regeneration Proliferative Capacities of Tissues Stem Cells REPAIR BY CONNECTIVE TISSUE Angiogenesis Migration of Fibroblasts and ECM Deposition (Scar Formation) PATHOLOGIC ASPECTS OF REPAIR

1. TISSUE REPAIR:
REGENERATION, HEALING,
AND FIBROSIS
Mark Anthony I. Jose, MSc.

2. REGENERATION

3. ■ Process of replacing the damaged components and essentially
return to a normal state.
■ Repair refers to the restoration of tissue architecture and function
after an injury
■ If the injured tissues are incapable of complete restitution, or if the
supporting structures of the tissue are severely damaged, repair
occurs by laying down of connective (fibrous) tissue, a process
termed healing that results in scar formation.
■ The term fibrosis is most often used to describe the extensive
deposition of collagen that occurs in the lungs, liver, kidney, and
other organs as a consequence of chronic inflammation, or in the
myocardium after extensive ischemic necrosis (infarction). If fibrosis
develops in a tissue space occupied by an inflammatory exudate it is
called organization (as in organizing pneumonia affecting the lung).

4. Proliferative Capacities of Tissues
■ Continuously Dividing Tissues
■ Stable Tissues
■ Permanent Tissues

5. Stem Cells
■ Stem cells are characterized by two important properties: self-
renewal capacity and asymmetric replication cells means that after
each cell division, some progeny enter a differentiation pathway,
while others remain undifferentiated, self-renewal capacity. Stem
cells with the capacity to generate multiple cell lineages (pluripotent
stem cells and are called embryonic stem (ES) cells.
■ stem cells are normally present in proliferative tissues lineages
specific for the tissue. However, it is now recognized that stem cells
with the capacity to generate multiple the bone marrow and several
other tissues of adult individuals. These cells are called tissue stem
cells stem cells have similar differentiation capacity (referred to as
differentiation plasticity) as ES cells remains the subject and much
dispute. Bone marrow stem cells have very broad differentiation
capabilities, being able to generate fat, endothelium, and muscle.

6. CELL PROLIFERATION, THE CELL CYCLE, AND STEM CELLS CELL
PROLIFERATION IS REGULATED BY CYCLINS COMPLEXED WITH CYCLIN-
DEPENDENT KINASES (CDKS), REGULATE THE PHOSPHORYLATION OF
PROTEINS CELL CYCLE PROGRESSION LEADING TO DNA REPLICATION
AND MITOSIS. THE CELL CYCLE IS TIGHTLY REGULATED STIMULATORS
AND INHIBITORS, AND CONTAINS INTRINSIC CHECKPOINT CONTROLS
TO PREVENT REPLICATION OF CELLS. TISSUES ARE DIVIDED INTO
LABILE, STABLE AND PERMANENT, ACCORDING TO THE PROLIFERATIVE
CAPACITY THEIR CELLS. CONTINUOUSLY DIVIDING TISSUES (LABILE
TISSUES) CONTAIN STEM CELLS THAT DIFFERENTIATE TO LOST CELLS
AND MAINTAIN TISSUE HOMEOSTASIS.

7. ■ cell renewal occurs continuously in labile tissues, such as the bone marrow, gut
epithelium, epithelia or an increased loss of blood cells can be corrected by the
proliferation and differentiation of stem cells and, by proliferation of more
differentiated progenitors. The renewal of hematopoietic cells is driven by growth
factors factors (CSFs), which are produced in response to increased consumption
or loss of blood cells. It is not known if in the renewal of labile epithelia.
■ Tissue regeneration can occur in parenchymal organs with stable cell populations,
but with the exception of the liver, limited process. Pancreas, adrenal, thyroid, and
lung tissues have some regenerative capacity.
■ The surgical removal the contralateral kidney a compensatory response that
consists of both hypertrophy and hyperplasia of proximal duct mechanisms
underlying this response are not understood.
■ Much more dramatic, however, is the regenerative response occurs after surgical
removal of hepatic tissue. As much as 40% to 60% of the liver may be removed in
a procedure transplantation, in which a portion of the liver is resected from a
normal individual and is transplanted into a recipient disease

8. REPAIR BY CONNECTIVE TISSUE
■ If tissue injury is severe or chronic, and results in damage to parenchymal cells and epithelia as
well as the stromal nondividing cells are injured, repair cannot be accomplished by regeneration
alone. Under these conditions, repair of the nonregenerated cells with connective tissue.
■ Repair begins within 24 hours of injury by the emigration of fibroblasts and the induction of
fibroblast and endothelial to 5 days, a specialized type of tissue that is characteristic of healing,
called granulation tissue, is apparent.
■ The term derives from the pink, soft, granular gross appearance, such as that seen beneath the
scab of a skin wound. Its histologic characterized by proliferation of fibroblasts and new thin-
walled, delicate capillaries (angiogenesis), in a loose ECM Granulation tissue then progressively
accumulates connective tissue matrix, eventually resulting in the formation of which may remodel
over time.
■ Repair by connective tissue deposition consists of four sequential processes:
■ Formation of new blood vessels (angiogenesis)
■ Migration and proliferation of fibroblastsDeposition of ECM formation)
■ Maturation and reorganization of the fibrous tissue (remodeling)

9. Angiogenesis
■ Blood vessels are assembled by two processes: vasculogenesis, in which the
primitive vascular network is assembled (endothelial cell precursors) during
embryonic development; and angiogenesis, or neovascularization, out capillary
sprouts to produce new vessels
■ Angiogenesis is a critical process in healing at sites of injury, of collateral
circulations at sites of ischemia, and in allowing tumors to increase in size beyond
the constraints of their It has recently been found that endothelial precursor cells
may migrate from the bone marrow to areas of injury and angiogenesis at these
sites.

10. Migration of Fibroblasts and ECM
Deposition (Scar Formation)
■ Scar formation builds on the granulation tissue framework of new vessels and
loose ECM that develop early at the two steps: (1) migration and proliferation of
fibroblasts into the site of injury and (2) deposition of ECM by these cells.
■ stimulation of fibroblasts is driven by many growth factors, including PDGF, FGF-2
(described above), and TGF-β.
■ Factors is the activated endothelium, but more importantly, growth factors are also
elaborated by inflammatory cells. particular, are important cellular constituents of
granulation tissue, and besides clearing extracellular debris and fibrin they
elaborate a host of mediators that induce fibroblast proliferation and ECM
production. Sites of inflammation are and with the appropriate chemotactic milieu
lymphocytes may also be present. Each of these can contribute directly fibroblast
proliferation and activation.

11. ■ As healing progresses, the number of proliferating fibroblasts and
new vessels decreases; however, the fibroblasts more synthetic
phenotype, and hence there is increased deposition of ECM.
■ Collagen synthesis, in particular, is critical of strength in a healing
wound site. As described later, collagen synthesis by fibroblasts
begins early in wound healing continues for several weeks,
depending on the size of the wound.
■ As described below, many of the same growth fibroblast
proliferation also participate in stimulating ECM synthesis. Net
collagen accumulation, however, depends synthesis but also on
diminished collagen degradation.
■ As the scar matures, there is progressive vascular regression, which
eventually transforms the highly vascularized tissue into a pale,
largely avascular scar.

12. PATHOLOGIC ASPECTS OF REPAIR
■ Infection is the single most important cause of delay in healing; it prolongs the
inflammation phase of the process increases the local tissue injury.
■ Nutrition has profound effects on wound healing; protein deficiency, for example,
vitamin C deficiency, inhibits collagen synthesis and retards healing.
■ Glucocorticoids (steroids) have well-documented effects, and their administration
may result in poor wound strength due to diminished fibrosis. however, the anti-
inflammatory effects of glucocorticoids are desirable.