Dentistry and Medicine: 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

Quiescent (not a very long or dominent phase)

Pre-synthetic, but cell growth taking place

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

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*)

Embryonic
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

Collagen one - bone (main component of bone)
Collagen two - cartwolage (main component of cartilage)
Collagen three - rethreeculate (main component of reticular fibers)
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”