Regeneration healing (repair)-General Pathology Lecture note



Objectives of this Post
  • Review the normal physiology and concepts of cell proliferation, cell growth, cell “cycle”, and cell differentiation
  • Understand the basic factors of tissue regeneration
  • Understand the relationships between cells and their extracellular matrix (eECM)
  • Understand the roles of the major players of healing---angiogenesis, growth factors (GFS), and fibrosis
  • Differentiate 1st & 2nd intention healing
Definitions:
Regeneration: growth of cells to replace lost tissues
Healing: a reparative tissue response to a wound, inflammation or necrosis, often leads to fibrosis 
Granulation tissue 
“Organizing” inflamation

Regeneration
  • Replacement of lost structures
  • Is dependent on the type of normal turnover the original tissue has
  • Can be differentiated from “compensatory” growth

Healing (repair)
  • Needs a wound, inflammatory process, or necrosis
  • Many disease appearances anatomically are the result of “healing” such as atherosclerosis
  • Often ends with a scar
  • Fibrosis, as one of the 3 possible outcomes of inflammation, follows “healing”
  • Requires a connective tissue “scaffold”
  • Fibrosis occurs in proportion to the damage of the ECM
 
Cell population fates
Proliferation
  • Hormonal, especially steroid hormones
  • Eg., EPO, CSF
Differentiation*
  • Unidirectional, gain and loss

Apoptosis
*One of the most key concepts in neoplasia
  • Ectoderm
  • Mesoderm
  • Entoderm

Cell cycle

G0
Quiescent (not a very long or dominent phase)

G1
Pre-synthetic, but cell growth taking place

S
  • Cells which have continuous “turnover” have longer, or larger s-phases, i.e., dna synthesis
  • S-phase of tumor cells can be prognostic
G2
Pre-mitotic

M (mitotic:, P,M,A,T cytokinesis)

Cell types
Labile: eg. marrow, GI
Quiescent: liver, kidney
Non-mitotic: neuron, striated muscle

Stem cells (totipotential*)
  1. Embryonic
  2. Adult
Embryonic stem cells
  • Differentiation
  • Knockout mice (mice raised with specific gene defects)
  • Repopulation of damaged tissues, in research
Adult Stem cells

Marrow (hemocytoblast)
(hematopoetic stem cells)

Non-marrow (reserve)

Marrow stromal cell

Adult tissue differentiation and regeneration parallels embryonic development

Growth factors (GFS)
Polypeptides
Cytokines
  • Locomotion
  • Contractility
  • Differentiation
  • Angiogenesis
Growth factors (GFS)
Epidermal
Transforming (alpha, beta)
Hepatocyte
Vascular endothelial
Platelet derived
Fibroblast
Keratinocyte
Cytokines (TNF, IL-1, interferons)


Cell players (source and targets)
  • Lymphocytes, especially t-cells
  • Macrophages
  • Platelets
  • Endothelial cells
  • Fibroblasts
  • Keratinocytes
  • “mesenchymal” cells
  • Smooth muscle cells
E(epidermal) GF
  • Made in platelets, macrophages
  • Present in saliva, milk, urine, plasma
  • Acts on keratinocytes to migrate, divide
  • Acts on fibroblasts to produce “granulation” tissue
T(transforming) GF-alpha
  • Made in macrophages, t-cells, keratinocytes
  • Similar to egf, also effect on hepatocytes
H(hepatocyte) GF
  • Made in “mesenchymal” cells
  • Proliferation of epithelium, endothelium, hepatocytes
  • Effect on cell “motility”
Ve(vascular endothelial) GF
  • Made in mesenchymal cells
  • Triggered by hypoxia
  • Increases vascular permeability
  • Mitogenic for endothelial cells
  • Key substance in promoting “granulation” tissue
Pd(platelet derived) GF
  • Made in platelets, but also many other cell types
  • Chemotactic for many cells
  • Mitogen for fibroblasts
  • Angiogenesis
  • Another key player in granulation tissue
F(fibroblast) GF
  • Made in many cells
  • Chemotactic and mitogenic, for fibroblasts and keratinocytes
  • Re-epithelialization
  • Angiogenesis, wound contraction
  • Hematopoesis
  • Cardiac/skeletal (striated) muscle
T(transforming) GF-beta
  • Made in many cells
  • Chemotactic for PMNS and many other types of cells
  • Inhibits epithelial cells
  • Fibrogenic
  • Anti-inflammatory
K(keratinocyte) GF

  • Made in fibroblasts
  • Stimulates keratinocytes:
    • Migration
    • Proliferation
    • Differentiation
I (insulin-like) GF-1
  • Made in macrophages, fibroblasts
  • Stimulates:
    • Sulfated proteoglycans
    • Collagen
    • Keratinocyte migration
    • Fibroblast proliferation
  • Action similar to gh (pituitary growth hormone)
TNF (tumor necrosis factor)
  • Made in macrophages, mast cells, t-cells
  • Activates macrophages
  • Key influence on other cytokines
Interleukins
  • Made in macrophages, mast cells, t-cells, but also many other cells
  • Many functions:
  • Chemotaxis
  • Angiogenesis
  • Regulation of other cytokines

Interferons
  • Made by lymphocytes, fibroblasts
  • Activates macrophages
  • Inhibits fibroblasts
  • Regulates other cytokines
Signaling
  • Autocrine (same cell)
  • Paracrine (next door neighbor) (many gfs)
  • Endocrine (far away, delivered by blood, steroid hormones)

Transcription factors
Hepatic
Regeneration
  • TNF
  • IL-6
  • HGF

Extracellular matrix (ECM)
  • Collagen(s) I-xviii
  • Elastin
  • Fibrillin
  • Cams (cell adhesion molecules)
    • Immunoglobulins, cadherins, integrins, selectins
  • Proteoglycans
  • Hyaluronic acid
ECM
  • Maintain cell differentiation
  • “scaffolding”
  • Establish microenvironment
  • Storage of GF’s
  1. Collagen one - bone (main component of bone)
  2. Collagen two - cartwolage (main component of cartilage)
  3. Collagen three - rethreeculate (main component of reticular fibers)
  4. Collagen four - floor - forms the basement membrane
Genetic collagen disorders
  • I                               osteogenesis imperfecta, e-d
  • Ii                              achondrogenesis type ii               
  • Iii                             vascular ehlers-danlos
  • V                             classical  e-d
  • Ix                            stickler syndrome
  • Iv                            alport syndrome
  • Vi                            bethlem myopathy
  • Vii                           dystrophic epidermolysis bullos.
  • Ix                            epiphyseal dysplasias
  • Xvii         gen. Epidermolysys bullosa
  • Xv, xviii knobloch syndrome

Definitions:
Regeneration: growth of cells to replace lost tissues
Healing: a reparative tissue response to a wound, inflammation or necrosis

Healing
  • Follows inflammation
  • Proliferation and migration of connective tissue cells
  • Angiogenesis (neovascularization)
  • Collagen, other ecm protein synthesis
  • Tissue remodeling
  • Wound contraction
  • Increase in wound strength (scar = fibrosis)
Angiogenesis (neovascularization)
  • From endothelial precursor cells
  • From pre-existing vessels
  • Stimulated/regulated by gf’s, especially VEGF
  • Also regulated by ECM proteins
  • AKA, “granulation”, “granulation tissue”, “organization”, “organizing inflammation”



Wound healing
1 intention
Edges lined up
 
2 intention
Edges not lined up
Ergo….
More granulation
More epithelialization
More fibrosis



“Healthy” granulation tissue

Fibrosis/scarring
  • Deposition of collagen by fibroblasts
  • With time (weeks, months, years?) The collagen becomes more dense, ergo, the tissue becomes “stronger”
Wound retarding factors (local)
  • Decreased blood supply
  • Denervation
  • Local infection
  • FB
  • Hematoma
  • Mechanical stress
  • Necrotic tissue
Wound retarding factors (systemic)
  • Decreased blood supply
  • Age
  • Anemia
  • Malignancy
  • Malnutrition
  • Obesity
  • Infection
  • Organ failure



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