REGENERATION AND HEALING
Regeneration and healing of damaged cells and tissues starts almost as soon as the inflammatory process begins. Tissue repair involves 5 overlapping processes:
· Hemostasis (coagulation, platelets)
· Inflammation (neutrophils, macrophages, lymphocytes, mast cells)
· Regeneration (stem cells and differentiated cells)
· Fibrosis (macrophages, granulation tissue [fibroblasts, angiogenesis], type III collagen)
· Remodeling (macrophages, fibroblasts, converting collagen III to I)
The extracellular matrix (ECM) is an important tissue scaffold with 2 forms, the interstitial matrix and the basement membrane (type IV collagen and laminin). There are 3 ECM components:
· Collagens and elastins
· Gels (proteoglycans and hyaluronan)
· Glycoproteins and cell adhesion molecules
Different tissues have different regenerative capacities.
· Labile cells (primarily stem cells) regenerate throughout life. Examplesinclude surface epithelial cells (skin and mucosal lining cells), hematopoietic cells, stem cells, etc.
· Stable cells (stem cells and differentiated cells) replicate at a low level through-out life and have the capacity to divide if stimulated by some initiating event. Examples include hepatocytes, proximal tubule cells, endothelium, etc.
· Permanent cells (few stem cells and/or differentiated cells with the capacityto replicate) have a very low level of replicative capacity. Examples include neurons and cardiac muscle.
Scar formation occurs in a series of steps when repair cannot be effected by regen-eration.
· Angiogenesis is promoted by vascular endothelial growth factor (VEGF) and the fibroblast growth factor (FGF) family of growth factors
· Platelet-derived growth factor (PDGF), fibroblast growth factor 2 (FGF-2), and transforming growth factor β (TGF-β) drive fibroblast activation
· TGF-β, PDGF, and FGF drive ECM deposition. Cytokines IL-1 and IL-13 stimulate collagen production.
Primary union (healing by first intention) occurs when wounds are closed physi-cally with sutures, metal staples, dermal adhesive, etc.
Secondary union (healing by secondary intention) occurs when wounds areallowed to heal by wound contraction and is mediated by myofibroblasts at the edge of the wound.
Repair in specific organs occurs as follows:
· Liver: Mild injury is repaired by regeneration of hepatocytes, sometimes withrestoration to normal pathology. Severe or persistent injury causes formation of regenerative nodules that may be surrounded by fibrosis, leading to hepatic cirrhosis.
· In the brain, neurons do not regenerate, but microglia remove debris and astrocytes proliferate, causing gliosis.
· Damaged heart muscle cannot regenerate, so the heart heals by fibrosis.
· In the lung, type II pneumocytes replace type I pneumocytes after injury.
· In peripheral nerves, the distal part of the axon degenerates while the proximal part regrows slowly, using axonal sprouts to follow Schwann cells to the muscle.
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