DOC PREVIEW
Self-Organization of Muscle Cell Structure and Function

This preview shows page 1-2-3-4-5 out of 15 pages.

Save
View full document
View full document
Premium Document
Do you want full access? Go Premium and unlock all 15 pages.
Access to all documents
Download any document
Ad free experience
View full document
Premium Document
Do you want full access? Go Premium and unlock all 15 pages.
Access to all documents
Download any document
Ad free experience
View full document
Premium Document
Do you want full access? Go Premium and unlock all 15 pages.
Access to all documents
Download any document
Ad free experience
View full document
Premium Document
Do you want full access? Go Premium and unlock all 15 pages.
Access to all documents
Download any document
Ad free experience
View full document
Premium Document
Do you want full access? Go Premium and unlock all 15 pages.
Access to all documents
Download any document
Ad free experience
Premium Document
Do you want full access? Go Premium and unlock all 15 pages.
Access to all documents
Download any document
Ad free experience

Unformatted text preview:

Self-Organization of Muscle Cell Structure and FunctionAnna Grosberg., Po-Ling Kuo., Chin-Lin Guo, Nicholas A. Geisse, Mark-Anthony Bray, William J. Adams,Sean P. Sheehy, Kevin Kit Parker*Disease Biophysics Group, Wyss Institute for Biologically Inspired Engineering, School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts,United States of AmericaAbstractThe organization of muscle is the product of functional adaptation over several length scales spanning from the sarcomereto the muscle bundle. One possible strategy for solving this multiscale coupling problem is to physically constrain themuscle cells in microenvironments that potentiate the organization of their intracellular space. We hypothesized thatboundary conditions in the extracellular space potentiate the organization of cytoskeletal scaffolds for directedsarcomeregenesis. We developed a quantitative model of how the cytoskeleton of neonatal rat ventricular myocytesorganizes with respect to geometric cues in the extracellular matrix. Numerical results and in vitro assays to control myocyteshape indicated that distinct cytoskeletal architectures arise from two temporally-ordered, organizational processes: theinteraction between actin fibers, premyofibrils and focal adhesions, as well as cooperative alignment and parallel bundlingof nascent myofibrils. Our results suggest that a hierarchy of mechanisms regulate the self-organization of the contractilecytoskeleton and that a positive feedback loop is responsible for initiating the break in symmetry, potentiated byextracellular boundary conditions, is required to polarize the contractile cytoskeleton.Citation: Grosberg A, Kuo P-L, Guo C-L, Geisse NA, Bray M-A, et al. (2011) Self-Organization of Muscle Cell Structure and Function. PLoS Comput Biol 7(2):e1001088. doi:10.1371/journal.pcbi.1001088Editor: Edmund J. Crampin, University of Auckland, New ZealandReceived November 24, 2009; Accepted January 19, 2011; Published February 24, 2011Copyright: ß 2011 Grosberg et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permitsunrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Funding: This work has been supported by the Nanoscale Science and Engineering Center of the National Science Foundation under NSF award number PHY-0117795, the Harvard Materials Research Science and Engineering Center under NSF award number DMR-021 3805, the DARPA Biomolecular Motors program, andNIH grant 1 R01 HL079126 (KKP). Mark-Anthony Bray acknowledges salary support from a UNCF-Merck Science Initiative postdoctoral fellowship. The funders hadno role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Competing Interests: The authors have declared that no competing interests exist.* E-mail: [email protected]. These authors contributed equally to this work.IntroductionDuring biological development, evolving forms are marked bydistinct functionalities. An interesting example is the organizationof myofibrils in striated muscle cells. As the myocyte matures, themyofibrils are rearranged from an irregularly dispersed patterninto tightly organized bundles spanning the length, rather than thewidth, of the cell [1]. Although assembly of the myofibril from itsmolecular constituents has been extensively investigated [2,3,4],how myofibrils build this specialized architecture and its functionalconsequences remains unanswered. This is important becausechanges in muscle structure accompany not only morphogenesis,but also pathogenesis [5,6].Myofibrils mature in a force-dependent manner [7,8,9],suggesting that the contractility of a cell may play an importantrole in polarizing the myofibrillar network. This has been shown innonmuscle cells where the cytoskeletal architecture within ageometrically-defined microcompartment becomes polarized withincreasing tractional forces [10,11]. Thus, we hypothesized thatgeometric cues in the extracellular matrix (ECM) can organize theintracellular architecture and potentiate directed myofibrillogen-esis. Because of the difficulty in identifying de novo sarcomeres inprimary harvest muscle cells in culture, one strategy for studyingmyofibrillogenesis is to coax the disassembly and reassembly ofmyofibrils by forcing myocytes to assume shapes that are notcommonly observed in vivo using engineered substrates in vitro[10,11]. To guide these experiments, we developed a computa-tional model of myofibrillar patterning to show the sensitivity ofthe intracellular architecture to the extracellular space. With thesetools, we sought to understand the critical events in the globalassembly and organization of the contractile apparatus in cardiacmyocytes. By comparing experimental results with our computa-tional model, we were able to elucidate the role of maturingmyofibrils, their parallel coupling, and their functional attachmentto the focal adhesion assembly and how these processes are guidedspatially by the boundary conditions imposed on the cell. Afterdetermining the roles of these parameters in myofibrillogenesis, wethen expanded our model to test the functional implications ofthese architectures. We developed a novel method for micro-patterning on soft substrates and were able to engineer myocyteshape on substrates that would allow us to measure thecontractility of these artificial shapes and compare them with themodel results. Together, these results suggest that the self-assemblyand -organization of the contractile apparatus is facilitated by asymmetry-breaking event that is potentiated by either a geometriccue in the extracellular space or a random event in theintracellular space.ResultsQualitative Description of the ModelOur theoretical approach focuses on the interaction between themyofibril and the ECM, as well as adjacent myofibrils (Fig. 1).Inherent to our model are two key assumptions: 1) the force thatPLoS Computational Biology | www.ploscompbiol.org 1 February 2011 | Volume 7 | Issue 2 | e1001088the myofibrillar bundle exerts on the substrate is fiber length-dependent [12] and 2) adjacent myofibrils affect each other tofacilitate lateral coupling, which is akin to them exerting torque oneach other. We have modeled only the maturation of cytoskeletalstructural elements responsible for contraction and integrinbinding to the ECM. We define these components using


Self-Organization of Muscle Cell Structure and Function

Download Self-Organization of Muscle Cell Structure and Function
Our administrator received your request to download this document. We will send you the file to your email shortly.
Loading Unlocking...
Login

Join to view Self-Organization of Muscle Cell Structure and Function and access 3M+ class-specific study document.

or
We will never post anything without your permission.
Don't have an account?
Sign Up

Join to view Self-Organization of Muscle Cell Structure and Function 2 2 and access 3M+ class-specific study document.

or

By creating an account you agree to our Privacy Policy and Terms Of Use

Already a member?