Control of cell growth and repair

Stem Cells

• Adult stem cells
  

  • Many adult tissues contain stem cells

  • More restricted differentiation capacity

  • Located in niches, which differ in varying tissues

  • Bone marrow stem cells

    • Have a larger differentiation capacity

      • [...] 

        • specific differntiation -- give rise to all blood cell lineages 

      • [...]

        • capable of differentiation into various lineages

• Hematopoietic stem cells 

• Stromal cells

Stem Cells

• Adult stem cells
  

  • [...]

    • the multiplicity of stem cell differentiation options (greatest in bone marrow stem cells) 

• Developmental plasticity

Stem Cells

• Adult stem cells
  

  • [...]

    • a change in stem cell differentiation from one cell type to another

• Transdifferentiation

Stem Cells

• Characterized by:
  

  • [...]

  • [...]

    • After each cell division, some progeny enter a differentiation pathway, while others remain undifferentiated 

• Self-renewal capacity

• Asymmetric replication

Stem Cells

• Embryonic stem cells
  

  • Embryos contain [...] stem cells which can produce all the tissues of the human body

  • Can be found in the umbilical cord 

pluripotent

Regenerative Capacity of Cells

• [Labile, Quiescent, or Nondividing?]
  

  • Proliferate throughout life

  • Continuously replacing dying cells

  • Examples:

    • Epithelia (skin, oral cavity, vagina, GI tract, transitional epithelium of urinary bladder) 

• Continuously dividing (labile) cells

Regenerative Capacity of Cells

• [...]
  

  • Cannot undergo further mitotic division in postnatal life

  • Whatever proliferative capacity may exist, it isn’t enough to produce tissue regeneration after injury

  • Example:

    • Cardiac muscle 

• Permanent (nondividing) cells

Regenerative Capacity of Cells

• [Labile, Quiescent, or Nondividing?]
  

  • Low level of replication

  • At baseline in G0

  • Can be driven into G1 when needed

  • Examples:

    • Liver, kidney, pancreas, vascular endothelial cells, fibroblasts 

• Stable (quiescent) cells)

Normal Cell Proliferation

• Entry and progression of cells through the cell cycle
  

  • Controlled by [...]

    • Changes in levels

    • Changes in activities

    • Work by complexing with and activating [...] 

• cyclins

• cyclin dependent kinases (CDKs) 

Cell Cycle and the Regulation of Cell Division

• Check points
  

  • Surveillance mechanism

    • Between G1/S and G2/M

  • Ensures that critical transitions occur correctly and in proper order 

  • Cell cycle is delayed & problem corrected

    • if not possible the cell undergoes [...] 

apoptosis 

Cell Cycle and the Regulation of Cell Division

• Epidermal growth factor family (EGF) -- EGF-α
  

  • [...]

    • has similar biologic activities and uses the same receptor 

• TGF- α

Cell Cycle and the Regulation of Cell Division

• Growth inhibition
  

  1. [...]

     • cell stops growing if it is contacting others on all sides

  2. [...]

  3. Some polypeptide growth factors 
     

     • example: [...] 

1. Contact inhibition

2. Growth suppression

3. TGF-β 

Cell Cycle and the Regulation of Cell Division

• [...]
  

  • In vitro (in lab)
    

    • Mitogenic for a variety of epithelial cells and fibroblasts 

  • In vivo (body)

    • Causes hepatic cell division 

  • Widely distributed

• Epidermal growth factor family (EGF) -- EGF-α

Cell Cycle and the Regulation of Cell Division

• Epidermal growth factor family (EGF) -- EGF-α
  

  • In vitro (in lab)
    

    • Mitogenic for a variety of [...] and [...] 

  • In vivo (body)

    • Causes [...] 

  • Widely distributed

• epithelial cells and fibroblasts 

• hepatic cell division 

Cell Cycle and the Regulation of Cell Division

• Cyclins – A, B, and E
  

  • E

    • [...] to [...]

  • A

    • [...] to [...]

  • B

    • [...] to [...]

• G1 to S

• S to G2

• G2 to M

Cell Cycle and the Regulation of Cell Division

• Cyclins – A, B, and E
  

  • [...]

    • G1 to S

  • [...]

    • S to G2

  • [...]

    • G2 to M

• E

• A

• B

Cell Cycle and the Regulation of Cell Division

• Cyclins – responsible for what functions?
  

  1. [...]

  2. [...]

  3. [...] 

1. DNA replication

2. Depolymerization of nuclear lamina

3. Formation of mitotic spindle 

Cell Cycle and the Regulation of Cell Division

• [...]
  

  • Cyclins form complexes with them to perform their functions

• Cyclin-dependent kinases

Cell Cycle and the Regulation of Cell Division

• [...]
  

  • Control the entry and progression of the cell through the cell cycle 

• Cyclins and cyclin dependent kinases

Cell Receptors

• Classes of cell surface receptors
  

  • [...]

  • [...]

  • [...]

• Receptors with intrinsic kinase activity

• Receptors without intrinsic kinase activity

• G-protein linked receptors

Cell Receptors

• Location: 

  • on [...]

  • in the [...] 

  • in the [...] 

• on surface

• in the cytoplasm 

• in the nucleus 

Cell Receptors

• Receptor activation
  

  • Receptors with intrinsic kinase activity

    • Ligand binding causes:

      • [...] 

      • [...]

  • Others

    • Recruit cytosolic kinases or 

    • activate other pathways to generate second messengers

• dimerization of the receptor (causing amplification) 

• autophosphorylation

Cell Receptors

• Receptor activation
  

  • Receptors with intrinsic kinase activity

    • Ligand binding causes:

      • dimerization of the receptor (causing amplification) 

      • autophosphorylation

  • Others

    • Recruit [...] or 

    • activate other pathways to generate [...]

• cytosolic kinases

• second messengers

Cell Receptors

• Signal Transduction & Second Messengers – transfer information to the nucleus
  

  • Ras activation and MAP-kinases (mitogen-activated protein)

    • [...] is a frequently mutated gene found in human tumors

Ras

Cell Receptors

• Signal Transduction & Second Messengers – transfer information to the nucleus
  

  • [...]

    • frequently invovled in tumor growth

  • [...]

  • [...]

  • [...]

• Ras activation and MAP-kinases (mitogen-activated protein)

• IP3 pathway (inosol 1,4,5-triphosphate)

• PI3 kinase pathway (phosphoinositide-3-kinase)

• Phospholipase C-γ

Ras is a frequently mutated gene found in human tumors

Cell Receptors

• Transcription Factors
  

  • Control the transcription of genes

  • Bind to DNA and either increase or decrease transcription

  • Includes:

    • [...]

    • [...] 

• Proto-oncogenes

• Tumor suppressor genes 

Cell Receptors

• [What type of] binding
  

  • Binding of a growth factor to its specific receptor 

Ligand-Receptor

Growth Factors

• Fibroblast growth factor (FGF)
  

  • Binds tightly to [which drug]

  • Made by a variety of cells

heparin (anti-coagulation drug)

Growth Factors

• Fibroblast growth factor (FGF)
  

  • FGF activities
    

    • [...] 

      • by bFGF

      • Stimulates the proliferation of endothelial cells

    • [...]
      

      • Macrophage, fibroblast and endothelial cell migration

    • Development
      

      • [...] development and [...] formation

    • [...]

• Angiogenesis 

• Wound repair

• Skeletal muscle

• lung

• Hematopoiesis

Growth Factors

• Fibroblast growth factor (FGF)
  

  • FGF activities
    

    • Angiogenesis 

      • by [a or b]FGF

      • Stimulates the proliferation of endothelial cells

    • Wound repair
      

      • Macrophage, fibroblast and endothelial cell migration

    • Development
      

      • Skeletal muscle development and lung formation

    • Hematopoiesis

b

Growth Factors

• Fibroblast growth factor (FGF)
  

  • Two forms:

    • [...] (aFGF or FGF-1)

    • [...] (bFGF- or FGF-2)

• acidic

• basic

Growth Factors

• Transforming growth factor- β (TGF- β)
  

  • Belongs to a family of homologous polypeptides including TGF- β1, - β2, β3 and other cytokines like bone morphogenetic proteins

    • [Which] isoform is widely distributed and is usually referred to as TGF- β 

TGF- β1

Growth Factors

• Transforming growth factor- β (TGF- β)
  

  • Stimulates production of: 

    • [...]

    • [...]

    • [...] 

  • Inhibits collagen degradation by:
    

    • Decreasing metalloproteinase activity

    • Increasing the activity of TIMPs (Tissue inhibitors of metalloproteases)

• collagen

• fibronectin

• proteoglycans 

Example: Collagenase is a metalloproteinase enzyme that removes type III collagen 

Growth Factors

• Transforming growth factor- β (TGF- β)
  

  • Stimulates production of: 

    • collagen

    • fibronectin

    • proteoglycans 

  • Inhibits collagen degradation by:
    

    • [Increasing or decreasing] metalloproteinase activity

    • [Increasing or decreasing] the activity of TIMPs (Tissue inhibitors of metalloproteases)

• Decreasing

• Increasing

Example: Collagenase is a metalloproteinase enzyme that removes type III collagen

Growth Factors

• Transforming growth factor- β (TGF- β)
  

  • Stimulates production of: 

    • collagen

    • fibronectin

    • proteoglycans 

  • Inhibits collagen degradation by:
    

    • Decreasing [...] activity

    • Increasing the activity of [...]

• metalloproteinase

• TIMPs (Tissue inhibitors of metalloproteases)

Example: Collagenase is a metalloproteinase enzyme that removes type III collagen 

Growth Factors

• Transforming growth factor- β (TGF- β)
  

  • TGF- β -- Has many and often opposite effects

    • Can promote or inhibit growth depending on the cell type and its metabolic state
      

      • Promotes growth 
        

        • in [high or low] concentrations 

        • Induces synthesis and secretion of [...]

      • Inhibits growth 
        

        • in [high or low] concentrations

        • Inhibits [...] expression 

• low

• PDGF

• high

• PDGF

Growth Factors

• Transforming growth factor- β (TGF- β)
  

  • TGF- β
    

    • Levels in the tissue are regulated by:
      

      • Post-transcriptional activation of [...]

      • Rate of secretion of the active molecule

      • Factors in the ECM (most notably [...]) that enhance or diminish TGF- β activity

• latent TGF- β

• integrins

Growth Factors

• Transforming growth factor- β (TGF- β)
  

  • TGF- β
    

    • The factor binds to two cell surface receptors with serine-threonine kinase activity 
      

      • Triggers phosphorylation of transcription factors called [...]

Smads

Growth Factors

• Transforming growth factor- β (TGF- β)
  

  • [Stimulates or Inhibits] lymphocyte proliferation and activity of other leukocytes 

Inhibits

Needed for transition from an inflammatory process to repair process

Growth Factors

• Transforming growth factor- β (TGF- β)
  

  • [What is its role in the inflammation process?]  

• Is an anti-inflammatory cytokine that serves to limit and terminate inflammatory response  

Needed for transition from an inflammatory process to repair process

Growth Factors

• Vascular endothelial growth factor (VEGF)
  

  • Family or related growth factors
    

    • VEGF-A, -B, -C, -D, -E and placental growth factor

    • [Which one] is just referred to as VEGF and is the major inducer of angiogenesis after injury and in tumors

VEGF-A

Growth Factors

• Vascular endothelial growth factor (VEGF)
  

  • Family or related growth factors
    

    • VEGF-A, -B, -C, -D, -E and placental growth factor

    • VEGF-A is just referred to as VEGF and is the major inducer of [...] after injury and in tumors

angiogenesis

Growth Factors

• [...]
  

  • Induce fibroblast proliferation

  • Chemotactic for fibroblasts

  • Stimulate the synthesis of collagen and collagenases (for remodeling)

• Cytokines (IL-1 and TNF)

Growth Factors

• [...]
  

  • Stored in platelet α granules and produced by a variety of cells

  • Causes migration and proliferation of: 

    • fibroblasts

    • smooth muscle cells 

    • monocytes

  • Chemotactic for neutrophils

• Platelet-derived growth factors (PDGF)

Growth Factors

• Platelet-derived growth factors (PDGF)
  

  • Stored in platelet α granules and produced by a variety of cells

  • Causes migration and proliferation of: 

    • [...]

    • [...] 

    • [...]

  • Chemotactic for [...]

• fibroblasts

• smooth muscle cells 

• monocytes

• neutrophils

Growth Factors

• Vascular endothelial growth factor (VEGF)
  

  • Stimulates the migration of [...]

  • Promotes vasodilation by stimulating production of [...]

• endothelial cells

• NO

Growth Factors

• [...]
  

  • Stimulates the migration of endothelial cells

  • Promotes vasodilation by stimulating production of NO

• Vascular endothelial growth factor (VEGF)

Polypeptide growth factors

• Mechanisms of action

  • [...]

    • Target site on same cell

  • [...]

    • For cell adjacent to GF producing cells 

  • [...] 

    • For distant cells producing GF 

• Autocrine

• Paracrine

• Endocrine

Pleiotropic: Producing or having multiple effects from a single gene

Polypeptide growth factors

• Most growth factors have pleiotropic (multiple, unrelated) effects

• Stimulate
  

  • [...]

  • [...]

  • [...]

  • [...]

• Cell proliferation

• Migration

• Differentiation

• Synthesis of specialized proteins

Pleiotropic: Producing or having multiple effects from a single gene

Polypeptide growth factors

• Target the function of [...] 

• proto-oncogenes 

Proto-oncogenes: A gene involved in normal cell growth

Pleiotropic: Producing or having multiple effects from a single gene

Repair

• Cell Cycle
  

  • G1

    • [...]

  • S

    • [...] 

  • G2

    • [...]

  • M

    • [...]

  • G0

    • [...] 

• presynthetic

• DNA synthesis 

• Premitotic

• mitotic

• quiescent cells 

Repair

• Cell Cycle
  

  • [...]

    • presynthetic

  • [...]

    • DNA synthesis 

  • [...]

    • Premitotic

  • [...]

    • mitotic

  • [...]

    • quiescent cells 

• G1

• S

• G2

• M

• G0

Repair

• Regulation of Cell Population
  

  • Increasing rate of [...]

  • Decreasing rate of [...]

  • Changing rate of [...] 

  • Changing rate of [...] 

• cell death

• cell death

• proliferation 

• differentiation 

Repair

• Has two possible outcomes:
  

  • [...]

  • [...] 

• Regeneration → tissue returns to normal (common with mild, superficial injuries)

• Replacement by connective tissue → scar formation (common with deeper, more severe injuries) 

[...]

• Exaggeration of process of contraction in secondary union

• Results in deformities

• Compromise the movement of joints

• Frequently seen on the palms, soles, and following burns 

Contractures

Contractures

• Exaggeration of process of contraction in secondary union

• Results in deformities

• Compromise the movement of joints

• Frequently seen on the palms, soles, and following [...] 

burns