[PATHOLO] Lecture 3: Regeneration and Healing

(1) regeneration

(1) Growth of cells to replace lost tissues (no injury)

(1) healing

(1) A reparative tissue response to a wound, inflammation or necrosis, often leads to fibrosis (scarring) (injury)

(1) granulation tissue

(1) Characterized by presence of proliferation of fibroblast or epithelial cells or endothelial cells and formation of new capillaries

(2) granulation tissue

(2) Part of healing process where cells begin to replace what is lost during injury

“organizing” inflammation

inflammation with fibrosis/ repair.

(1) neovascularization

(1) Part of healing; deals with formation of new blood vessels as the body tries to replace the injured tissue and to supply new tissues

(2) regeneration

Replacement of lost structures to replace normal cells; is dependent on the type of normal turnover the original tissue has

(3) regeneration

(3) can be differentiated from “compensatory” growth

(2) healing

(2) Needs a wound, inflammatory process, or necrosis.

(3) healing

(3) may begin during or after the inflammatory process; Often ends with a scar or fibrosis; Requires a connective tissue “scaffold”

scaffold

Where the other new tissues will begin.

(1) fibrosis

(1) scarring. Possible outcome of inflammation after healing

(2) fibrosis

(2) Occurs in proportion to the damage of the extracellular matrix (ECM)

stem cells

Differentiate into the baseline cell population

proliferation

Caused by hormones, especially steroid hormones

differentiation

May turn to any other type of tissue – depending on the type of tissue or signals that is received.

unidirectional

Trait of differentiation that makes sure that a cell can only turn to one type of tissue

G1 phase

Organelles in the cell begin to grow. Pre-synthetic but cell and organelle growth takes place

(1) S phase

(1) Growth and DNA synthesis. Cells which have a continuous “turnover” have longer, or larger S-phases, i.e. DNA synthesis

(2) S phase

(2) can be prognostic (in tumor, cells are rapidly dividing so their S-phases are longer)

G2 phase

Growth and final preparations for division. Pre-mitotic or POST-synthetic

M phase

cell division

(1) labile

(1) cell type found in marrow, GI

(2) labile

(2) Cells that are continuously being lost and replaced (and thus continuously multiplying)

(1) quiescent

(1) cell type found in liver and kidney

(2) quiescent

(2) Cellular state where cells remain OUT of the cell cycle. They no longer multiply but retain the capacity to in case of injury

(1) non-mitotic

(1) cell type found in neuron and striated muscle

(2) non-mitotic

(2) Permanent cells that are terminally differentiated and non-proliferative throughout the POSTNATAL life. They can only proliferate during fetal development prior to birth

Totipotent cells

they are able give rise to differentiated tissues.

embryonic stem cells

Can differentiate into different types of tissues. Important in repopulation of damaged tissuesThey rely on signals and genetic makeup of the organism

“knockout” mice theory

Research where certain characteristics in mice where certain genes were knocked out and then replaced with an artificial DNA that resulted in the loss of gene activity of the DNA removed and changed the phenotype of the mouse.

adult stem cells

Can be hematopoietic stem cells (bone marrow, hemocytoblast) or reserve stem cells (non-marrow)

pluripotent stromal cells

are helped by growth factors, cytokines, matrix that signal the stromal cells to differentiate into a particular type of cell of tissue

vascular endothelial growth factor + fibroblast growth factor 2

cause the pluripotent stromal cells to become endothelial cells

Myo D or myogenin

cause PCS to become skeletal muscles (myotubes)

PPARy

cause PCS to become fat cells

CBFA1

cause PCS to become osteoblast (bones)

SOX9

cause PCS to become chondroblast (cartilage)

endoderm

gives rise to epithelial cells of liver, lungs, GI tract

mesoderm

gives rise to mesodermal progenitor cell and hematopoietic progenitor cells

mesodermal progenitor cell

gives rise to myocytes, osteoblasts, chondrocytes, adipocytes, endothelial cells

hematopoeitic progenitor cells

gives rise to bone marrow cells, red blood cells

ectoderm

gives rise to keratinocyte precursors, neurons, oligodendrocytes, ependymal cells

(1) growth factors

(1) may be polypeptides or cytokines

epidermal growth factor

Made in platelets, macrophages.

Present in saliva, milk, urine, plasma

Acts on keratinocytes to migrate, divide

Acts on fibroblasts to produce “granulation” tissue

TGF-alpha

Made in macrophages, T-cells, keratinocytes;

similar to function to EGF,

affect hepatocytes

TGF-beta

Made in many cells

Chemotactic for PMNs and MANY other types of cells

Inhibits epithelial cells

Fibrogenic

Anti-inflammatory

Has inhibitory functions compared to other growth factors; thus is important for development control

hepatocyte growth factor

Made in “mesenchymal” cells.

Proliferation of epithelium, endothelium, hepatocytes

Effect on cell “motility”

vascular endothelial growth factor

Made in mesenchymal cells

Triggered by hypoxia (decrease in oxygen or O2 supply)

Increases vascular permeability

Mitogenic (can cause mitosis) for endothelial cells

KEY substance in promoting “granulation” tissue

plant derived growth factor

Made in platelets, but also MANY other cell types

Chemotactic (ability to attract cells) for MANY cells

Mitogenic for fibroblast

Angiogenesis (formation of new blood vessels)

Another KEY player in granulation tissue (since it can cause angiogenesis)

epidermal growth factor

Made in MANY cells

Chemotactic and mitogenic for fibroblasts and keratinocytes

Re-epithelialization

Angiogenesis, wound contraction

Hematopoiesis

Cardiac/skeletal (striated muscle)

keratinocyte growth factor

Made in fibroblasts

Stimulate keratinocytes:

• Migration (motility)

• Proliferation (mitogen)

• Differentiation

Insuline-like growth factor 1

Made in macrophages, fibroblasts

Stimulates

• Sulfated proteoglycans

• Collagen

• Keratinocyte migration

• Fibroblast proliferation

Action similar to GH (pituitary growth hormone)

Tumor Necrosis Factor (TNF) alpha and beta

Made in macrophages, mast cells, T-cells

Activates macrophages

KEY influences on other cytokines (also called TNF-alpha/ cachectin/ cachexin)

Responsible for increase in gluconeogenesis, loss of adipose tissue, and proteins (proteolysis).

Seen in cancer patients

interleukins

Made in macrophages, mast cells, T-cells, but also many other cells

Many functions

• Chemotexis

• Angiogenesis

• Regulation of other cytokines (some stimulates, some inhibits the process)

interferons

Made by lymphocytes, fibroblasts

Activates macrophages, inhibits fibroblasts

Regulates other cytokines

autocrine

Same cell signaling. The cell releases hormones but works on itself

paracrine

The cell releases hormones that work on its neighbors or adjacent targets. True for most GFs

endocrine

Stimulates or releases signals from far away, by releasing to the blood vessels and delivered by blood. Ex. steroid hormones

Transcription factors / sequence specific DNA binding factor

Take order from growth factor. Type of protein that will bind with specific DNA sequences that allow them to control the movement of the genetic information or control transcription of DNA mRNA via the RNA polymerase

Extracellular matrix

maintain cell differentiation. Scaffolding. Establish a microenvironment. Storage of GFs

collagen one

main component of bone

collagen two

main component of cartilage

collagen three

main component of reticular fiber

collagen four

forms the basement membrane

angiogenesis

From endothelial precursor cells

From pre-existing vessels

stimulated/ regulated by GFs (esp VEGF)

Also regulated by ECM proteins)

timeline: inflammation

Clot formation

Chemotaxis. Attraction of cells to site of inflammation/injury

proliferation

Re-epithelizaization

Angiogenesis and granulation tissue

Provisional matrix

maturation

Collagen matrix

Wound concentration

healing by first intention

Often seen in surgical scars (wherein the wound is a straight line)

healing by second intention

often seen in wounds that are bigger with much greater ECM destruction. More likely to produce more fibrosis (as there are more to replace for granulation tissue)

fibrosis

Deposition of collagen by fibroblasts.

decreased blood supply

Makes healing harder due to decreased nutrients and angiogenesis

local wound retarding factors

Decreased blood supply.

Local infection. Causes continuous inflammation

FB

Mechanical stress

Necrotic tissue

systemic wound retarding factors

Decreased blood supply.

Age

Anemia

Malignancy

Malnutrition

Obesity

Infection

Organ failure