvironment, on macrophage phenotypes have not been explored. Here, we used three-dimensional biomimetic models to reveal that macrophages can sense and respond to pathophysiological levels of interstitial fluid flow reported in tumors (∼3 µm/s). Specifically, interstitial flow (IF) polarizes macrophages toward an M2-like phenotype via integrin/Src-mediated mechanotransduction pathways involving STAT3/6. Consistent with this flow-induced M2 polarization, macrophages treated with IF migrate faster and have an enhanced ability to promote cancer cell migration. Moreover, IF directs macrophages to migrate against the flow. Since IF emanates from the tumor to the surrounding stromal tissues, our results suggest that IF could not only induce M2 polarization of macrophages but also recruit these M2 macrophages toward the tumor masses, contributing to cancer cell invasion and tumor progression. Collectively, our study reveals that IF could be a critical regulator of tumor immune environment.

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Section: Resultssupporting

confidence: 93%

Interstitial flow promotes macrophage polarization toward an M2 phenotype

Serrano

Xing

et al. 2018

MBoC

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“…This is consistent with our observations of mouse macrophage migration (Fig 5A-D). Prior studies have also shown that M2-like macrophages are typically more migratory, which is consistent with the oxidative metabolic shift in mouse macrophages localized closest to the tumor layer (actively-migrating) ( Fig 5E-G) 102,103 . Overall, metabolic autofluorescence imaging and microfluidic models of 3D microenvironment illustrate tumor-driven spatiotemporal changes in macrophage metabolism.…”

Section: Discussionsupporting

confidence: 85%

Autofluorescence imaging of 3D tumor-macrophage microscale cultures resolves spatial and temporal dynamics of macrophage metabolism

Heaster

Humayun

et al. 2020

Preprint

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Macrophages within the tumor microenvironment (TME) exhibit a spectrum of pro-tumor and antitumor functions, yet it is unclear how the TME regulates this macrophage heterogeneity. Standard methods to measure macrophage heterogeneity require destructive processing, limiting spatiotemporal studies of function within the live, intact 3D TME. Here, we demonstrate twophoton autofluorescence imaging of NAD(P)H and FAD to non-destructively resolve spatiotemporal metabolic heterogeneity of individual macrophages within 3D microscale TME models. Fluorescence lifetimes and intensities of NAD(P)H and FAD were acquired at 24, 48, and 72 hours post-stimulation for mouse macrophages (RAW 264.7) stimulated with IFN-γ or IL-4 plus IL-13 in 2D culture, validating that autofluorescence measurements capture known metabolic phenotypes. To quantify metabolic dynamics of macrophages within the TME, mouse macrophages or human monocytes (RAW264.7 or THP-1) were cultured alone or with breast cancer cells (mouse PyVMT or primary human IDC) in 3D microfluidic platforms. Human monocytes and mouse macrophages in tumor co-cultures exhibited significantly different FAD mean lifetimes and greater migration than mono-cultures at 24, 48, and 72 hours post-seeding. In co-cultures with primary human cancer cells, actively-migrating monocyte-derived macrophages had greater redox ratios (NAD(P)H/FAD intensity) compared to passively-migrating monocytes at 24 and 48 hours post-seeding, reflecting metabolic heterogeneity in this subpopulation of monocytes. Genetic analyses further confirmed this metabolic heterogeneity. These results establish label-free autofluorescence imaging to quantify dynamic metabolism, polarization, and migration of macrophages at single-cell resolution within 3D microscale models. This combined culture and imaging system provides unique insights into spatiotemporal tumorimmune crosstalk within the 3D TME.

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“…To calculate diffusivities for each case, mean square displacement (MSD) of polymersomes was measured by tracking the motion of each polymersome at 1 min intervals by using FIJI software. Traces are processed using a custom suite of MATLAB (The MathWorks, Natick, MA) scripts that have been used to study the motility of white blood cells . Scattergrams of the motion of polymersomes at 11.1 × 10 −3 and 121.6 × 10 −3 m H 2 O 2 (Figure C,D) show that polymersomes in 121.6 × 10 −3 m H 2 O 2 show more avid motion, as evidenced by larger displacements in the same period of time, as compared to those in 11.1 × 10 −3 m H 2 O 2 .…”

Section: Resultsmentioning

confidence: 99%

“…Diffusive motion for polymersomes were observed with Zeiss Axiovert 200 (Oberkochen, Germany) inverted microscope. Polymersomes′ motility quantification is performed using Fiji and a custom suite of MATLAB (The MathWorks, Natick, MA) scripts which were previously used to study the white blood cell motility …”

Section: Methodsmentioning

confidence: 99%

Enzymatically Powered Surface‐Associated Self‐Motile Protocells

Jang

Kim

Gao

et al. 2018

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Cell motility is central to processes such as wound healing, immune cell surveillance, and embryonic development. Motility requires the conversion of chemical to mechanical energy. An active area of research is to create motile particles, such as microswimmers, using catalytic and enzymatic reactions. Here, autonomous motion is demonstrated in adhesive polymer-based protocells by incorporating and harnessing the energy production of an enzymatic reaction. Biotinylated polymer vesicles that encapsulate catalase, an enzyme which converts hydrogen peroxide to water and oxygen, are prepared and these vesicles are adhered weakly to avidin-coated surfaces. Upon addition of hydrogen peroxide, which diffuses across the membrane, catalase activity generates a differential impulsive force that enables the breakage and reformation of biotin-avidin bonds, leading to diffusive vesicle motion resembling random motility. The random motility requires catalase, increases with the concentration of hydrogen peroxide, and needs biotin-avidin adhesion. Thus, a protocellular mimetic of a motile cell.

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Effect of M1–M2 Polarization on the Motility and Traction Stresses of Primary Human Macrophages

Cited by 57 publications

References 26 publications

Interstitial flow promotes macrophage polarization toward an M2 phenotype

Interstitial flow promotes macrophage polarization toward an M2 phenotype

Autofluorescence imaging of 3D tumor-macrophage microscale cultures resolves spatial and temporal dynamics of macrophage metabolism

Enzymatically Powered Surface‐Associated Self‐Motile Protocells

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