Healing Flashcards
Healing occurs by _____ or ______
Regeneration or repair
Define regeneration
Regenetation is the replacement of lost cells by new cells of the same kind.
List two examples where wounds are healed by regeneration alone
- Abrasians of the skin
2. Loss of intestinal villi
The capacity of a tissue to regenerate arises largely from ____ cells
stem cells
What are stem cells?
Undifferentiated cells with the capacity to generate one (unipotential), several (multipotential) or all (pluripotential) differentiated cell types.
Stem cells are usually _____ (non-dividing), but with infinite proliferative potential
quiescent
Stem cells divide at a rate that is dictated by ____ ______.
tissue demand
Stem cells generate progeny known as ____ which divide vigorously by transiently
Transit amplifying cells (TAC)
Stems cells can divvide in which two ways? Which way is more common?
- Asymmetrically - one differentiating and one replacement cell
- Symmetrically - identical daughter cells
What is the drawback of symmetrical stem cell division?
Division with reduced probabilities of generating stem cells may lead to atrophy
Division with increased probabilities of generating stem cells may lead to _____
tumours
List three types of tissue states
- Mitotically active
- Normally quiescent
- Terminally differentiated
Describe mitotically active tissues and give examples
Constantly undergoing mitosis - such as bone marrow haematopoietic cells, skin, gut, respiratory and genitourinary epithelium
- regenerate readily after injury
What is colon crypt regeneration stimulated by? List the molecules/cells involved
LPS -> macrophage TLR4 -> COX2, PGE2
Describe normally quiescent tissues and give examples
Normally non-mitosing, but can be induced into regenerative cell division by injury - examples include: endocrine glands, liver
If ≤ __% of the liver is lost, division of mature hepatocytes and stromal cells can replace tissue.
≤ 70%
What molecules do mature hepatocytes respond to in the event of injury and regenerative cell division?
Kupffer cell-derived TNF, IL-6, HGF and TGFα
Describe terminally differentiated tissues and give examples
Terminally differentiated cells cannot re-enter the cell cycle, and are not replaced after death - examples include most neurons and cardiomyocytes
Which transcription factors programme differentiated cells into induced pluripotent stem (iPS) cells?
Transcription factors Oct4, Sox2, Klf4 and Myc
Define repair and when it occurs
Repair follows loss of both functional (parenchymal) and connective (stromal) components of tissues
Tissue cannot be “made new” again, so the wound is replaced by a fibrous scar.
Which cells regulate each step of repair?
Macrophages
Describe the first step of repair
Haemostasis via clotting
Platelets aggregate and degranulate at sites of blood vessel damage, fibrinogen is converted into fibrin and cross-linked with fibronectin (FN) and other ECM proteins by transglutaminases.
What functions does clotting serve? (5)
- Provides temporary mechanical stability
- Forms a barrier to invading microorganisms
- Prevents desiccation and further loss of plasma
- Provides a provisional matrix into which cells involved in repair migrate
- Generates a matrix rich in cytokines and growth factors such as PDGF, TGFβ and VEGF
What is the second step of repair?
Inflammation - necrotic tissue and foreign objects are removed (debridement); must occur before repair can proceed
Describe the process of debridement (5)
Neutrophils, followed by macrophages:
- phagocytose tissue debris, foreign material and bacteria
- Secrete proteases such as collagenases that liquify necrotic tissue
- Generate ROS that are chemotactic and mitogenic to inhibit microbial growth, and at high concentrations damage normal cells
- Secrete growth factors for fibroblasts, endothelial cells (to induce granulation tissue) and epithelial cells
- Proces santigens to activate adaptive immunity
What is the third step of repair?
Tissue formation or proliferation - following injury, both stromal (connective tissue) and epithelial cells proliferate
What is granulation tissue?
A highly vascular connective tissue that forms of the surfaces of a wound during the healing process.
What do fibroblasts do during tissue formation/proliferation?
Fibroblasts proliferate and migrate into the provisional matrix and form a new matrix including collagen III (initially), collagen I (later), fibronectin and glycosaminoglycans
Fibroblasts differentiate into myofibroblasts when stimulated by: (3)
- PDGF and TGFβ from platelets and macrophages
- An embryonic alternatively-spliced isoform of fibronectin, ED-A Fibronectin
- Mechanical tension
What do myofibroblasts lay down?
Collagen fibres - like fibroblasts do
What do myofibroblasts express?
α-smooth muscle actin and bundles of contractile myofilaments (like smooth muscle cells)
Myofibroblasts have well developed ____ ______, which link intracellular actomyosin filaments (stress fibres) with extracellular fibronectin
focal adhesions
Myofibroblasts attach to each other and _____________
ED-A fibronectin
Contraction of myofibroblasts and ED-A fibronectin causes:
Pulling of the edges of the wound together - may reduce the width of a wound to 30-50% of its original span and accelerates healing
Myofibroblasts dia via ____ at the end of the granulation phase
apoptosis
What is the function of VEGF?
Stimulates angiogenesis (growth of new blood vessels from existing ones)
Endothelial cells proliferate and migrate chemotactically in response to macrophage-derived _____
VEGF
_____ stabilise endothelial cells and are produced in response to _____
Pericytes, PDGF
Endothelial cell progenitors (ECPs) may generate new blood vessels from scratch, which is known as _______
vasculogenesis
Define reepithelialisation
Reepithelialisation is when epithelial cells recover an area from which they have been removed.
Normally, basal epithelial cells adhere to basement membrane _____ using _____ receptors
laminin, integrin
Growth factors EGF, TGFα induce epithelial cells to: (4)
- upregulate the EGF receptor
- Express a new set of integrins and migrate along the wound margin
- Move through cross-linked fibrin attached to the underlying stroma by activating proteolytic enzymes
- Regain their original phenotype when they have formed a continuous layer
What is the function of urokinase plasminogen activator (uPA) during reepithelialisation?
Urokinase plasminogen activator (uPA) converts plasminogen into plasmin
Plasmin degrades fibrin and activates MMPs
Reepithelialisation may also arise from:
suprabasal cells “leapfrogging” over each other to cover the exposed area
If the injury is not too deep, most new epithelial cells may arise from which cells of which region?
Stem cells from the bulge region of hair follicles
What is the fourth and final step of repair?
Tissue remodelling
Describe the process of tissue remodelling (4)
- Granulation tissue replaced with acellular scar tissue
- Disorganised collagen III fibres replaced by parallel bundles of collagen I
- Collagen accumulates to a maximum after 2-3 months, when the equilibrium between collagen deposition and degradation by MMPs is restored
- The strength of the collagen continues to increase by cross-linking
When does failure of wound healing occur? (3) What does this lead to?
- The wound is ischaemic - e.g in diabetes or peripheral vascular diseases
- Vasculogenic progenitor cell activity is compromised - e.g in obesity
- Broken ends of bone are not brought together
Failure of wound healing leads to chronic wounds
What does excessive (pathological, fibrotic) scarring cause? (4)
Disfigurement
Pain
Narrowing of tubes (strictures)
Loss of mobility
What does over-expression of scar tissue arise from?
- Excessive inflammatory response to infection or the presence of foreign bodies
- Excessive production of fibrinogenic cytokines such as TGFβ
- Prolonged presence of myofibroblasts, perhaps due to a reduced sensitivity to apoptosis
What is the full name of EGF and its effects?
Epidermal growth factor - epithelial cell migration, proliferation
What is the full name of HGF and its effects?
Hepatocyte growth factor - epithelial migration
What is the full name of PDGF and its effects?
Platelet-derived growth factor - fibroblast migration, proliferation
What is the full name of TGFα and its effects?
Transforming growth factor α - Epithelial cell migration, proliferation
What is the full name of TGFβ and its effects?
Transforming growth factor β - synthesis of stromal proteins
What is the full name of VEGF and its effects?
Angiogenesis
Which growth factors are responsible for both epithelial cell migration and proliferation?
EGF and TGFα
