Tissue Renewal, Regeneration, and Repair Notes

Tissue Renewal, Regeneration, and Repair

Introduction and Objectives

  • Gain knowledge about:

    • Types of tissue renewal.

    • Types of cells according to division power.

    • Stem cells: definition, characteristics, division.

    • Cell cycle: characteristics and functions.

    • Angiogenesis and granulation tissue.

    • Types, steps, and complications of wound healing.

    • Bone healing.

    • Nervous tissue repair.

Tissue Renewal

  • The process by which the body forms new cells to replace structures damaged in pathological processes.

  • Two types:

    • Regeneration: Healing by the same type of cells.

    • Repair: Healing by a mixture of the same cells and fibrosis.

Conditions for Regeneration

  • Tissue composed of labile or stable cells.

  • Presence of a good number of stem cells.

  • Less amount of tissue damage.

  • Intact connective tissue matrix.

  • Examples: Very superficial skin wound, bone fracture.

Conditions for Repair

  • Tissue composed of permanent cells.

  • Small number of stem cells due to tissue damage.

  • Severe tissue damage.

  • Destruction of the connective tissue matrix.

  • Chronic inflammation.

  • Examples: Wound healing (1st & 2nd intention).

Labile Cells

  • Examples: Epidermis, GIT, Endometrium, and blood cells.

  • Characteristics: Short life span, continuous proliferation, large number of stem cells.

Stable Cells

  • Examples: Liver, fibroblast, osteoblast.

  • Characteristics:

    • Replicate until reaching the adult size, then stop.

    • Most of their life in G0 of the cell cycle.

    • Can be active and replicate again if stimulated (e.g., bone fracture).

Permanent Cells

  • Examples: Nerve cells, cardiac muscle, and skeletal muscle fibers.

  • Don’t replicate in postnatal life.

  • Under tissue stress, they tend to increase in size (hypertrophy) or functional capacity (CNS cells).

  • In damage conditions, they are replaced by fibrous tissue (glial tissue).

Stem Cells

  • Undifferentiated cells that can:

    • Turn into many types of differentiated cells.

    • Self-renew: divide to make more stem cells.

  • Maintain their numbers and population through two types of divisions:

    • Symmetric division: One stem cell replicates itself and creates two stem cells.

    • Asymmetric division: One stem cell divides into one similar stem cell and one differentiated cell.

Stem Cell Division Types

  • Symmetric, replicating division: Parental stem cell replicates, yielding two self-renewed daughter cells.

  • Asymmetric, replicating, differentiating division: Parental stem cell divides into one self-renewed daughter cell and one differentiated daughter cell.

  • Symmetric, differentiating division

Stem Cell Lineage

  • A: Stem cell

  • B: Progenitor cell

  • C: Differentiated cell

  • 1: Symmetric stem cell division

  • 2: Asymmetric stem cell division

  • 3: Progenitor division

  • 4: Terminal differentiation

Adult Stem Cells

  • Adult (somatic) stem cells: Identified in many mature tissues such as bone marrow, GIT, skin, liver, pancreas, and adipose tissue.

  • Typically have a more limited capacity to differentiate.

  • Sources: Bone marrow, adipose tissue, blood, and umbilical cord blood.

Cell Cycle

  • Ordered sequence of events that occurs in a cell in preparation for cell division.

  • Four-stage process:

    • G1 (growth) stage: Increase in size.

    • S (DNA synthesis) stage: Copies its DNA.

    • G2 (growth and preparation for mitosis) stage: Prepare to divide.

    • M (mitosis) stage: Divides.

Cell Cycle Regulation

  • Cell cycle checkpoints monitor DNA and chromosomal aberrations.

  • If issues are detected:

    • DNA repair.

    • Apoptosis (cell death) may be triggered.

    • Proliferation inhibition.

  • The goal is to maintain genome integrity and prevent cancer.

Cyclin and Cyclin-Dependent Kinases (CDKs)

  • The cell cycle phases:

    • Interphase: G1, S, G2

    • Mitosis: Prophase, Metaphase, Anaphase, Telophase

  • Key regulators:

    • G1 Phase: Cdk4/6-cyclin D, Cdk2-cyclin E

    • S Phase: Cdk2-cyclin A

    • G2/M Phase: Cdk1-cyclin A/B

  • Other regulatory molecules: Ink4, Cip/Kip, CAK, CDC25, Wee1/Myt1

Characteristics of the Cell Cycle

  • Continuously dividing labile cells can enter G1 phase directly after completing mitosis (M) phase.

  • Stable cells can re-enter the cycle from G0 to G1 when needed.

  • Cell cycle has two checkpoints: (G1-S) and (G2-M), which act as surveillance for any DNA damage.

  • The cell cycle progression is controlled by a family of proteins named cyclins and cyclin-dependent kinases (CDKs).

  • The main role of these complexes is controlling and signaling the cells that are ready to pass into the next phase during the cell cycle.

Cell Cycle Regulation: Positive and Negative Regulators

  • Positive regulators (e.g., growth factors) typically increase the activity of cyclins and CDKs.

  • Epidermal growth factor receptors (EGFR) are a family of four different transmembrane proteins. Mutation and overexpression of EGFR1 are associated with different malignancies.

  • EGFR2, also called HER-2/neu receptor, overexpression is associated with poor prognosis of breast cancer.

  • Negative regulators (e.g., DNA damage) typically decrease or block the activity of cyclins and CDKs.

  • P53 is a tumor suppressor protein that works to ensure that cells with DNA damage do not pass through cell division by triggering the production of Cdk inhibitors.

Angiogenesis

  • Definition: Formation of new blood vessels (neovascularization).

  • Importance:

    • Formation of granulation tissue.

    • Vascularization of ischemic tissues.

  • Granulation tissue: New tissue formed of fibroblasts, collagen, newly formed blood vessels, and inflammatory cells.

    • Used to replace damaged tissues that cannot regenerate.

    • Ends in fibrosis and scar formation.

Steps of Angiogenesis

  1. Vasodilation of preexisting vessels by nitric oxide.

  2. Increased permeability by vascular endothelial growth factor (VEGF).

  3. Breakdown of the basement membrane by metalloproteinases.

  4. Disruption of endothelial cell contact by plasmin.

  5. Proliferation of endothelial cells.

  6. Maturation of endothelial cells.

  7. Recruitment of peri-endothelial cells as pericytes and vascular smooth muscle.

Angiogenesis Process

  • Angiogenic cytokines stimulate sprouting from an arteriole towards ischemic tissue.

  • Endothelial division and migration lead to capillary formation.

  • The new capillary connects to a venule.

Granulation Tissue

  • Granulation tissue is highly vascularized connective tissue composed of newly formed capillaries, proliferating fibroblasts, and residual inflammatory cells.

  • The term "granulation tissue" derives its name from the slightly granular and pink appearance of the tissue.
    Each granule corresponds histologically to the proliferation of new small blood vessels which are slightly lifted on the surface by a thin covering of fibroblasts and young collagen.

  • Granulation tissue is new connective tissue and tiny blood vessels that form on the surfaces of a wound during the healing process.

  • Granulation tissue typically grows from the base of a wound and can fill wounds of almost any size.

  • Granulation tissue forms and fills the injured area while the necrotic debris is being removed.

Types of Wound Healing

  • Healing by first intention (primary union) vs. healing by second intention (secondary union).

  • Healing by First Intention

    • Clean cut wounds, surgical incisions.

    • Minimal cell death and minimal basement membrane damage.

    • The edges of the wound are closely approximated by suture.

    • No foreign body or infection.

    • Minimal fibrosis and good re-epithelialization (minimal scar).

    • No scar contracture.

  • Healing by Second Intention

    • Septic wounds, ulcers, and abscesses.

    • Marked cell death and marked basement membrane damage.

    • A wide gap is present; the edges are not in contact.

    • Foreign body or infection may be present.

    • Dense fibrosis, greater angiogenesis, and abundant collagen deposition (dense scar).

    • Significant scar contracture.

First vs Second Intention

  • First Intention

    • Neutrophils appear in 24 hours.

    • Clot forms in 3 to 7 days.

    • Limited scarring or wound contraction. "Clean" incision.

  • Second Intention

    • Ulcers or lacerations involve granulation tissue and fibrous union.

    • Often scarring and wound contraction.

Steps of Wound Healing

  1. Formation of blood clot.

  2. Formation of granulation tissue.

  3. Cell proliferation and collagen deposition.

  4. Scar formation.

  5. Wound contraction.

  6. Connective tissue remodeling.

Complications of Wound Healing

  • Infection.

  • Inadequate granulation tissue formation leads to ulceration.

  • Keloid formation: Excessive formation of granulation tissue that produces a hypertrophic scar covered by a thin epidermis. Keloid is due to overdone repair.

  • Wound contracture: Reduction in the size of the scar due to excessive contraction.

Keloid and Wound Contracture

  • Images illustrating Keloid and Wound contracture.

Bone Healing

  • Bone healing is an example of regeneration.

  • Steps of bone healing:

    • Formation of hematoma.

    • Polymorphs, macrophages, fibroblasts, and new blood vessels infiltrate.

    • Osteoprogenitor cells, osteoblasts, and osteoclasts participate.

    • Osteoid tissue forms: collagen, fibroblasts, a little amount of calcium.

    • Osteoblasts secrete alkaline phosphatase leading to more calcification.

    • The osteoid tissue acts as a fixator and is arranged in three layers termed calli.

Callus Formation

  • A) External callus: to the outside under the periosteum.

  • B) Internal callus: in the medullary canal.

  • C) Intermediate or permanent callus: found in between the two ends of fractured bones.

  • The osteoblasts of the intermediate callus will form the bony callus by progressive mineralization.

  • The external and internal calli will be gradually removed by osteoclasts.

Bone Healing Process

  • Hematoma formation.

  • Callus formation (fibrocartilaginous callus).

  • Callus ossification (bony callus of spongy bone).

  • Bone remodeling (compact bone).

Repair of the Nervous System

  • 1- The Central Nervous System (CNS)

    • The nerve cells are permanent cells.

    • Injury to the central nervous system is not followed by extensive regeneration.

    • It is limited by the inhibitory influences of the glial and extracellular environment.

    • Steps of CNS repair:

      • Necrosis and liquefaction of the injured area.

      • Microglia (macrophages of the CNS) removes debris.

      • Astrocytes (supporting cells) proliferate and replace the lost area (Gliosis or glial scar).

  • 2- The Peripheral Nerves

    • The peripheral nervous system has an intrinsic ability for regeneration.

    • Steps of peripheral nerve regeneration:

      • The axon distal to the injury becomes irregular, and the myelin sheath breaks into droplets up to the level of the first node of Ranvier (Wallerian degeneration).

      • Macrophages and Schwann cells remove debris.

      • The Schwann cells (supporting cell) in both the proximal and the distal ends proliferate and unite together, forming a tube in which new myelin is formed by oligodendroglia.

      • A new axon grows from the proximal segment (axonal sprouts) and elongates gradually until it reaches the required length.