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1
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Janes KA, Lazzara MJ. Systems Biology of the Cancer Cell. Annu Rev Biomed Eng 2025; 27:1-28. [PMID: 39689262 DOI: 10.1146/annurev-bioeng-103122-030552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2024]
Abstract
Questions in cancer have engaged systems biologists for decades. During that time, the quantity of molecular data has exploded, but the need for abstractions, formal models, and simplifying insights has remained the same. This review brings together classic breakthroughs and recent findings in the field of cancer systems biology, focusing on cancer cell pathways for tumorigenesis and therapeutic response. Cancer cells mutate and transduce information from their environment to alter gene expression, metabolism, and phenotypic states. Understanding the molecular architectures that make each of these steps possible is a long-term goal of cancer systems biology pursued by iterating between quantitative models and experiments. We argue that such iteration is the best path to deploying targeted therapies intelligently so that each patient receives the maximum benefit for their cancer.
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Affiliation(s)
- Kevin A Janes
- Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia, USA
- Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, USA; ,
| | - Matthew J Lazzara
- Department of Chemical Engineering, University of Virginia, Charlottesville, Virginia, USA
- Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, USA; ,
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2
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Hansen J, Jain AR, Nenov P, Robinson PN, Iyengar R. From transcriptomics to digital twins of organ function. Front Cell Dev Biol 2024; 12:1240384. [PMID: 38989060 PMCID: PMC11234175 DOI: 10.3389/fcell.2024.1240384] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Accepted: 05/30/2024] [Indexed: 07/12/2024] Open
Abstract
Cell level functions underlie tissue and organ physiology. Gene expression patterns offer extensive views of the pathways and processes within and between cells. Single cell transcriptomics provides detailed information on gene expression within cells, cell types, subtypes and their relative proportions in organs. Functional pathways can be scalably connected to physiological functions at the cell and organ levels. Integrating experimentally obtained gene expression patterns with prior knowledge of pathway interactions enables identification of networks underlying whole cell functions such as growth, contractility, and secretion. These pathways can be computationally modeled using differential equations to simulate cell and organ physiological dynamics regulated by gene expression changes. Such computational systems can be thought of as parts of digital twins of organs. Digital twins, at the core, need computational models that represent in detail and simulate how dynamics of pathways and networks give rise to whole cell level physiological functions. Integration of transcriptomic responses and numerical simulations could simulate and predict whole cell functional outputs from transcriptomic data. We developed a computational pipeline that integrates gene expression timelines and systems of coupled differential equations to generate cell-type selective dynamical models. We tested our integrative algorithm on the eicosanoid biosynthesis network in macrophages. Converting transcriptomic changes to a dynamical model allowed us to predict dynamics of prostaglandin and thromboxane synthesis and secretion by macrophages that matched published lipidomics data obtained in the same experiments. Integration of cell-level system biology simulations with genomic and clinical data using a knowledge graph framework will allow us to create explicit predictive models that mechanistically link genomic determinants to organ function. Such integration requires a multi-domain ontological framework to connect genomic determinants to gene expression and cell pathways and functions to organ level phenotypes in healthy and diseased states. These integrated scalable models of tissues and organs as accurate digital twins predict health and disease states for precision medicine.
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Affiliation(s)
- Jens Hansen
- Department of Pharmacological Science and Institute for Systems Biomedicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Abhinav R Jain
- Department of Pharmacological Science and Institute for Systems Biomedicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Philip Nenov
- Department of Pharmacological Science and Institute for Systems Biomedicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States
- College of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, United States
| | - Peter N Robinson
- Berlin Institute of Health at Charité Rahel Hirsch Center for Translational Medicine, Berlin, Germany
| | - Ravi Iyengar
- Department of Pharmacological Science and Institute for Systems Biomedicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States
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3
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Bonilla-Quintana M, Rangamani P. Biophysical Modeling of Actin-Mediated Structural Plasticity Reveals Mechanical Adaptation in Dendritic Spines. eNeuro 2024; 11:ENEURO.0497-23.2024. [PMID: 38383589 DOI: 10.1523/eneuro.0497-23.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Accepted: 01/13/2024] [Indexed: 02/23/2024] Open
Abstract
Synaptic plasticity is important for learning and memory formation; it describes the strengthening or weakening of connections between synapses. The postsynaptic part of excitatory synapses resides in dendritic spines, which are small protrusions on the dendrites. One of the key features of synaptic plasticity is its correlation with the size of these spines. A long-lasting synaptic strength increase [long-term potentiation (LTP)] is only possible through the reconfiguration of the actin spine cytoskeleton. Here, we develop an experimentally informed three-dimensional computational model in a moving boundary framework to investigate this reconfiguration. Our model describes the reactions between actin and actin-binding proteins leading to the cytoskeleton remodeling and their effect on the spine membrane shape to examine the spine enlargement upon LTP. Moreover, we find that the incorporation of perisynaptic elements enhances spine enlargement upon LTP, exhibiting the importance of accounting for these elements when studying structural LTP. Our model shows adaptation to repeated stimuli resulting from the interactions between spine proteins and mechanical forces.
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Affiliation(s)
- Mayte Bonilla-Quintana
- Department of Mechanical and Aerospace Engineering, University of California San Diego, La Jolla, California 92093
| | - Padmini Rangamani
- Department of Mechanical and Aerospace Engineering, University of California San Diego, La Jolla, California 92093
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4
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Controlling the shape and topology of two-component colloidal membranes. Proc Natl Acad Sci U S A 2022; 119:e2204453119. [PMID: 35914159 PMCID: PMC9371715 DOI: 10.1073/pnas.2204453119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
Changes in the geometry and topology of self-assembled membranes underlie diverse processes across cellular biology and engineering. Similar to lipid bilayers, monolayer colloidal membranes have in-plane fluid-like dynamics and out-of-plane bending elasticity. Their open edges and micrometer-length scale provide a tractable system to study the equilibrium energetics and dynamic pathways of membrane assembly and reconfiguration. Here, we find that doping colloidal membranes with short miscible rods transforms disk-shaped membranes into saddle-shaped surfaces with complex edge structures. The saddle-shaped membranes are well approximated by Enneper's minimal surfaces. Theoretical modeling demonstrates that their formation is driven by increasing the positive Gaussian modulus, which in turn, is controlled by the fraction of short rods. Further coalescence of saddle-shaped surfaces leads to diverse topologically distinct structures, including shapes similar to catenoids, trinoids, four-noids, and higher-order structures. At long timescales, we observe the formation of a system-spanning, sponge-like phase. The unique features of colloidal membranes reveal the topological transformations that accompany coalescence pathways in real time. We enhance the functionality of these membranes by making their shape responsive to external stimuli. Our results demonstrate a pathway toward control of thin elastic sheets' shape and topology-a pathway driven by the emergent elasticity induced by compositional heterogeneity.
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5
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Angstadt S, Zhu Q, Jaffee EM, Robinson DN, Anders RA. Pancreatic Ductal Adenocarcinoma Cortical Mechanics and Clinical Implications. Front Oncol 2022; 12:809179. [PMID: 35174086 PMCID: PMC8843014 DOI: 10.3389/fonc.2022.809179] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 01/05/2022] [Indexed: 12/23/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers due to low therapeutic response rates and poor prognoses. Majority of patients present with symptoms post metastatic spread, which contributes to its overall lethality as the 4th leading cause of cancer-related deaths. Therapeutic approaches thus far target only one or two of the cancer specific hallmarks, such as high proliferation rate, apoptotic evasion, or immune evasion. Recent genomic discoveries reveal that genetic heterogeneity, early micrometastases, and an immunosuppressive tumor microenvironment contribute to the inefficacy of current standard treatments and specific molecular-targeted therapies. To effectively combat cancers like PDAC, we need an innovative approach that can simultaneously impact the multiple hallmarks driving cancer progression. Here, we present the mechanical properties generated by the cell’s cortical cytoskeleton, with a spotlight on PDAC, as an ideal therapeutic target that can concurrently attack multiple systems driving cancer. We start with an introduction to cancer cell mechanics and PDAC followed by a compilation of studies connecting the cortical cytoskeleton and mechanical properties to proliferation, metastasis, immune cell interactions, cancer cell stemness, and/or metabolism. We further elaborate on the implications of these findings in disease progression, therapeutic resistance, and clinical relapse. Manipulation of the cancer cell’s mechanical system has already been shown to prevent metastasis in preclinical models, but it has greater potential for target exploration since it is a foundational property of the cell that regulates various oncogenic behaviors.
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Affiliation(s)
- Shantel Angstadt
- Department of Pathology Johns Hopkins University School of Medicine, Baltimore, MD, United States
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Qingfeng Zhu
- Department of Pathology Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Elizabeth M. Jaffee
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Douglas N. Robinson
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- *Correspondence: Douglas N. Robinson, ; Robert A. Anders,
| | - Robert A. Anders
- Department of Pathology Johns Hopkins University School of Medicine, Baltimore, MD, United States
- *Correspondence: Douglas N. Robinson, ; Robert A. Anders,
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6
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Djakbarova U, Madraki Y, Chan ET, Kural C. Dynamic interplay between cell membrane tension and clathrin-mediated endocytosis. Biol Cell 2021; 113:344-373. [PMID: 33788963 PMCID: PMC8898183 DOI: 10.1111/boc.202000110] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 03/08/2021] [Accepted: 03/19/2021] [Indexed: 12/26/2022]
Abstract
Deformability of the plasma membrane, the outermost surface of metazoan cells, allows cells to be dynamic, mobile and flexible. Factors that affect this deformability, such as tension on the membrane, can regulate a myriad of cellular functions, including membrane resealing, cell motility, polarisation, shape maintenance, membrane area control and endocytic vesicle trafficking. This review focuses on mechanoregulation of clathrin-mediated endocytosis (CME). We first delineate the origins of cell membrane tension and the factors that yield to its spatial and temporal fluctuations within cells. We then review the recent literature demonstrating that tension on the membrane is a fast-acting and reversible regulator of CME. Finally, we discuss tension-based regulation of endocytic clathrin coat formation during physiological processes.
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Affiliation(s)
| | - Yasaman Madraki
- Department of Physics, The Ohio State University, Columbus, OH 43210, USA
| | - Emily T. Chan
- Interdiscipiinary Biophysics Graduate Program, The Ohio State University, Columbus, OH 43210, USA
- Molecular Biophysics Training Program, The Ohio State University, Columbus, OH 43210, USA
| | - Comert Kural
- Department of Physics, The Ohio State University, Columbus, OH 43210, USA
- Interdiscipiinary Biophysics Graduate Program, The Ohio State University, Columbus, OH 43210, USA
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7
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Bonilla-Quintana M, Wörgötter F. Exploring new roles for actin upon LTP induction in dendritic spines. Sci Rep 2021; 11:7072. [PMID: 33782451 PMCID: PMC8007616 DOI: 10.1038/s41598-021-86367-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 03/15/2021] [Indexed: 01/21/2023] Open
Abstract
Dendritic spines, small protrusions of the dendrites, enlarge upon LTP induction, linking morphological and functional properties. Although the role of actin in spine enlargement has been well studied, little is known about its relationship with mechanical membrane properties, such as membrane tension, which is involved in many cell processes, like exocytosis. Here, we use a 3D model of the dendritic spine to investigate how polymerization of actin filaments can effectively elevate the membrane tension to trigger exocytosis in a domain close to the tip of the spine. Moreover, we show that the same pool of actin promotes full membrane fusion after exocytosis and spine stabilization.
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8
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Pearce KM, Bell M, Linthicum WH, Wen Q, Srinivasan J, Rangamani P, Scarlata S. Gαq-mediated calcium dynamics and membrane tension modulate neurite plasticity. Mol Biol Cell 2020; 31:683-694. [PMID: 31825720 PMCID: PMC7202066 DOI: 10.1091/mbc.e19-09-0536] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 12/02/2019] [Accepted: 12/05/2019] [Indexed: 12/30/2022] Open
Abstract
The formation and disruption of synaptic connections during development are a fundamental step in neural circuit formation. Subneuronal structures such as neurites are known to be sensitive to the level of spontaneous neuronal activity, but the specifics of how neurotransmitter-induced calcium activity regulates neurite homeostasis are not yet fully understood. In response to stimulation by neurotransmitters such as acetylcholine, calcium responses in cells are mediated by the Gαq/phospholipase Cβ (PLCβ)/phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) signaling pathway. Here, we show that prolonged Gαq stimulation results in the retraction of neurites in PC12 cells and the rupture of neuronal synapses by modulating membrane tension. To understand the underlying cause, we dissected the behavior of individual components of the Gαq/PLCβ/PI(4,5)P2 pathway during retraction and correlated these with the retraction of the membrane and cytoskeletal elements impacted by calcium signaling. We developed a mathematical model that combines biochemical signaling with membrane tension and cytoskeletal mechanics to show how signaling events are coupled to retraction velocity, membrane tension, and actin dynamics. The coupling between calcium and neurite retraction is shown to be operative in the Caenorhabditis elegans nervous system. This study uncovers a novel mechanochemical connection between Gαq/PLCβ /PI(4,5)P2 that couples calcium responses with neural plasticity.
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Affiliation(s)
| | - Miriam Bell
- Mechanical and Aerospace Engineering Department, University of California, San Diego, La Jolla, CA 92093
| | | | - Qi Wen
- Department of Biomedical Engineering, and
| | - Jagan Srinivasan
- Department of Biology and Biotechnology, Worcester Polytechnic Institute, Worcester, MA 01609
| | - Padmini Rangamani
- Mechanical and Aerospace Engineering Department, University of California, San Diego, La Jolla, CA 92093
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9
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Akamatsu M, Vasan R, Serwas D, Ferrin MA, Rangamani P, Drubin DG. Principles of self-organization and load adaptation by the actin cytoskeleton during clathrin-mediated endocytosis. eLife 2020; 9:49840. [PMID: 31951196 PMCID: PMC7041948 DOI: 10.7554/elife.49840] [Citation(s) in RCA: 107] [Impact Index Per Article: 21.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Accepted: 01/16/2020] [Indexed: 12/20/2022] Open
Abstract
Force generation by actin assembly shapes cellular membranes. An experimentally constrained multiscale model shows that a minimal branched actin network is sufficient to internalize endocytic pits against membrane tension. Around 200 activated Arp2/3 complexes are required for robust internalization. A newly developed molecule-counting method determined that ~200 Arp2/3 complexes assemble at sites of clathrin-mediated endocytosis in human cells. Simulations predict that actin self-organizes into a radial branched array with growing ends oriented toward the base of the pit. Long actin filaments bend between attachment sites in the coat and the base of the pit. Elastic energy stored in bent filaments, whose presence was confirmed by cryo-electron tomography, contributes to endocytic internalization. Elevated membrane tension directs more growing filaments toward the base of the pit, increasing actin nucleation and bending for increased force production. Thus, spatially constrained actin filament assembly utilizes an adaptive mechanism enabling endocytosis under varying physical constraints. The outer membrane of a cell is a tight but elastic barrier that controls what enters or leaves the cell. Large molecules typically cannot cross this membrane unaided. Instead, to enter the cell, they must be packaged into a pocket of the membrane that is then pulled inside. This process, called endocytosis, shuttles material into a cell hundreds of times a minute. Endocytosis relies on molecular machines that assemble and disassemble at the membrane as required. One component, a protein called actin, self-assembles near the membrane into long filaments with many repeated subunits. These filaments grow against the membrane, pulling it inwards. But it was not clear how actin filaments organize in such a way that allows them to pull on the membrane with enough force – and without a template to follow. Akamatsu et al. set about identifying how actin operates during endocytosis by using computer simulations that were informed by measurements made in living cells. The simulations included information about the location of actin and other essential molecules, along with the details of how these molecules work individually and together. Akamatsu et al. also developed a method to count the numbers of molecules of a key protein at individual sites of endocytosis. High-resolution imaging was then used to create 3D pictures of actin and endocytosis in action in human cells grown in the laboratory. The analysis showed the way actin filaments arrange themselves depends on the starting positions of a few key molecules that connect to actin. Imaging confirmed that, like a pole-vaulting pole, the flexible actin filaments bend to store energy and then release it to pull the membrane inwards during endocytosis. Finally, the simulations predicted that the collection of filaments adapts its shape and size in response to the resistance of the elastic membrane. This makes the system opportunistic and adaptable to the unpredictable environment within cells.
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Affiliation(s)
- Matthew Akamatsu
- Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
| | - Ritvik Vasan
- Department of Mechanical and Aerospace Engineering, University of California, San Diego, La Jolla, United States
| | - Daniel Serwas
- Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
| | - Michael A Ferrin
- Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
| | - Padmini Rangamani
- Department of Mechanical and Aerospace Engineering, University of California, San Diego, La Jolla, United States
| | - David G Drubin
- Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
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10
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Tsygankova OM, Keen JH. A unique role for clathrin light chain A in cell spreading and migration. J Cell Sci 2019; 132:jcs.224030. [PMID: 30975920 DOI: 10.1242/jcs.224030] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2018] [Accepted: 04/01/2019] [Indexed: 12/12/2022] Open
Abstract
Clathrin heavy chain is the structural component of the clathrin triskelion, but unique functions for the two distinct and highly conserved clathrin light chains (CLCa and CLCb, also known as CLTA and CLTB, respectively) have been elusive. Here, we show that following detachment and replating, CLCa is uniquely responsible for promoting efficient cell spreading and migration. Selective depletion of CLCa, but not of CLCb, reduced the initial phase of isotropic spreading of HeLa, H1299 and HEK293 cells by 60-80% compared to siRNA controls, and wound closure and motility by ∼50%. Surface levels of β1-integrins were unaffected by CLCa depletion. However, CLCa was required for effective targeting of FAK (also known as PTK2) and paxillin to the adherent surface of spreading cells, for integrin-mediated activation of Src, FAK and paxillin, and for maturation of focal adhesions, but not their microtubule-based turnover. Depletion of CLCa also blocked the interaction of clathrin with the nucleation-promoting factor WAVE complex, and altered actin distribution. Furthermore, preferential recruitment of CLCa to budding protrusions was also observed. These results comprise the first identification of CLCa-specific functions, with implications for normal and neoplastic integrin-based signaling and cell migration.
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Affiliation(s)
- Oxana M Tsygankova
- Department of Biochemistry and Molecular Biology, Cell Biology and Signaling Program of the Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - James H Keen
- Department of Biochemistry and Molecular Biology, Cell Biology and Signaling Program of the Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
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11
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Alimohamadi H, Rangamani P. Modeling Membrane Curvature Generation due to Membrane⁻Protein Interactions. Biomolecules 2018; 8:E120. [PMID: 30360496 PMCID: PMC6316661 DOI: 10.3390/biom8040120] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 10/15/2018] [Accepted: 10/16/2018] [Indexed: 01/03/2023] Open
Abstract
To alter and adjust the shape of the plasma membrane, cells harness various mechanisms of curvature generation. Many of these curvature generation mechanisms rely on the interactions between peripheral membrane proteins, integral membrane proteins, and lipids in the bilayer membrane. Mathematical and computational modeling of membrane curvature generation has provided great insights into the physics underlying these processes. However, one of the challenges in modeling these processes is identifying the suitable constitutive relationships that describe the membrane free energy including protein distribution and curvature generation capability. Here, we review some of the commonly used continuum elastic membrane models that have been developed for this purpose and discuss their applications. Finally, we address some fundamental challenges that future theoretical methods need to overcome to push the boundaries of current model applications.
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Affiliation(s)
- Haleh Alimohamadi
- Department of Mechanical and Aerospace Engineering, University of California, San Diego, CA 92093, USA.
| | - Padmini Rangamani
- Department of Mechanical and Aerospace Engineering, University of California, San Diego, CA 92093, USA.
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12
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Spill F, Bakal C, Mak M. Mechanical and Systems Biology of Cancer. Comput Struct Biotechnol J 2018; 16:237-245. [PMID: 30105089 PMCID: PMC6077126 DOI: 10.1016/j.csbj.2018.07.002] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Revised: 07/03/2018] [Accepted: 07/11/2018] [Indexed: 12/18/2022] Open
Abstract
Mechanics and biochemical signaling are both often deregulated in cancer, leading toincreased cell invasiveness, proliferation, and survival. The dynamics and interactions of cytoskeletal components control basic mechanical properties, such as cell tension, stiffness, and engagement with the extracellular environment, which can lead to extracellular matrix remodeling. Intracellular mechanics can alter signaling and transcription factors, impacting cell decision making. Additionally, signaling from soluble and mechanical factors in the extracellular environment, such as substrate stiffness and ligand density, can modulate cytoskeletal dynamics. Computational models closely integrated with experimental support, incorporating cancer-specific parameters, can provide quantitative assessments and serve as predictive tools toward dissecting the feedback between signaling and mechanics and across multiple scales and domains in tumor progression.
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Affiliation(s)
- Fabian Spill
- School of Mathematics, University of Birmingham, Birmingham B15 2TT, UK
| | - Chris Bakal
- Division of Cancer Biology, Chester Beatty Laboratories, The Institute of Cancer Research, London SW3 6JB, UK
| | - Michael Mak
- Department of Biomedical Engineering, Yale University, New Haven, USA
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13
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Chabanon M, Stachowiak JC, Rangamani P. Systems biology of cellular membranes: a convergence with biophysics. WILEY INTERDISCIPLINARY REVIEWS. SYSTEMS BIOLOGY AND MEDICINE 2017; 9. [PMID: 28475297 PMCID: PMC5561455 DOI: 10.1002/wsbm.1386] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Revised: 02/02/2017] [Accepted: 02/21/2017] [Indexed: 12/12/2022]
Abstract
Systems biology and systems medicine have played an important role in the last two decades in shaping our understanding of biological processes. While systems biology is synonymous with network maps and '-omics' approaches, it is not often associated with mechanical processes. Here, we make the case for considering the mechanical and geometrical aspects of biological membranes as a key step in pushing the frontiers of systems biology of cellular membranes forward. We begin by introducing the basic components of cellular membranes, and highlight their dynamical aspects. We then survey the functions of the plasma membrane and the endomembrane system in signaling, and discuss the role and origin of membrane curvature in these diverse cellular processes. We further give an overview of the experimental and modeling approaches to study membrane phenomena. We close with a perspective on the converging futures of systems biology and membrane biophysics, invoking the need to include physical variables such as location and geometry in the study of cellular membranes. WIREs Syst Biol Med 2017, 9:e1386. doi: 10.1002/wsbm.1386 For further resources related to this article, please visit the WIREs website.
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Affiliation(s)
- Morgan Chabanon
- Department of Mechanical and Aerospace Engineering, University of California San Diego, La Jolla, CA, USA
| | - Jeanne C Stachowiak
- Department of Biomedical Engineering, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, TX, USA
| | - Padmini Rangamani
- Department of Mechanical and Aerospace Engineering, University of California San Diego, La Jolla, CA, USA
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14
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Lohrer MF, Hanna DM, Liu Y, Wang KH, Liu FT, Laurence TA, Liu GY. Applying Pattern Recognition to High-Resolution Images to Determine Cellular Signaling Status. IEEE Trans Nanobioscience 2017; 16:438-446. [PMID: 28644811 PMCID: PMC5633003 DOI: 10.1109/tnb.2017.2717871] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Two frequently used tools to acquire high- resolution images of cells are scanning electron microscopy (SEM) and atomic force microscopy (AFM). The former provides a nanometer resolution view of cellular features rapidly and with high throughput, while the latter enables visualizing hydrated and living cells. In current practice, these images are viewed by eye to determine cellular status, e.g., activated versus resting. Automatic and quantitative data analysis is lacking. This paper develops an algorithm of pattern recognition that works very effectively for AFM and SEM images. Using rat basophilic leukemia cells, our approach creates a support vector machine to automatically classify resting and activated cells. Ten-fold cross-validation with cells that are known to be activated or resting gives a good estimate of the generalized classification results. The pattern recognition of AFM images achieves 100% accuracy, while SEM reaches 95.4% for our images as well as images published in prior literature. This outcome suggests that our methodology could become an important and frequently used tool for researchers utilizing AFM and SEM for structural characterization as well as determining cellular signaling status and function.
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Affiliation(s)
- Michael F. Lohrer
- Department of Electrical and Computer Engineering, Oakland University, Rochester MI 48309, USA
| | - Darrin M. Hanna
- Department of Electrical and Computer Engineering, Oakland University, Rochester MI 48309, USA
| | - Yang Liu
- Department of chemistry, University of California, Davis, CA 95616 USA
| | - Kang-Hsin Wang
- Department of chemistry, University of California, Davis, CA 95616 USA
| | - Fu-Tong Liu
- Department of Dermatology, University of California, Davis Medical Center, Sacramento, CA 95817, USA
| | - Ted A. Laurence
- Lawrence Livermore National Laboratory, Livermore, CA 94550, USA
| | - Gang-Yu Liu
- Department of chemistry, University of California, Davis, CA 95616 USA
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15
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Getz MC, Nirody JA, Rangamani P. Stability analysis in spatial modeling of cell signaling. WILEY INTERDISCIPLINARY REVIEWS-SYSTEMS BIOLOGY AND MEDICINE 2017; 10. [PMID: 28787545 DOI: 10.1002/wsbm.1395] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Revised: 06/06/2017] [Accepted: 06/11/2017] [Indexed: 11/08/2022]
Abstract
Advances in high-resolution microscopy and other techniques have emphasized the spatio-temporal nature of information transfer through signal transduction pathways. The compartmentalization of signaling molecules and the existence of microdomains are now widely acknowledged as key features in biochemical signaling. To complement experimental observations of spatio-temporal dynamics, mathematical modeling has emerged as a powerful tool. Using modeling, one can not only recapitulate experimentally observed dynamics of signaling molecules, but also gain an understanding of the underlying mechanisms in order to generate experimentally testable predictions. Reaction-diffusion systems are commonly used to this end; however, the analysis of coupled nonlinear systems of partial differential equations, generated by considering large reaction networks is often challenging. Here, we aim to provide an introductory tutorial for the application of reaction-diffusion models to the spatio-temporal dynamics of signaling pathways. In particular, we outline the steps for stability analysis of such models, with a focus on biochemical signal transduction. WIREs Syst Biol Med 2018, 10:e1395. doi: 10.1002/wsbm.1395 This article is categorized under: Biological Mechanisms > Cell Signaling Analytical and Computational Methods > Dynamical Methods Models of Systems Properties and Processes > Mechanistic Models.
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Affiliation(s)
- Michael C Getz
- Chemical Engineering Graduate Program, University of California San Diego, La Jolla, CA, USA
| | - Jasmine A Nirody
- Biophysics Graduate Program, University of California, Berkeley, CA, USA
| | - Padmini Rangamani
- Department of Mechanical and Aerospace Engineering, University of California San Diego, La Jolla, CA, USA
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Mamiya A, Kitano H, Kokubun S, Hidai C. Activation peptide of coagulation factor IX regulates endothelial permeability. Transl Res 2016; 177:70-84.e5. [PMID: 27392935 DOI: 10.1016/j.trsl.2016.06.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2016] [Revised: 06/11/2016] [Accepted: 06/15/2016] [Indexed: 01/07/2023]
Abstract
Endothelial hyperpermeability is involved in several critical illnesses, and its regulatory mechanisms have been intensively investigated. It was recently reported that the activation peptide of coagulation factor IX enhances cell matrix and intercellular adhesion. The aim of this study was to investigate the role of activation peptide of coagulation factor IX in intercellular adhesion of endothelial cells and evaluate its effects on endothelial permeability. In the presence of activation peptide, cells spread with lamellipodium-like broad protrusions multidirectionally, increasing the area of adhesion to matrix by 16% within 30 minutes. In intercellular adhesion, treatment with activation peptide induced overlapping of adjacent cell edges and remodeling of intercellular adhesion sites, with colocalization of the adherens junction proteins VE-cadherin and β-catenin and a marker protein of the lateral border recycling compartment, PECAM. Activation peptide decreased gaps between cells by 66% in cultured endothelial cells and suppressed increased endothelial cell monolayer permeability induced by interleukin-1β in a dose-dependent manner. Treatment with activation peptide decreased eNOS protein expression and altered its subcellular distribution, decreasing intracellular cGMP. An analogue of cGMP suppressed the effects of activation peptide on cell spreading. In addition, the effect of activation peptide on hyperpermeability was investigated in mice injected with lipopolysaccharide. Intravenous injection of lipopolysaccharide increased lung weight by 28%, and treatment with activation peptide significantly suppressed the increase in lung weight to 5%. Our results indicate that activation peptide of factor IX regulates endothelial intercellular adhesion and thus could be used in the treatment of vascular hyperpermeability.
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Affiliation(s)
- Atsushi Mamiya
- Department of Otorhinolaryngology-Head and Neck Surgery, Nihon University School of Medicine, Tokyo, Japan
| | - Hisataka Kitano
- Department of Otorhinolaryngology-Head and Neck Surgery, Nihon University School of Medicine, Tokyo, Japan
| | - Shinichiro Kokubun
- Department of Biomedical Science, Nihon University School of Medicine, Tokyo, Japan
| | - Chiaki Hidai
- Department of Biomedical Science, Nihon University School of Medicine, Tokyo, Japan.
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17
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Paradoxical signaling regulates structural plasticity in dendritic spines. Proc Natl Acad Sci U S A 2016; 113:E5298-307. [PMID: 27551076 DOI: 10.1073/pnas.1610391113] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Transient spine enlargement (3- to 5-min timescale) is an important event associated with the structural plasticity of dendritic spines. Many of the molecular mechanisms associated with transient spine enlargement have been identified experimentally. Here, we use a systems biology approach to construct a mathematical model of biochemical signaling and actin-mediated transient spine expansion in response to calcium influx caused by NMDA receptor activation. We have identified that a key feature of this signaling network is the paradoxical signaling loop. Paradoxical components act bifunctionally in signaling networks, and their role is to control both the activation and the inhibition of a desired response function (protein activity or spine volume). Using ordinary differential equation (ODE)-based modeling, we show that the dynamics of different regulators of transient spine expansion, including calmodulin-dependent protein kinase II (CaMKII), RhoA, and Cdc42, and the spine volume can be described using paradoxical signaling loops. Our model is able to capture the experimentally observed dynamics of transient spine volume. Furthermore, we show that actin remodeling events provide a robustness to spine volume dynamics. We also generate experimentally testable predictions about the role of different components and parameters of the network on spine dynamics.
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18
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Kollimada SA, Kulkarni AH, Ravan A, Gundiah N. Advancing Edge Speeds of Epithelial Monolayers Depend on Their Initial Confining Geometry. PLoS One 2016; 11:e0153471. [PMID: 27078632 PMCID: PMC4831833 DOI: 10.1371/journal.pone.0153471] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2015] [Accepted: 03/30/2016] [Indexed: 02/04/2023] Open
Abstract
Collective cell migrations are essential in several physiological processes and are driven by both chemical and mechanical cues. The roles of substrate stiffness and confinement on collective migrations have been investigated in recent years, however few studies have addressed how geometric shapes influence collective cell migrations. Here, we address the hypothesis that the relative position of a cell within the confinement influences its motility. Monolayers of two types of epithelial cells--MCF7, a breast epithelial cancer cell line, and MDCK, a control epithelial cell line--were confined within circular, square, and cross-shaped stencils and their migration velocities were quantified upon release of the constraint using particle image velocimetry. The choice of stencil geometry allowed us to investigate individual cell motility within convex, straight and concave boundaries. Cells located in sharp, convex boundaries migrated at slower rates than those in concave or straight edges in both cell types. The overall cluster migration occurred in three phases: an initial linear increase with time, followed by a plateau region and a subsequent decrease in cluster speeds. An acto-myosin contractile ring, present in the MDCK but absent in MCF7 monolayer, was a prominent feature in the emergence of leader cells from the MDCK clusters which occurred every ~125 μm from the vertex of the cross. Further, coordinated cell movements displayed vorticity patterns in MDCK which were absent in MCF7 clusters. We also used cytoskeletal inhibitors to show the importance of acto-myosin bounding cables in collective migrations through translation of local movements to create long range coordinated movements and the creation of leader cells within ensembles. To our knowledge, this is the first demonstration of how bounding shapes influence long-term migratory behaviours of epithelial cell monolayers. These results are important for tissue engineering and may also enhance our understanding of cell movements during developmental patterning and cancer metastasis.
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Affiliation(s)
- Somanna A. Kollimada
- Department of Mechanical Engineering, Indian Institute of Science, Bangalore, India
| | - Ankur H. Kulkarni
- Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, India
| | - Aniket Ravan
- Department of Mechanical Engineering, Indian Institute of Science, Bangalore, India
| | - Namrata Gundiah
- Department of Mechanical Engineering, Indian Institute of Science, Bangalore, India
- * E-mail: ;
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Zeigler AC, Richardson WJ, Holmes JW, Saucerman JJ. Computational modeling of cardiac fibroblasts and fibrosis. J Mol Cell Cardiol 2016; 93:73-83. [PMID: 26608708 PMCID: PMC4846515 DOI: 10.1016/j.yjmcc.2015.11.020] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Revised: 11/18/2015] [Accepted: 11/18/2015] [Indexed: 12/31/2022]
Abstract
Altered fibroblast behavior can lead to pathologic changes in the heart such as arrhythmia, diastolic dysfunction, and systolic dysfunction. Computational models are increasingly used as a tool to identify potential mechanisms driving a phenotype or potential therapeutic targets against an unwanted phenotype. Here we review how computational models incorporating cardiac fibroblasts have clarified the role for these cells in electrical conduction and tissue remodeling in the heart. Models of fibroblast signaling networks have primarily focused on fibroblast cell lines or fibroblasts from other tissues rather than cardiac fibroblasts, specifically, but they are useful for understanding how fundamental signaling pathways control fibroblast phenotype. In the future, modeling cardiac fibroblast signaling, incorporating -omics and drug-interaction data into signaling network models, and utilizing multi-scale models will improve the ability of in silico studies to predict potential therapeutic targets against adverse cardiac fibroblast activity.
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Affiliation(s)
- Angela C Zeigler
- University of Virginia, Biomedical Engineering Department, 415 Lane Road, Charlottesville, VA 22903, USA.
| | - William J Richardson
- University of Virginia, Biomedical Engineering Department, 415 Lane Road, Charlottesville, VA 22903, USA.
| | - Jeffrey W Holmes
- University of Virginia, Biomedical Engineering Department, 415 Lane Road, Charlottesville, VA 22903, USA.
| | - Jeffrey J Saucerman
- University of Virginia, Biomedical Engineering Department, 415 Lane Road, Charlottesville, VA 22903, USA.
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20
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Sachs F. Mechanical transduction by ion channels: A cautionary tale. World J Neurol 2015; 5:74-87. [PMID: 28078202 PMCID: PMC5221657 DOI: 10.5316/wjn.v5.i3.74] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2014] [Revised: 08/23/2014] [Accepted: 07/17/2015] [Indexed: 02/06/2023] Open
Abstract
Mechanical transduction by ion channels occurs in all cells. The physiological functions of these channels have just begun to be elaborated, but if we focus on the upper animal kingdom, these channels serve the common sensory services such as hearing and touch, provide the central nervous system with information on the force and position of muscles and joints, and they provide the autonomic system with information about the filling of hollow organs such as blood vessels. However, all cells of the body have mechanosensitive channels (MSCs), including red cells. Most of these channels are cation selective and are activated by bilayer tension. There are also K+ selective MSCs found commonly in neurons where they may be responsible for both general anesthesia and knockout punches in the boxing ring by hyperpolarizing neurons to reduce excitability. The cationic MSCs are typically inactive under normal mechanical stress, but open under pathologic stress. The channels are normally inactive because they are shielded from stress by the cytoskeleton. The cationic MSCs are specifically blocked by the externally applied peptide GsMtx4 (aka, AT-300). This is the first drug of its class and provides a new approach to many pathologies since it is nontoxic, non-immunogenic, stable in a biological environment and has a long pharmacokinetic lifetime. Pathologies involving excessive stress are common. They produce cardiac arrhythmias, contraction in stretched dystrophic muscle, xerocytotic and sickled red cells, etc. The channels seem to function primarily as “fire alarms”, providing feedback to the cytoskeleton that a region of the bilayer is under excessive tension and needs reinforcing. The eukaryotic forms of MSCs have only been cloned in recent years and few people have experience working with them. “Newbies” need to become aware of the technology, potential artifacts, and the fundamentals of mechanics. The most difficult problem in studying MSCs is that the actual stimulus, the force applied to the channel, is not known. We don’t have direct access to the channels themselves but only to larger regions of the membrane as seen in patches. Cortical forces are shared by the bilayer, the cytoskeleton and the extracellular matrix. How much of an applied stimulus reaches the channel is unknown. Furthermore, many of these channels exist in spatial domains where the forces within a domain are different from forces outside the domain, although we often hope they are proportional. This review is intended to be a guide for new investigators who want to study mechanosensitive ion channels.
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Abstract
Dynamic models can offer deep understanding of information processing mechanisms in physiology, cell signaling, and biological regulation when they are appropriately detailed. Here, we describe some of the key aspects of the model-building process, including proper parameterization and error analysis, as well as common mistakes, such as model-tweaking and oversimplification, which can decrease the value of the models.
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Affiliation(s)
- Evren U Azeloglu
- Department of Pharmacology and Systems Therapeutics, Systems Biology Center New York, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Ravi Iyengar
- Department of Pharmacology and Systems Therapeutics, Systems Biology Center New York, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
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22
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Multiscale modeling of cell shape from the actin cytoskeleton. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2014; 123:143-67. [PMID: 24560144 DOI: 10.1016/b978-0-12-397897-4.00002-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The actin cytoskeleton is a dynamic structure that constantly undergoes complex reorganization events during many cellular processes. Mathematical models and simulations are powerful tools that can provide insight into the physical mechanisms underlying these processes and make predictions that can be experimentally tested. Representation of the interactions of the actin filaments with the plasma membrane and the movement of the plasma membrane for computation remains a challenge. Here, we provide an overview of the different modeling approaches used to study cytoskeletal dynamics and highlight the differential geometry approach that we have used to implement the interactions between the plasma membrane and the cytoskeleton. Using cell spreading as an example, we demonstrate how this approach is able to successfully capture in simulations, experimentally observed behavior. We provide a perspective on how the differential geometry approach can be used for other biological processes.
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23
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Rangamani P, Lipshtat A, Azeloglu EU, Calizo RC, Hu M, Ghassemi S, Hone J, Scarlata S, Neves SR, Iyengar R. Decoding information in cell shape. Cell 2013; 154:1356-69. [PMID: 24034255 DOI: 10.1016/j.cell.2013.08.026] [Citation(s) in RCA: 124] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2013] [Revised: 05/30/2013] [Accepted: 08/14/2013] [Indexed: 12/28/2022]
Abstract
Shape is an indicator of cell health. But how is the information in shape decoded? We hypothesize that decoding occurs by modulation of signaling through changes in plasma membrane curvature. Using analytical approaches and numerical simulations, we studied how elongation of cell shape affects plasma membrane signaling. Mathematical analyses reveal transient accumulation of activated receptors at regions of higher curvature with increasing cell eccentricity. This distribution of activated receptors is periodic, following the Mathieu function, and it arises from local imbalance between reaction and diffusion of soluble ligands and receptors in the plane of the membrane. Numerical simulations show that transient microdomains of activated receptors amplify signals to downstream protein kinases. For growth factor receptor pathways, increasing cell eccentricity elevates the levels of activated cytoplasmic Src and nuclear MAPK1,2. These predictions were experimentally validated by changing cellular eccentricity, showing that shape is a locus of retrievable information storage in cells.
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Affiliation(s)
- Padmini Rangamani
- Department of Pharmacology and Systems Therapeutics and Systems Biology Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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24
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Kapustina M, Elston TC, Jacobson K. Compression and dilation of the membrane-cortex layer generates rapid changes in cell shape. ACTA ACUST UNITED AC 2013; 200:95-108. [PMID: 23295349 PMCID: PMC3542801 DOI: 10.1083/jcb.201204157] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
A cyclic process of membrane-cortex compression and dilation generates a traveling wave of cortical actin density that in turn generates oscillations in cell morphology. Rapid changes in cellular morphology require a cell body that is highly flexible yet retains sufficient strength to maintain structural integrity. We present a mechanism that meets both of these requirements. We demonstrate that compression (folding) and subsequent dilation (unfolding) of the coupled plasma membrane–cortex layer generates rapid shape transformations in rounded cells. Two- and three-dimensional live-cell images showed that the cyclic process of membrane-cortex compression and dilation resulted in a traveling wave of cortical actin density. We also demonstrate that the membrane-cortex traveling wave led to amoeboid-like cell migration. The compression–dilation hypothesis offers a mechanism for large-scale cell shape transformations that is complementary to blebbing, where the plasma membrane detaches from the actin cortex and is initially unsupported when the bleb extends as a result of cytosolic pressure. Our findings provide insight into the mechanisms that drive the rapid morphological changes that occur in many physiological contexts, such as amoeboid migration and cytokinesis.
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Affiliation(s)
- Maryna Kapustina
- Department of Cell Biology and Physiology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
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25
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Choi JC, Doh J. High-throughput quantitative imaging of cell spreading dynamics by multi-step microscopy projection photolithography based on a cell-friendly photoresist. LAB ON A CHIP 2012; 12:4964-4967. [PMID: 23059818 DOI: 10.1039/c2lc40695k] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
A new method for the high-throughput study of cell spreading dynamics is devised by multi-step microscopy projection photolithography based on a cell-friendly photoresist. By releasing a large number of rounded cells in single cell arrays and monitoring their spreading dynamics by interference reflection microscopy, a large number of cell spreading data can be acquired by a single experiment.
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Affiliation(s)
- Jong-Cheol Choi
- Department of Mechanical Engineering, POSTECH, San31, Hyoja-dong, Nam-Gu, Pohang, 790-784, Gyeongbuk, Korea.
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26
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Sukharev S, Sachs F. Molecular force transduction by ion channels: diversity and unifying principles. J Cell Sci 2012; 125:3075-83. [PMID: 22797911 DOI: 10.1242/jcs.092353] [Citation(s) in RCA: 110] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Cells perceive force through a variety of molecular sensors, of which the mechanosensitive ion channels are the most efficient and act the fastest. These channels apparently evolved to prevent osmotic lysis of the cell as a result of metabolite accumulation and/or external changes in osmolarity. From this simple beginning, nature developed specific mechanosensitive enzymes that allow us to hear, maintain balance, feel touch and regulate many systemic variables, such as blood pressure. For a channel to be mechanosensitive it needs to respond to mechanical stresses by changing its shape between the closed and open states. In that way, forces within the lipid bilayer or within a protein link can do work on the channel and stabilize its state. Ion channels have the highest turnover rates of all enzymes, and they can act as both sensors and effectors, providing the necessary fluxes to relieve osmotic pressure, shift the membrane potential or initiate chemical signaling. In this Commentary, we focus on the common mechanisms by which mechanical forces and the local environment can regulate membrane protein structure, and more specifically, mechanosensitive ion channels.
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Affiliation(s)
- Sergei Sukharev
- Department of Biology, University of Maryland, College Park, MD 20742, USA.
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27
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Ryan GL, Watanabe N, Vavylonis D. A review of models of fluctuating protrusion and retraction patterns at the leading edge of motile cells. Cytoskeleton (Hoboken) 2012; 69:195-206. [PMID: 22354870 DOI: 10.1002/cm.21017] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2011] [Revised: 12/30/2011] [Accepted: 02/03/2012] [Indexed: 01/03/2023]
Abstract
A characteristic feature of motile cells as they undergo a change in motile behavior is the development of fluctuating exploratory motions of the leading edge, driven by actin polymerization. We review quantitative models of these protrusion and retraction phenomena. Theoretical studies have been motivated by advances in experimental and computational methods that allow controlled perturbations, single molecule imaging, and analysis of spatiotemporal correlations in microscopic images. To explain oscillations and waves of the leading edge, most theoretical models propose nonlinear interactions and feedback mechanisms among different components of the actin cytoskeleton system. These mechanisms include curvature-sensing membrane proteins, myosin contraction, and autocatalytic biochemical reaction kinetics. We discuss how the combination of experimental studies with modeling promises to quantify the relative importance of these biochemical and biophysical processes at the leading edge and to evaluate their generality across cell types and extracellular environments.
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Affiliation(s)
- Gillian L Ryan
- Department of Physics, Lehigh University, Bethlehem, Pennsylvania 18015, USA
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