Tissue Repair Flashcards
Regeneration of injured cells and tissues involves cell proliferation, which is driven by what and dependent on what?
driven by growth factors
dependent on the integrity of the ECM
Which cell types proliferate during repair? (3)
remnants of injured tissue - attempt to restore normal tissue structure
vascular endothelial - create new vessels for repair
fibroblasts - source of fibrous tissue that forms scar to fill defects that cannot be corrected via regeneration
repair proliferation is driven by growth factors - production of these growth factors and the tissue response determines?
the adequacy of the repair
intrinsic proliferative capacity of tissues influences ability to repair (3 groups of tissue)
labile (continuously dividing)
stable
permanent
labile tissue?
continuous turnover from stem cells and proliferation of mature cells (e.g. bone marrow, surface epithelium such as skin, oral cavity, GI, ducts, epithelium, etc.)
Stable tissues?
quiescent with minimal replicative activity, although capable of proliferating in response to injury or loss of tissue mass (e.g. parchyma of most solid organs such as liver, kidney, pancreas; also endothelial cells, fibroblasts, smooth muscle cells); with exception of liver stable tissues have limited capcity to regenerate after injury
Permanent tissues?
terminally differentiated and non-proliferative. Most neurons and cardiac muscle cells. Limited stem cell replication and differentiation, but insufficient for regeneration. Thus, repair dominated by scar formation
Proliferative capacity of tissues - labile / stable / permanent - what do most mature tissues contain?
with exception of permanent tissues, most mature tissues contain variable proportions of three cell types
regenerative capacity in most dividing tissues?
in most dividing tissues, mature cells are terminally differentiated and short lived
what happens when mature cell dies, tissue =
replaced by differentiation of cells generated from stem cells
what two properties characterize stem cells?
self renewal
asymmetric replication
two types of stem cells?
embryonic
adult
embryonic stem cells -
most undifferentiated, present in inner mass of blastocyst can form all three germ layers
adult stem cell -
aka tissue stem cells, less undifferentiated than ES cells found among differentiated cells within an organ or tissue. More limited self-renewal capacity, and more restricted lineage potential, Important in tissue homeostasis
what are growth factors?
proteins that stimulate the survival and proliferation of particular cells, and may also promote migration, differentiation, and other cellular responses
where do growth factors come from?
may be produced by macrophages and lymphocytes recruited to site of injury (or activated on-site) or by parenchymal / stromal cells
growth factors signaling types (3)
autocrine
paracrine
endocrine
ECM definition
complex of several proteins that assembles into a network that surrounds cells and constitutes a significant proportion of any tissue; regulates proliferation, movement and differentiation of cells, provides substrate for cell adhesion and migration, and serves as reservoir for growth factors
Components of extracellular matrix (3)
- fibrous structural proteins (collagens, elastins - tensile strength and recoil)
- water-hydrated gels (proteoglycans and hyaluronan - resilience and lubrication)
- adhesion glycoproteins - connect the matrix elements to one another and to cells
Two basic forms of ECM
Interstitial
Basement membrane
Interstitial matrix
- present where
- synthesized by
- components?
- present in spaces between cells in CT
- synthesized by mesenchymal cells
- major components: fibrillar and non-fibrillar collagens, fibronectin, elastin, proteoglycans, hyaluronate
Basement membrane
- present where
- synthesized by
- components?
- present beneath epithelial, endothelial, and smooth muscle cells
- synthesized by overlying epithelium and underlying mesenchyme
- major components: amorphous non-fibrillar type IV collagen and laminin
ECM main functions (4)
- mechanical support
- control of cell proliferation
- scaffolding for tissue renewal
- establishment of tissue microenvironments
ECM and role in tissue regeneration?
an intact ECM is required for tissue regeneration, and if the ECM is damage, repair can be accompished by scar formation only
regeneration in tissue repair
- labile tissues - what happens?
injured cells rapidly replaced by proliferation of residual cells and differentiation of tissue stem cells (provided underlying BM is intact)
regeneration in tissue repair
- stable tissues - what happens?
regeneration can occur, but (with exception of liver) usually more limited process
Role of regeneration in tissue repair - the liver?
the liver is unique in its robust regenerative capacity
as much as 40-60% of the liver can be removed in living-donor transplantation
liver also can regenerate after other insults (hepatitis etc.) if enough of tissue framework intact
what is tissue repair?
healing - restoration of tissue architecture and function (if possible) after injury
scar formation results when
repair cannot be accomplished by regeneration alone
- -> tissue injury is severe or chronic and results in damage to parenchymal cells and epithelia as well as the CT
- -> non dividing cells are injured
how does scar formation occur?
via replacement of non-regenerated cells with CT leading to formation of scar, or by combination of regeneration of some cells and scar formation
steps in scar formation (3)
- angiogensis - formation of new blood vessels
- migration and proliferation of fibroblasts and deposition of CT (granulation tissue)
- maturation and reorganization of the fibrous tissue to produce a stable scar
Angiogensis is mediated by?
Growth factor VEGF
Deposition of CT (2)
- migration and proliferation of fibroblasts into the site of injury
- deposition of ECM proteins produced by these cells
what / who orchestrates deposition of CT
Orchestrated by locally produced cytokines and GFs - including
- TGF - b
- PDGF
- FGF - 2
what are the sources of GFs and cytokines mediating CT deposition
inflammatory cells - particularly activated (M2) macrophages
which GF is most important cytokine in synthesis and deposition of CT proteins (scar formation)
TGF-b
Remodeling of CT - what influences outcome of repair?/
balance between synthesis and degradation of ECM proteins
What accomplishes the degradation of ECM?
MMPs
What produces MMPs?
variety of cell types (fibroblasts, macrophages, neutrophils, etc.) and include interstitial collagenases, gelatinases, stromelysins
Systemic factors influencing tissue repair? (3)
nutrition
metabolic
vascular
how does nutrition influence tissue repair?
protein deficiency
vitamin c deficiency
both can impair collagen synthesis
how do metabolic factors influence tissue repair?
delay repair
e.g. diabetes
glucocorticoids can inhibit TGF-beta production and diminish fibrosis (some cases may be useful)?
how do vascular factors influence tissue repair?
ischemia, venous drainage
- thrombosis
- ateriosclerosis and atherosclerosis / diabetic changes
- venous drainage impairment: vericose veins
Local factors influencing tissue repair
A major consideration regarding whether repair will take place effectively is whether or not (2)
- the inciting insult has been terminated or persists
2. the new insult in introduced (e.g. infection)
infection influence on tissue repair?
infection prolongs inflammation and increases local tissue injury
what 5 factors influence tissue repair locally?
infection persistence of insult trauma - early movement prior to completion of repair foreign material size / location
aberrations of cell growth and ECM production (2) influencing tissue repair locally?
hypertrophic scar (Regresses) keloid (does not regress)
does a hypertrophic scar regress?
yes
does a keloid regress?
no
what is a contracture
scar - any process that crosses joint space
what is a keloid
a scar that does not regress
- could be absence of MMP or
- excessive collagen deposition
Tissue repair
4 phases following injury
- vascular reaction
- acute inflammatory
- chronic inflammatory
- repair phase
Vascular reaction is tissue repair (2)
- vessel dilation / congestion
2. vessel permeabilit increased
Acute + chronic inflammatory phase in tissue repair (2)
inflammatory cell reaction to injury
- native / sentinel cells
- recruited from blood stream
repair phase in tissue repair (3)
- fibroblast –> collagen/elastin
- endothelial cells –> blood vessels
- epithelial or mesenchymal cells –> re-epitheliazation –> regeneration (if possible)
scar formation following injury (4 phases)
- early cell necrosis (hrs)
- acute phase (PMNs)
- Chronic phase
- Scar
in Acute phase scar formation we see
PMNs
in chronic phase scar formation we see
- lymphs, macs
- fibroblasts
- endothelial cells
in chronic phase scar maturation, we see?
- scant mononuclear cells
healing by first intention
epithelial regeneration is the principal mechanism of repair
- superficial clean wounds - no contracture
healing by second intention?
more complex repair involving combination of regeneration and scarring - get contracture
healing by second intention is accomplished via?
myofibroblasts that contract tissue together
4 differences between secondary healing and primary
- larger clot / scab rich in fibrin and fibronectin
- inflammation more intense
- larger volume granulation tissue
- wound contraction (myofibroblasts)
wound strength of sutured wound
70 % normal skin
three months out 70-80%
