Cell Elasticity Determines Macrophage Function

Patel, Naimish; Bole, Medhavi; Chen, Cheng; Hardin, C. Corey; Kho, Alvin T.; Mih, Justin D.; Deng, Linhong; Butler, James P.; Tschumperlin, Daniel J.; Fredberg, Jeffrey J.; Krishnan, Ramaswamy; Koziel, Henryk

doi:10.1371/journal.pone.0041024

Cited by 231 publications

(249 citation statements)

References 46 publications

(77 reference statements)

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“…58 Recent research showed that the cell mechanical properties determined the macrophage functions. 59 Here the measured Young's modulus of macrophages was in the range of 1−3 kPa and became 2−5 kPa after the activation of phagocytosis, comparable to the measured values of the cell Young's modulus by other groups. In the era of personalized medicine, investigating the properties of patients at single-cell levels is increasingly important.…”

Section: Resultssupporting

confidence: 88%

Nanoscale Imaging and Mechanical Analysis of Fc Receptor-Mediated Macrophage Phagocytosis against Cancer Cells

Liu

et al. 2014

Langmuir

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Fc receptor-mediated macrophage phagocytosis against cancer cells is an important mechanism in the immune therapy of cancers. Traditional research about macrophage phagocytosis was based on optical microscopy, which cannot reveal detailed information because of the 200-nm-resolution limit. Quantitatively investigating the macrophage phagocytosis at micro-and nanoscale levels is still scarce. The advent of atomic force microscopy (AFM) offers an excellent analytical instrument for quantitatively investigating the biological processes at single-cell and singlemolecule levels under native conditions. In this work, we combined AFM and fluorescence microscopy to visualize and quantify the detailed changes in cell morphology and mechanical properties during the process of Fc receptor-mediated macrophage phagocytosis against cancer cells. Lymphoma cells were discernible by fluorescence staining. Then, the dynamic process of phagocytosis was observed by time-lapse optical microscopy. Next, AFM was applied to investigate the detailed cellular behaviors during macrophage phagocytosis under the guidance of fluorescence recognition. AFM imaging revealed the distinct features in cellular ultramicrostructures for the different steps of macrophage phagocytosis. AFM cell mechanical property measurements indicated that the binding of cancer cells to macrophages could make macrophages become stiffer. The experimental results provide novel insights in understanding the Fc-receptor-mediated macrophage phagocytosis.

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Section: Resultssupporting

confidence: 88%

Nanoscale Imaging and Mechanical Analysis of Fc Receptor-Mediated Macrophage Phagocytosis against Cancer Cells

Liu

et al. 2014

Langmuir

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“…S6) has been reported in previous studies using magnetic twisting cytometry (58). This effect is not likely due to a low expression level of myosin IIA in macrophages (59,60).…”

Section: Discussionsupporting

confidence: 71%

Myosin II Activity Softens Cells in Suspension

Chan

Ekpenyong

Golfier

et al. 2015

Biophysical Journal

102

105

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The cellular cytoskeleton is crucial for many cellular functions such as cell motility and wound healing, as well as other processes that require shape change or force generation. Actin is one cytoskeleton component that regulates cell mechanics. Important properties driving this regulation include the amount of actin, its level of cross-linking, and its coordination with the activity of specific molecular motors like myosin. While studies investigating the contribution of myosin activity to cell mechanics have been performed on cells attached to a substrate, we investigated mechanical properties of cells in suspension.To do this, we used multiple probes for cell mechanics including a microfluidic optical stretcher, a microfluidic microcirculation mimetic, and real-time deformability cytometry. We found that nonadherent blood cells, cells arrested in mitosis, and naturally adherent cells brought into suspension, stiffen and become more solidlike upon myosin inhibition across multiple timescales (milliseconds to minutes). Our results hold across several pharmacological and genetic perturbations targeting myosin. Our findings suggest that myosin II activity contributes to increased whole-cell compliance and fluidity. This finding is contrary to what has been reported for cells attached to a substrate, which stiffen via active myosin driven prestress. Our results establish the importance of myosin II as an active component in modulating suspended cell mechanics, with a functional role distinctly different from that for substrate-adhered cells.

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“…Adhesion to a rigid (not soft) substrate for many cell types drives cell spreading with assembly of stress fibers and polarization of nonmuscle myosin-II 44,46,52,53 ; macrophages are certainly mechanosensitive in adhesion 45,54,55 and phagocytosis. 35 Target rigidity can therefore contribute to the generation of contractile forces during the phagocytosis of foreign cells.…”

Section: Resultsmentioning

confidence: 99%

Cell rigidity and shape override CD47’s “self”-signaling in phagocytosis by hyperactivating myosin-II

Sosale

Rouhiparkouhi

Bradshaw

et al. 2015

Blood

127

132

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Key Points• Rigidity of an opsonized red cell that contacts a macrophage is found to hyperactivate myosin-II and thus overpowers CD47's self-signaling. • Red cell shape modulates CD47's signaling of self and highlights biophysical contributions to phagocytosis.A macrophage engulfs another cell or foreign particle in an adhesive process that often activates myosin-II, unless the macrophage also engages "marker of self" CD47 that inhibits myosin. For many cell types, adhesion-induced activation of myosin-II is maximized by adhesion to a rigid rather than a flexible substrate. Here we demonstrate that rigidity of a phagocytosed cell also hyperactivates myosin-II, which locally overwhelms selfsignaling at a phagocytic synapse. Cell stiffness is one among many factors including shape that changes in erythropoiesis, in senescence and in diseases ranging from inherited anemias and malaria to cancer. Controlled stiffening of normal human red blood cells (RBCs) in different shapes does not compromise CD47's interaction with the macrophage self-recognition receptor signal regulatory protein alpha (SIRPA). Uptake of antibodyopsonized RBCs is always fastest with rigid RBC discocytes, which also show that maximal active myosin-II at the synapse can dominate self-signaling by CD47. Rigid but rounded RBC stomatocytes signal self better than rigid RBC discocytes, highlighting the effects of shape on CD47 inhibition. Physical properties of phagocytic targets thus regulate self signaling, as is relevant to erythropoiesis, to clearance of rigid RBCs after blood storage, clearance of rigid pathological cells such as thalassemic or sickle cells, and even to interactions of soft/stiff cancer cells with macrophages. (Blood. 2015;125(3):542-552)

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Cell Elasticity Determines Macrophage Function

Cited by 231 publications

References 46 publications

Nanoscale Imaging and Mechanical Analysis of Fc Receptor-Mediated Macrophage Phagocytosis against Cancer Cells

Nanoscale Imaging and Mechanical Analysis of Fc Receptor-Mediated Macrophage Phagocytosis against Cancer Cells

Myosin II Activity Softens Cells in Suspension

Cell rigidity and shape override CD47’s “self”-signaling in phagocytosis by hyperactivating myosin-II

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