Tissue Injury and Repair: Basic Mechanisms

Question 1

Repair

Answer 1

restoration of tissue structure AND function after an injury

Question 2

regeneration

Answer 2

replacement of normal components and return to a normal state (rare)

Question 3

scar formation

Answer 3

healing with scar formation is most common and happens if: 1) tissues are incapable of complete restitution or 2) they are, but supporting structures are severely damaged.

Question 4

Repair requirements

Answer 4

repair usually involves both regeneration and scar formation in varying degrees

Repair requires: cellular proliferation, interactions between various cells, interactions between cells and ECM

Question 5

Cellular proliferation

Answer 5

several types of cells proliferate

remnants of normal tissue attempt to restore normal structure

vascular endothelial cells (new BVs)

fibroblasts–> produce new fibrous tissue to fill defects

Question 6

Cell cycle

Answer 6

sequence of events controlling proliferation of cells; key processes are DNA replication and mitosis; series of steps where cell checks for accuracy of the process and instructs itself to proceed to the next step

G1=presynthetic growth phase 1

S= DNA synthesis phase

G2= premitotic growth phase 2

M= mitotic phase

Non-dividing cells are either in G1 or exit cycle (G0).

Question 7

Cell cycle checkpoints

Answer 7

G1 (restriction): between G1 and S. makes decision of whether cell should divide, delay division or enter resting stage. controlled by CDK ihibitor P16. this inhibits CDK4/6. Ince active CDK4/6-cyclin D complexes form, phosphorylate tumor suppressor PRb, which relieves inhbition of transcription factor E2F. Cycle can then go on to S phase.

G2 checkpoint: check for DNA damage–> determines whether it can go into mitotic phase

Question 8

Labile cells

Answer 8

=continuously dividing tissues

continuously lost and replaced

maturation from stem cells and proliferation of mature cells

hematopoietic cells, surface epithelia (skin, GIT, urinary tract)

Question 9

Mechanisms regulating cell populations

Answer 9

proliferation, differentiation, cell death, stem cells

Question 10

Stem cells

Answer 10

in continuously dividing tissues (labile cells); replacement by differentiation of cells generated from stem cells; equilibrium between this and death of mature cells (in normal skin is balanced)

Stem cells usually in small numbers in the basal layer, close to the basement membrane.

Transient amplifying cells arise from stem cells and divide a finite number of times until they become differentiated.

Question 11

2 important properties of stem cells

Answer 11

1) self-renewal capacity–> every time a stem cell divides, one of the daughter cells is another stem cell
2) asymmetric replication (some stem cells remain undifferentiated)

Question 12

Skin stem cells

Answer 12

epidermal basal layer

exist as a bulge near a hair follicle

can regenerate follicles and epidermis

Question 13

Latest info on stem cells

Answer 13

Slow-cycling and only divide (asymmetrically) 4-6x/year.

Rapidly dividing progenitor cells (transit amplifying cells) take care of daily maintenace, but only a small and short-lived contribution to the wound response.

Following a wound, the slow-cycling stem cells make a greater and more sustained contribution.

Question 14

Digestive tract cells

Answer 14

Paneth cells: located just below interstitial stem cells in crypts: contain eosinophilic granules which likely protect stem cells and are important in immunity and host defenses

Neuroendocrine cells: produce GI hormones/peptides in response to stimuli

Goblet cells: produce mucus

Enterocyte: absorptive cells

M- cells: important in stimulating mucosal immunity

Question 15

Embyronic vs. adult stem cells

Answer 15

Embryonic: pluripotent (can make any cell type)

Adult: bone marrow= hematopoietic and mesenchymal (chondrocytes, osteoblasts, fibrocytes, etc). Small numbes of stem cells among differentiated cells in a tissue or organ– can yield some or all of the major specialized cell types of THAT tissue or organ (mesenchymal stem cells are also found in tissues).

Induced pluripotent stem cells: repress protein Mbd3. Stem cells express certain TFs which normal cells don’t express. To induce, put factors in. Mbd3 normally stops pluripotentcy program in cells as an embryo develops and then remains in mature cells. If you repress Mbd3, and have proper txn factors–> pluripotentcy.

Question 16

Stable tissues

Answer 16

in G0 stage, i.e. quiescent

can proliferate in response to injury- parenchymal cells (liver, kidney, pancreas), endothelial cells, fibroblasts, smooth muscle cells–> have limited capacity to regenerate

Question 17

Renal tubular regeneration

Answer 17

Nephrotoxins: BM stays intact, but lots of cell death

Ischemia: e.g. infarct– can damage BM–> results in tubular atrophy and fibrosis.

There can be regeneration after ischemia if there is reperfusion.

Epithelial cells proliferate over BM–> form a low cuboidal rather than mature columnar lining (within 3 days). Normal appearance at 7-14 days. Not identical to original cells but there is eventual restitution of function.

Question 18

Liver regeneration

Answer 18

from as little as 25% of parenchyma e.g. partial hepatectomy

liver adjusts to size of the animal

oval cells: hepatic progenitor cells; second tier of cells which can regenerate liver parenchyma if mature hepatocytes can’t.

can differentiate into hepatocytes or bile duct epithelial cells (cholagniocytes); only identified when resident hepatocytes can’t enter cell cycle.

Question 19

Permanent tissues

Answer 19

terminally differentiated and not proliferative in post-natal life– includes neurons, cardiac muscle cells

limited proliferative capacity isn’t sufficient for regeneration

skeletal muscle: permament but satellite cells provide some regenerative capacity

Question 20

Skeletal muscle regeneration

Answer 20

Satellite cells: between basal lamina and sarcolemma. Released by injury, activated and enter the cell cycle.

Basal lamina MUST remain intact as a scaffold (can bridge 2-4mm gap).

Satellite cells become myoblasts and fuse end to end- myotubes, then maturation with nuclei becoming peripheral.

If basal lamina is disrupted, myoblasts which are trying to proliferate from each end for muscle giant cells.

Trauma, infarction, bacterial infection

satellite cells may be killed

any major damage to skeletal muscle results in scarring