The Cell - American Academy of Osteopathy
Transcript of The Cell - American Academy of Osteopathy
From Molecules to Tissue
The body as a continuous interwoven matrix linking macro-organism to subcellular
structureF.H. Willard, Ph.D.
Department of AnatomyUniversity of New England
College of Osteopathic MedicineBiddeford, Maine
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Mechanotransduction
Can an external mechanical stimulus alter gene expression in a cell?
If so, how?
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Nucleus
M. H. Ross and W. Pawlina. Histology, A text and atlas with correlated cell and molicular biology, Philadelphia:Lippincott, Williams & Wilkins, 2011.
EnvelopeMatrixPores
Nucleoplasm
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Nuclear Pores
M. H. Ross and W. Pawlina. Histology, A text and atlas with correlated cell and molecular biology, Philadelphia:Lippincott, Williams & Wilkins, 2011.
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The Nuclear Matrix
M. H. Ross and W. Pawlina. Histology, A text and atlas with correlated cell and molicular biology, Philadelphia:Lippincott, Williams & Wilkins, 2011.
Laminin
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LINC
• Linker of Nucleoskeleton and Cytoskeleton
• Involves several complexes of peptides:
• Nesprin
• Lamin
• Sun
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M. H. Ross and W. Pawlina. Histology, A text and atlas with correlated cell and molecular biology, Philadelphia:Lippincott, Williams & Wilkins, 2011.
Chromatin and Chromosome Structure
HistonesNucleosome
Chromatin fibrilLoop domains
Chromosome fibersChromosome
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V. Kumar, A. K. Abbas, and N. Fausto. Robbins and Cotran Pathological Basis of Disease, Philadelphia:W.B. Saunders
Co., 2005.
Cell CycleRegulation
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V. Kumar, A. K. Abbas, and N. Fausto. Robbins and Cotran Pathological Basis of Disease, Philadelphia:W.B. Saunders
Co., 2005.
Cell CycleRegulation
Sunday, May 5, 13
V. Kumar, A. K. Abbas, and N. Fausto. Robbins and Cotran Pathological Basis of Disease, Philadelphia:W.B. Saunders
Co., 2005.
Cell CycleRegulation
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V. Kumar, A. K. Abbas, and N. Fausto. Robbins and Cotran Pathological Basis of Disease, Philadelphia:W.B. Saunders
Co., 2005.
Cell CycleRegulation
TFGβ
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V. Kumar, A. K. Abbas, and N. Fausto. Robbins and Cotran Pathological Basis of Disease, Philadelphia:W.B. Saunders
Co., 2005.
Cell CycleRegulation
Sunday, May 5, 13
V. Kumar, A. K. Abbas, and N. Fausto. Robbins and Cotran Pathological Basis of Disease, Philadelphia:W.B. Saunders
Co., 2005.
Cell CycleRegulation
cMyC +
estrogen +
Wnt +Shh +
EGF +
TGF-B -
cKit +Wnt +
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A. J. Macario and de Macario Conway. Sick chaperones, cellular stress, and disease. N Engl J Med 353 (14):1489-1501, 2005.
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Endoplasmic Reticulum and Pathology
Deposition Diseases
• Demyelination
–Charcot-Marie-Tooth syndrome
• Degeneration
–Alzheimer’s disease
Ubiquitin-Proteosome PathwaySunday, May 5, 13
Thin Filaments
F-Actin membrane
attachments to the ECM
SpectrinDystrophin
Sol-Gel Model
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Integral Membrane Proteins
M. H. Ross and W. Pawlina. Histology, A text and atlas with correlated cell and molecular biology, Philadelphia:Lippincott, Williams & Wilkins, 2011.
Sunday, May 5, 13
Cell Signaling Pathways
G-Proteins
1) Receptor conformational change2) GDP exchanged for GTP3) Dissociation of subunits4) Activation of adenylate cyclase5) ATP converted to cAMP + PPi6) GTPase (GAP) hydrolyzes GTP
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Receptor Mechanisms
D. Julius and A. I. Basbaum. Molecular mechanisms of nociception. Nature 413 (6852):203-210, 2001.
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Cell Signaling PathwaysRas, Rho, ROCK
Messenger-dependent transmission
vs.Distortion-dependent
tranmission
GAP - GTPase Activating Protein
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MAPK Pathway
Gortazar AR, Martin-Millan M, Bravo B, Plotkin LI, Bellido T. 2013. Crosstalk between caveolin-1/ERKs and beta-catenin survival pathways in osteocyte
mechanotransduction. J Biol Chem.
Mechanical stress activates the MAPK (ERK) pathway preventing apoptosis in cultured osteocytes
Mitogen-activated Protein Kinase
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Transforming Growth Factor - beta Pathway
DAXX Pathway SMAD Pathway
TGF-β, acting through its signaling pathway, stops the cell cycle at the G1 stage to stop proliferation, induce differentiation, or promote apoptosis.
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c-KIT or CD117Receptor Tyrosine Kinase
AKT = Protein kinase BSCF = Stem Cell Factor
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Cell Membrane
M. H. Ross and W. Pawlina. Histology, A text and atlas with correlated cell and molicular biology, Philadelphia:Lippincott, Williams & Wilkins, 2011.
Polarity
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Epithelial Cell Polarity
Occluding junctionsAnchoring junctions
Communicating junctionsM. H. Ross and W. Pawlina. Histology, A text and atlas with correlated cell and molecular biology, Philadelphia:Lippincott, Williams & Wilkins, 2011.
Sunday, May 5, 13
Occluding Junctions
M. H. Ross and W. Pawlina. Histology, A text and atlas with correlated cell and molecular biology, Philadelphia:Lippincott, Williams & Wilkins, 2011.
Zonula Occludens
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Anchoring Junctions
Cell-to-Cell
Zonula adherens
Macula adherens
Cell Adhesion Molecules
Actin-binding
Intermediate filament-binding
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CDH-1 Gene
Cadherin-1or
E-cadherin
E-cadherin Endothelia
N-cadherin Neurons
P-cadherin Placental
Cadherin-12 Neurons
Desmoglein Epidermis
Desmocollin Epidermis
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Anchoring Junctions
Cell-to-Matrix
Focal AdhesionInvolve Actin filaments
“Tent-Pegs”
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Focal Adhesion Gartner LP, Hiatt JL. 2000. Color Atlas of Histology. 3rd ed. Philadelphia: Lippincott Williams & Williams.
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Focal Adhesions
• Involve actin filaments
• Mechanosensitive
• Sensitive to cell shape and force in ECM
• ECM side: integrins, fibronectin, laminin, vitronectin
• Cell side: talin, actinin, filamin, vinculin, paxillin, focal adhesion kinase
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Integrin“Adhesome”
B. Geiger, J. P. Spatz, and A. D. Bershadsky. Environmental
sensing through focal adhesions. Nat.Rev.Mol.Cell Biol. 10 (1):
21-33, 2009.
Sunday, May 5, 13
M. H. Ross and W. Pawlina. Histology, A text and atlas with correlated cell and molecular biology, Philadelphia:Lippincott, Williams & Wilkins, 2011.
Cell Junctions
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Collagen
• 25 Known types
• 1 Most connective tissue
• II Cartilage
• III Reticular fibers
• IV Basal lamina
• X Bone mineral matrix
M. H. Ross and W. Pawlina. Histology, A text and atlas with correlated cell and molecular biology, Philadelphia:Lippincott, Williams & Wilkins, 2011.
Sunday, May 5, 13
M. H. Ross and W. Pawlina. Histology, A text and atlas with correlated cell and molecular biology, Philadelphia:Lippincott, Williams & Wilkins, 2011.
CollagenTypes
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Elastic Fibers
M. H. Ross and W. Pawlina. Histology, A text and atlas with correlated cell and molecular biology, Philadelphia:Lippincott, Williams & Wilkins, 2011.
Sunday, May 5, 13
M. H. Ross and W. Pawlina. Histology, A text and atlas with correlated cell and molicular biology, Philadelphia:Lippincott, Williams & Wilkins, 2011.
Fibroblasts
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ECM
• Hyaluronic acid
• Glycosoaminoglycans
• Proteoglycans
• Multiadhesive glycoproteins
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ECM Structure
M. H. Ross and W. Pawlina. Histology, A text and atlas with correlated cell and molecular biology, Philadelphia:Lippincott, Williams & Wilkins, 2011.
GAGsProteoglycans
Sunday, May 5, 13
M. H. Ross and W. Pawlina. Histology, A text and atlas
with correlated cell and molecular biology,
Philadelphia:Lippincott, Williams & Wilkins, 2011.
Glycosoaminoglycans
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ProteoglycanMonomers
M. H. Ross and W. Pawlina. Histology, A text and atlas with correlated cell and molecular biology,
Philadelphia:Lippincott, Williams & Wilkins, 2011.
Cartilage
Connectivetissues
Fibroblastmembranes
Connectivetissues
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Multiadhesive Glycoproteins:
FibronectinLamininTenascin
OsteopontinEntactin/Nidogn
Anchoring Junctions
Cell-to-ECM
“The Adhesome”Binding sites; Interact with cell-surface receptors
Sunday, May 5, 13
A. Mammoto, T. Mammoto, and D. E. Ingber. Mechanosensitive mechanisms in transcriptional regulation. J.Cell Sci. 125 (Pt 13):3061-3073, 2012.
Mechanotransduction Pathways Responding to Mechanical Stress
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Force Transduction from Skin to Skeleton
The Cellular and Molecular Organization of the Body
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Summary
The integrated multi-dimensional network, involving cells and extracellular matrix, that exists from the external surface into the deepest of the internal structures.
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Force
Anchoringjunction
Cytoskeleton
Signal transductionpathway
Change in cellphysiology
Cell-MatrixInteractions
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Mechanical Force
Anchoringjunction
Cytoskeleton
Signal transductionpathway
Change in cellphysiology
Cell-MatrixInteractions
Change in geneexpression
Nucleus
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Mechanotransduction and Cell Metabolism
D. E. Ingber. Tensegrity: The architectural basis of cellular mechanotransduction. Ann.Rev.Physiol. 59:575-599, 1997.
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Cells need to feel the force
D. E. Jaalouk and J. Lammerding. Mechanotransduction gone awry. Nat.Rev.Mol.Cell Biol. 10 (1):63-73, 2009.
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Mechanotransduction
• Mechanical force acting on a cell membrane
• Opening of mechanosensitive pores
• Distortion of mechanosensitive proteins
• Signal transduction into the cell & nucleus
• Generation of a cellular response
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Mechanotransduction and Gene Expression
N. Wang, J. D. Tytell, and D. E. Ingber. Mechanotransduction at a distance: mechanically coupling the extracellular matrix with the nucleus. Nat.Rev.Mol.Cell Biol. 10 (1):75-82, 2009.
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Summary
• All cells of the body are interconnected in a “multiscale” matrix
• The matrix exists in a “prestressed” state
• All cells of the body can sense position and movement through this matix
• All cells of the body need this sense to survive within this matrix
• Extracellular fluids are important in maintaining the prestressed state
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