Tissue renewal

  1. the proliferation of cells and tissues to replace lost structures
  2. Tissues with high proliferative capacity:
    • hematopoietic system
    • epithelia
    • of the skin and gastrointestinal (GI) tract
  3. combination of regeneration and scar
    formation by the deposition of collagen
  4. Stimulation of cell proliferation
    • Physiologic stimuli 
    • The thyroid-stimulating hormone
    • Pathologic stimuli
  5. Terminally differentiated
    • Differentiated
    • cells incapable of replication
  6. Tissue proliferative

    3 types of tissues:
    • labile tissues
    • stable tissues
    • permanent tissues
  7. labile tissues
    • continuously
    • dividing
  8. stable tissues
    low level of replication
    can undergo rapid division in response to
    Quiescent tissues:
  9. permanent tissues
    contain cells that have left the cell cycle

    cannot undergo mitotic division in postnatal life
    Nondividing tissues:
  10. example of 
    Continuously dividing tissues
    • Øsurface
    • epithelia - stratified squamous 
    • epithelia of the skin, oral cavity, vagina, and cervix

    • Øthe lining mucosa of all the excretory ducts of the glands of the body (e.g.,
    • salivary glands, pancreas, biliary tract)

    Øthe columnar epithelium of the GI tract and uterus

    Ø the transitional epithelium of the urinary tract, and

    Ø cells of the bone marrow and hematopoietic tissues
  11. example of 
    Quiescent tissues:
    Øparenchymal cells of liver, kidneys, and pancreas

    Ø mesenchymal cells - fibroblasts and smooth muscle

    Øvascular endothelial cells

    Ølymphocytes and other leukocytes
  12. example of 
    Nondividing tissues:

    skeletal  muscle cells

    cardiac muscle cells
  13. embryonic
    stem (ES) cells are what part
    The cells of the inner cell mass
  14. pluripotent
    • Embryonic stem cells that generate different cells
    • study the specific signals and differentiation steps required for the development of
    • many tissues
  15. special micro environment in which the somatic stem cells reside and which  generate or transmit stimuli that regulate
    stem cell self-renewal and
    the generation of progeny cells.
    Niche cells:
  16. transferring
    the nucleus  from a differentiated cell
    to an enucleated oocyte. The
    implanted into a surrogate mother can generate cloned embryos that develop into
    complete animals
    Reproductive cloning
  17. Mechanisms that maintain pluripotency of ES cells
    What transcription factors?
    • Expression of four transcription factors, Oct3/4,
    • Sox2, c-myc,
    • and Klf4
  18. Mechanisms that maintain pluripotency of ES cells
    what prevents differentiation?
    • homeobox
    • protein Nanog
  19. Mechanisms that maintain pluripotency of ES cells
    what prevents differentiation?
    • homeobox
    • protein Nanog
  20. what will be reprogrammed into pluripotent cells by the transduction of four genes encoding transcription factors (Oct3/4, Sox2, c-myc and Kfl4 in
    one laboratory; Oct3/4, Sox2, Nanog, and Lin28 in experiments from another laboratory
    Human fibroblasts from adults and newborns
  21. What r the source for Adult (Somatic) Stem Cells
    bone marrow, the skin, and the lining of the GI tract
  22. Adult (Somatic) Stem Cells will divide in to
    • transit amplifying cells
    • Transdifferentiation
    • Developmental plasticity
  23. Types of cells in bone marrow
    • •Hematopoietic stem cells
    • •Stromal cells
  24. Hematopoietic stem cells: Sources
    for harvesting:
    • bone marrow
    • from umbilical cord blood
    • peripheral blood of individuals receiving cytokines such as GM-CSF 
    • (filgrastim)*** (pt.s who recive
    • radiation therapy will have bonemarow suppuration and
    • will recive filgrastim)
  25. Marrow Stromal Cells
  26. chondrocytes, osteoblasts, adipocytes, myoblasts, and
    endothelial cell precursors depending on the tissue to which they migrate
  27. Liver stem cells/progenior cells 
    located at
    canal of hering 
  28. Liver stem cells/progenior cells 
    cell types
    Hepatocytes and biliary cells
  29. Brain neural stem cells 
    located at
    • subventricular zone (SVZ) and
    • the dentate gyrus of the hippocampus
  30. Brain neural stem cells 
    of generating neurons such as
    astrocytes, and oligodendrocytes
  31. Skin
    of activation:
    stimulatory signals -Wnt pathway

    inhibition of signaling - bone morphogenetic protein (BMP) system.
  32. skin 
    Location of the stem cells:
    hair follicle bulge main niche area

    interfollicular areas of the surface epidermis

    sebaceous glands
  33. Intestinal epithelium
    Location of the stem cells:
    • above Paneth cells in the small intestine,
    •  At the base of the crypt in the colon (crypts of lieberkuhn)
  34. how long will it take to 
    Stem cellsin small intestine crypts regenerate the crypt
    in 3 to 5 days
  35. Intestinal epithelium regulation
    Wnt and BMP pathways
  36. Skeletal Muscle Stem
    cells are called
    and the location
    • satellite cells 
    • benith the myocyte basal laminal of the myocyte
  37. satellite cells 's role
    • growth
    • and regeneration of injured skeletal muscle
  38. Stimulation
    of  satellite cells
    • Active Notch signaling,
    • triggered by up-regulation of delta-like (Dll) ligands
  39. Cornea: 
    stem cell is called 
    and the location
    • limbal stem cells (LSCs)
    • -junction between the epithelium of the cornea and the conjunctiva
  40. limbal stem cells (LSCs) role:
    • maintain the integrity of the outermost corneal epithelium , responsible for corneal
    • transparency
  41. retinal stem cells are useful for
    • to correct the loss of photoreceptors that occurs in degenerative diseases of the
    • retina
  42. Phases of the normal cell cycle
    • G0 – quiescent cells
    • G1 - presynthetic
    • G2 - premitotic
    • S –DNA synthesis
    • M  - mitotic
  43. Checkpoints of the cell cycle
    • 1.G1/S transition – k.a. restriction
    • point
    • 2. G2/M checkpoint
  44. 1.G1/S transition – k.a. restriction
    Rate limiting step for replication

    monitors the integrity of DNA before replication

    • tightly regulated by proteins called cyclins and enzymes called cyclin-dependent
    • kinases
    • (CDKs)

    CDK inhibitors
  45. 2. G2/M checkpoint
    -checks DNA after replication

    • -monitors whether the cell can safely
    • enter mitosis
  46. Growth factors
    • Polypeptides in nature
    • Apart from cell proliferation, their other functions are:
    • promote cell survival
    • locomotion
    • contractility
    • Differentiation
    • angiogenesis
  47. Types of growth factors
    1.Epidermal Growth Factor (EGF)

    2.Transforming Growth Factor α (TGF-α)

    3.Hepatocyte Growth Factor (HGF)

    4.Platelet-Derived Growth Factor (PDGF).

    5.Vascular Endothelial Growth Factor (VEGF).

    6.Fibroblast Growth Factor (FGF)

    7.Transforming Growth Factor β (TGF-β)
  48. Types of growth factors
    • •Growth factors function as ligands that bind to specific receptors
    • •Deliver signals to target cells
    • •activate transcription of genes in silent cells
  49. Epidermal
    Growth Factor (EGF) and Transforming Growth Factor α (TGF-α): 
    common receptor?
    EGFR *****
  50. Epidermal Growth Factor (EGF) and Transforming Growth Factor α (TGF-α):
    when and what types of cells are they produced
    • -In healing wounds - produced by keratinocytes,
    • macrophages, and other inflammatory cells that migrate into the area
    • -mitogenic for a variety of epithelial cells, hepatocytes, and fibroblasts
  51. family of 4 membrane receptors with intrinsic tyrosine kinase activity
    and different types?
  52. EGFR responds to
    • EGF, TGF-α and other ligands of the EGF family, such as HB-EGF (heparin-binding EGF) and
    • amphiregulin
  53. EGFR1 mutations and amplification
    • cancers
    • of the lung, head and neck, and breast, glioblastomas,
    • and other cancers
  54. this receptors are overexpressed in a subset of breast
    cancers and is an important therapeutic target
    ERB B2 receptor
  55. Hepatocyte Growth Factor (HGF)
    • mitogenic
    • effects on hepatocytes and
    • most epithelial cells
  56. HGF produced by
    fibroblasts and most mesenchymalcells, endothelial cells, and liver nonparenchymalcells
  57. HGF Receptor
    c-MET *****
  58. c-MET is highlyexpressed  or mutated in
    • renal
    • and thyroid papillary carcinomas
  59. when HGF is required
    • survival
    • during embryonic development
  60. Platelet-Derived Growth Factor (PDGF)

    PDGFR α and β,
  61. where PDGF is stored and when it will be released
    • stored in platelet granules
    • released
    • on platelet activation
  62. PDGF function
    • migration and proliferation of fibroblasts, smooth muscle cells, and monocytes to
    • areas of inflammation and healing skin wounds

    stimulate wound contraction

    • activation of hepatic stellate
    • cells in the initial steps of liver fibrosis
  63. Vascular
    Endothelial Growth Factor (VEGF)
    includes :
    • VEGF-A (referred throughout as VEGF),
    • VEGF-B,
    • VEGF-C, 
    • VEGF-D,
    • and
    • PIGF (placental growth factor)
  64. VEGF function
    • -vasculogenesis
    • -Angiogenesis- in chronic inflammation, healing of wounds, and in tumors
  65. what are the receptors for VEGF
    • tyrosine kinase receptors:
    • VEGFR-1, VEGFR-2, VEGFR-3
  66. VEGFR-1 function
    • facilitate
    • the mobilization of endothelial stem cells and has a role in inflammation
  67. VEGF-2 function *****
    • is the main receptor for the vasculogenic
    • and angiogenic
    • effects of VEGF
  68. VEGFR-3
    - VEGF-C and VEGF-D bind to it to induce
  69. Fibroblast
    Growth Factor (FGF):
    • acidic FGF (aFGF, or FGF-1)
    • basic FGF (bFGF, or FGF-2)
  70. FGF receptors 
    • tyrosine kinase receptors (FGFRs 1–4)
    • FGF-7 is referred to as keratinocyte growth factor or KGF
  71. FGF function
    • Wound repair
    • New blood vessel formation (angiogenesis)
    • Hematopoiesis
    • Development
  72. Transforming Growth Factor β (TGF-β):
    three TGF-β isoforms (TGF-β1,TGF-β2, TGF-β3)
  73. Transforming Growth Factor β (TGF-β):
    • TGF-β1 has the most widespread distribution in mammals
    • Pleiotropic
    • Related growth factors - BMPs, activins, inhibins, and müllerian inhibiting substance
  74. TGF-β function
    • -Growth inhibitor for most epithelial cells
    • -Mesenchymal cells  - can promote invasion and metastasis during tumor growth ***QQQ
    • -potent fibrogenic agent - enhances the production of collagen, fibronectin,
    • and proteoglycans.It inhibits collagen degradation
    • -strong anti-inflammatory effect
    • -enhances the development of interleukin-17 (IL-17)–producing T cells (TH17) that may be involved in autoimmune
    • tissue injury,
    • -stimulates the production of IgA in the gut mucosa.
  75. TGF-β : potent fibrogenic agent - enhances the production of collagen, fibronectin,
    and proteoglycans.
    It inhibits collagen degradation 
    what CC?
    • -chronic inflammatory conditions -lungs,kidney, and liver
    • -hypertrophic scars
    • -systemic sclerosis 
    • -Marfan syndrome
  76. Cytokines:
    • -Tumor necrosis factor (TNF) and IL-1 - wound healing reactions
    • -TNF and IL-6 - initiation of liver regeneration
  77. Signaling mechanisms in
    Cell Growth
    • GF or cytokines -->
    • ligands + receptor = signal trasducution
  78. Three
    general modes of signaling:
    • Autocrine signaling
    • Paracrine signaling
    • Endocrine signaling
  79. what type of signaling has a role in liver regeneration and
    the proliferation of antigen-stimulated lymphocytes
    Autocrine signaling
  80. what will frequently
    overproduce growth factors and their receptors, thus stimulating their own
    proliferation through an autocrine
  81. what signaling has Notch effects in embryonic development, wound healing, and renewing tissues
    Paracrine signaling
  82. QQQQQ Properties of the major types of
    receptors and how they deliver signals to the cell interior
    • Receptors with intrinsic tyrosine kinase ctivity
    • Receptors lacking intrinsic tyrosine kinase activity that recruit kinases
    • G protein–coupled receptors
    • Steroid hormone receptors
  83. Receptors with intrinsic tyrosine kinase
    • Ligands:
    • growth factors such as EGF, TGF-α, HGF, PDGF, VEGF, FGF, c-KIT ligand, and
    • insulin
  84. tyrosine kinase
    Parts of the receptor:
    • -an extracellular ligand-binding
    • domain
    • -a transmembrane region
    • -a cytoplasmic tail that has intrinsic tyrosine kinase activity
  85. Pathway for receptor ligand complex
    GRB2->Sos->ras-> GDP->GTP->active RAS -> Mac kinase cascade stimulated and -->  cell proliferation
  86. Effector molecules activated by receptors with intrinsic tyrosine kinase
    activity include :
    phospholipase Cγ (PLCγ) 

    phosphatidyl inositol-3 kinase
  87. Receptors lacking intrinsic tyrosine kinase activity that recruit kinases
    - Ligands - IL-2, IL-3, and other interleukins; interferons α, β, and γ; erythropoietin; granulocyte colony-stimulating factor; growth hormone; and prolactin (PIG)

    - USE JAK (Janus kinase) family of proteins
  88. JAKs
    link the receptors with and ctivate transcription
    factors called ----------- and shuttle into the nucleus and -------------gene transcription

  89. G protein–coupled receptors
    signals into the cell through
    trimeric GTP-binding proteins (G proteins)
  90. G protein's ligands
    • chemokines,
    • vasopressin, serotonin, histamine, epinephrine and norepinephrine, calcitonin,
    • glucagon, parathyroid hormone, corticotropin, and
    • rhodopsin
  91. ????
    • Binding
    • of the ligand to
    • the receptor

    •   induces changes in the conformation of the
    • receptors


    • exchange
    • of GDP, present in the inactive G protein, with GTP

    • activates
    • the G  protein.

    • produces
    • many second messengers – calcium, cAMP


  92. Inheriteddefects involving G protein–coupled receptor signal transduction :
    retinitis pigmentosa

    corticotropin deficiencies

  93. Steroid hormone receptors:
    where located
    • located
    • in the nucleus
  94. Steroid hormone receptors:
    • steroid hormones,
    • thyroid hormone, vitamin D, and retinoids
  95. They are nuclear receptors that are involved in a broad range of responses that
    include adipogenesis , inflammation, and atherosclerosis.
    peroxisome proliferator-activated receptors
  96. pathway for steroid hormone receptor
    • Ligands diffuse through the cell membrane and bind the inactive receptors --> causing
    • their activation -->  activated receptor --> binds to specific DNA sequences known as hormone response elements (HRE)within
    • target genes, or they can bind to other transcription factors.
  97. Transcription Factors that
    regulate cell proliferation include products of


  98. what induce
    the synthesis or activity of transcription factors.
    growth factor
  99. ????
    • post translational modification of
    • transcription factors, rather than new synthesis that is used  for a rapid cellular response
  100. ????modifications
    • (a) heterodimerization
    • (b) phosphorylation
    • (c) release of inhibition
    • (d) release from membranes by proteolytic
    • cleavage, as for Notch receptors
  101. Mechanisms of tissue and organ
    • In mammals, Wnt/β-catenin
    • modulates stem cell functions in the intestinal epithelium, bone marrow, and
    • muscle, participates in liver regeneration
  102. ???Inadequacy
    of true regeneration in mammals has been attributed to the
    • absence
    • of blastema
    • formation (the source of cells for regeneration)

    • rapid
    • fibroproliferative
    • response after wounding.
  103. Liver  regeneration
    • Compensatory hyperplasia
    • Occurs
    • after partial hepatectomy
  104. Salient features of  liver regeneration
    depends on:
    • -paracrine effects of growth factors and cytokines such as HGF and IL-6 produced
    • by hepatic nonparenchymal
    • cells
    • -autocrine
    • activity of TGF-α
Card Set
Tissue renewal