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Yeh-Chuin Poh Department of Mechanical Science and Engineering 5 th May 2011

Mechanical Force Effects on Cellular Functions. Yeh-Chuin Poh Department of Mechanical Science and Engineering 5 th May 2011. May 2011. Introduction. What is “mechanotransduction”?.

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Yeh-Chuin Poh Department of Mechanical Science and Engineering 5 th May 2011

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  1. Mechanical Force Effects on Cellular Functions Yeh-Chuin Poh Department of Mechanical Science and Engineering 5th May 2011 May 2011

  2. Introduction What is “mechanotransduction”? The process and mechanisms by which living cells sense mechanical forces and convert them into biochemical signals. -S. Na et al, Science Signaling 2008 May 2011 2

  3. Introduction: Forces are Important in Living Cells • Forces play a major role in biological functions like: • Cell spreading • Cell migration (wound healing) • Cell contraction • Cell division • Regulates cell functions • Gene expression • Protein synthesis • Cell proliferation Ingber, Nat. Rev. Mol. Cell. Biol., 2005 May 2011 3

  4. Cells Respond to External Mechanical Stimuli Wu, CC et al., PNAS, 2007 Katsumi, A et al., JCB, 2002 Kurpinski, K et al., PNAS, 2006 May 2011 4

  5. Cells Respond to External Mechanical Stimuli Discher et al, Science Rev 2009 Hahn and Schwartz, Nat Rev Mol Cell Bio 2009 Discher et al, Science 2005 May 2011 5

  6. Force Unfolding of Proteins and Opening of Ion Channels Within Cells -spectrin undergoes force induced structure change exposing binding sites for ligands. Mechanosensitive ion channels Vogel & Sheetz, Nat Rev Mol Cell Biol, 2006 C Johnson et al., Science, 2009 May 2011 6

  7. Stress Induced Src Activation is Rapid S Na et al., PNAS, 2008 May 2011 7

  8. Rac Signaling Pathway PDGF Extracellular PDGF R Plasma membrane Cytoplasm Src Rac M Ouyang et al., PNAS, 2008 May 2011 8

  9. Stressed Induced Rac Signaling Pathway is Different from Soluble Factor +PP1 (10 mM, 1 hr) -Stress +Stress 3.0 Overlay 0.3 s 1.0 s 5.0 s 0.5 Brightfield Poh et al., PLoS ONE, 2009 May 2011 9

  10. E-cadherin are mechanosensors Vinculin potentiates E-cadherin mechanosensing and is recruited to actin-anchored sites within adherens junctions in a myosin II–dependent manner Le Duc et al., JCB, 2010 May 2011 10

  11. Mechanical Effects on Stem Cells • Maintain Pluripotency in ESCs mousehuman LIF bFGF 2i mTOR • Induce differentiation • RA • SaB-vitamin C • Proprietary chemicals • Endogenous factors • Natural products • iPS cell reprogamming with defined factors • Yamanaka coktail • Other defined factors Lutolf MP et al., Nat Biotechnol, 2005 May 2011 11

  12. Mechanical Effects on Stem Cells Pluripotency Force Force Discher, DE et al., Science, 2009 May 2011 12

  13. Substrate Rigidity Dictates Mesenchymal Stem Cells Differentiation Lineage Neurogenic Myogenic Osteogenic Engler et al, Cell 2006 May 2011 13

  14. Soft Substrate Promotes Self-Renewal of Embryonic Stem Cells F Chowdhury et al, PLoS ONE 2010 May 2011 14

  15. Cell Shape Affects Human Mesenchymal Stem Cell Differentiation Lineage Chen, CS et al., Dev. Cell, 2004 May 2011 15

  16. Topography Controls Adult Stem Cell Fate Chen, CS et al., Dev. Cell, 2004 May 2011 16

  17. Direct Mechanical Stress Induces Embryonic Stem Cell Differentiation Chowdhury et al, Nat Mat 2009 May 2011 17

  18. Stress Induced Spreading of Embryonic Stem Cell Chowdhury et al, Nat Mat 2009 May 2011 18

  19. Biomaterials in Stem Cell Differentiation OrthomimeticsTM received CE Mark of approval for the repair or articular cartilage and bone. Currently undergoing clinical trial. May 2011 19

  20. Conclusion • Cells respond to mechanical stimuli by altering cell shape, migration, contraction and division • Cell signaling pathways induced by mechanical stress and soluble factors are different • Mechanical environment (shape, substrate rigidity, forces, topography) affects stem cells differentiation lineage • Directed differentiation of stem cells requires both chemical and mechanical cues • Substrate rigidity may also promote embryonic stem cell self-renewal • Stem cells have promising therapeutic advantages. We need better mechanistic understanding of developmental and homeostatic conditions (physiological, pathological) May 2011 20

  21. Thank you for your attention! May 2011 21

  22. GC CFP SH2 YFP substrate 433 nm 476 nm Membrane-targeted Src reporter Y. Wang et al. Nature 2005 Plasma membrane 433 nm 527 nm Src + ATP SH2 May 2011 22

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