Tissue Repair and Regeneration

Question 1

3 Components of Tissue Homeostasis

Answer 1

• Apoptosis - programmed cell death
• Differentiation- degree of cell specialization (adult stem cells v terminal differentiation)
• Proliferation - replication of cells to replace lost structures

Question 2

3 Cell Types in Terms of Cell Cycle (+ examples of ea)

Answer 2

• Cont Dividing / Labile Tissue - high rate of cell death so need renewal; continuously in cell cycle (epidermis, GI mucosa, heme)
• Quiescent - alive but not replicating (G0) but can proliferate once stimulated (hepatocytes, fibroblasts, vascular endothelial cells)
• Non-dividing Tissues - no/extremely low regenerative capacity; once they leave cell cycle they stay in G0 and do NOT re-enter cell cycle (neurons and cardiomyocytes)

Question 3

Which cells are capable of regeneration? (4)

Answer 3

• Hematopoietic stem cells
• Epidermis
• GI Mucosa - crypt stem cells
• Liver - 2 possibilities
  
  • 1- surgical resection —> recreate liver mass but not liver shape; DOES NOT USE STEM CELLS
  • 2- liver damage over time —> use stem cells to compensate

Question 4

What stimulates proliferation in regeneration?

Answer 4

• Physical
  
  • Ex) liver resection —> inc blood flow to remaining liver —> stimulates regeneration
• Growth Factors
  
  • EGF and TGF-alpha
  • HGF (Hepatocyte Growth Factor)
  • VEGF

Question 5

Fibrosis Process

Answer 5

• Fill void w/ collagen and ECM deposition
• macrophages secrete TGF-beta —> activated fibroblasts (AKA activated stellate cells); fibroblasts then secrete collagen and ECM
• Some fibroblasts develop contractile properties (myofibroblasts); contraction pulls scar components tighter

Question 6

3 Phases of Cutaneous Wound Healing

Answer 6

Regeneration + Scar

• 1- Inflammation (24 hrs)
  
  • Clot formation (coag cascade) -seen as scab
  • VEGF secreted by keratinocytes and others —> inc vascular permeability/edema
  • Neutrophils at wound boundary (infiltration)
• 2- Proliferation (days 2-7)
  
  • Epidermal Response
    
    • Epithelial cells migrate to wound edge
    • Epithelial cells proliferate
    • Epidermal maturation
  • Dermal Response
    
    • Granulation tissue- matrix to fill wound defect; fibroblasts (TGF-beta), more metabolism, breakdown ECM (collagenases) so new vessels can grow (VEGF and HP1alpha response to hypoxia)
• 3- Maturation (weeks)
  
  • Epidermal Response - already essentially done
  • Dermal Response -
    
    • Regression of granular tissue
    • Collagen remodeling
    • Wound contracture (myofibroblasts)

Question 7

Primary v Secondary Intention

Answer 7

• Primary Union/First Intention - wound type w/ minimal defect, minimal inflammation, no infection and minimal scarring
• Secondary Union/Secondary Intention - frequent cells death, larger wound size to edges not close together —> greater chance of infection, inflammation; prominent scars

Question 8

Liver Resection

Answer 8

• Compensatory Hyperplasia- liver regenerates lost mass but not lost shape via proliferation of different cell types (hepatocytes, biliary epithelial cells or cholangiocytes and endothelial cells)
  
  • NO ADULT STEM CELLS
• 3 Stages
  
  • 1- Initiation/Priming
    
    • Main stimulus = abnormally high blood flow b/c same amount of blood flowing to less liver cells
    • Also growth factors (HGF, EGF, TNF-alpha)
    • Proteases breakdown ECM at this time too
  • 2- Proliferation
    
    • Cell types mentioned above proliferate (proliferation of mature liver cells); hepatocytes first
    • Usually 1-2 round of replication ea
    • ECM remodeling in this phase too
  • 3- Termination
    
    • Growth cues dec
    • TGF-beta reappears (inhibitor of growth)
• NO FIBROSIS OR GRANULATION TISSUE

Question 9

Cirrhosis of Liver

Answer 9

• Repeated hepatocyte injury —> hepatocyte proliferation and fibrosis (deposition of collagen) ALSO differentiation of hepatobiliary stem cells (so use mature cells and stem cells)
  
  • Alteration in liver architecture - fibrous septa + regenerative nodules
• Fibrous Septa - ROS, TNF-alpha and IL-1 stimulate fibroblasts (activated stellate cells) —> secrete collagen —> bands that leads directly to central vein b/n portal tracts
• Septa border areas of “ductular reactions” (clusters of hepatocytes transitioning from hepatobiliary stem cells —> hepatocytes)

Question 10

Clinical Consequences of Cirrhosis of Liver

Answer 10

• Vessels in septa —> high pressure/fast-moving conduits to central vein; blood rushes past hepatocytes w/o being able to detox
• Blood cannot get into liver due to fibrosis —> portal hypertension (MEDUSA)
• Hepatocellular carcinoma (tumor)
• Hepatic failure

Question 11

Dehiscence

Answer 11

separation of tissue edges b/c inadequate granulation tissue or inadequate scarring (most common in abdominal incision)

Question 12

Proud Flesh (exuberant granulation)

Answer 12

• excess granulation tissue (spongy material); prevent re-epitheliazation

Question 13

Contracture

Answer 13

excessive contraction (esp after severe burns) -can lead to joint immobility; myofibroblasts

Question 14

Adhesion

Answer 14

fibrous bands b/n tissues; fibrin acts as glue or bridge b/n tissues (esp b/n loops of bowel); can lead to bowel obstruction

Question 15

Hypertrophic/Keloid

Answer 15

excessive deposition leads to raised scar (hypertrophic) or extension of scar beyond wound boundaries (Keloid)

Question 16

Sclerosis

Answer 16

excess deposition of ECM; usually in response to injury

Question 17

2 Types of Pathological Calcification

Answer 17

• Dystrophic - normal Ca++ metabolism in area od necrosis; can lead to bone deposition
• Metastatic - abnormal Ca++ metabolism (hypercalcemia); usually calcifications in kidney, lungs, GI mucosa