HISTOLOGY FULL-TEXT

Chapter 3l REGENERATION

A GENERAL CONCEPTS

SOURCE CELLS     (a) Surviving differentiated cells (may de-differentiate)
     |           (b) Surviving undifferentiated stem cells
     |           (c) Circulating cells in the blood
     |
proliferation   1 Stimulated by: reduced density of cell packing?
     |             Physiological overload? Growth factors? Loss of growth
     |             inhibitors?
     |          2 Cell membranes 'feel' that tissue is missing, and are
     |             prompted to migrate? and proliferate?
     |
     |
     V                      Specialisation
GROWING CELL POPULATION -------------------------> DIFFERENTIATED CELLS
                            brought about by
                                                      
                       1 Maintained regulatory programmes
                       2 Continuity of regenerating part with mature,
                          specialized part, e.g., in skeletal muscle
                          fibre
                       3 Inducer substances/factors
                       4 Interactions with extracellular matrix
                       5 Cell contacts & gap junctions
                       6 Mechanically and electrically
                          polarized fields

3 Organization of the differentiating cells to repair an organ
l Coordination of regenerations of more than one tissue is needed, e.g., (a) glandular cells, blood vessels, and stromal cells, ECM and later reticular elements, to build new lobules in the liver; (b) skeletal muscle fibres, connective tissues, and nerve fibres, to regenerate muscle and restore musculo-skeletal function. Tissues interact inductively and trophically.
2 Regenerations of tissues may compete, with a functionally unfavourable outcome, e.g.,
.. (a) collagenous connective tissue may outgrow the regenerating cartilage and bone in a skeletal fracture, and fill the fracture gap with a fibrous tissue not rigid enough for support;
.. (b) in the injured brain, glial cells multiply, and actively inhibit the growth of axons.

4 Requirements for regeneration
l Space: the growth of tissue requires space and may, in itself, be a response acknowledging that a spatial defect exists. Where tissue has been damaged, phagocytosis and lysis of the necrotic tissue make room for the new cells. When the defect has been filled, the cell proliferation is reduced or stopped. This inhibition happens even when the 'wrong' tissue, e.g., fibrous CT, fills the gap.
2 Communication between the participating cells by means of cytokine and other agents.
3 Adequate hormone levels, e.g., thyroid.
4 Adequate stores or intake of amino acids, vitamins, etc., for the synthesis of new protein and other materials.
5 Freedom from infection.
6 An intact blood supply and drainage for the area. Sometimes, too, a continuing innervation is a necessary coordinating and trophic factor.

5 Hyperplasia and hypertrophy
l Hyperplasia is a response by the tissue involving mitosis and the formation of new cells, increasing cell number to meet a demand for greater output, e.g., of glandular secretion.
2 Hypertrophy again tries to meet a requirement for increased effort or output, not by cell proliferation, but rather by the cells in their original number increasing their size and hence content of productive organelles and materials, e.g., uterine smooth muscle cells in pregnancy.

6 Regeneration and physiological regeneration
l Physiological regeneration is a normal process going on continuously, e.g., in gut epithelium, or continually, e.g., in hair follicle epithelium, involving cell division for the replacement of cells lost naturally.
Blood cells, epithelial, bone and connective tissue cells show the phenomenon. Muscle, cartilage and nerve cells, on the other hand, are stable and static cells, in maturity.
2 Tissues regenerating physiologically without any injury are better able to regenerate to repair damage than those with stable, long-living cells.

E EPITHELIAL AND CONNECTIVE TISSUES

2 Below the epithelium
l Blood forms a clot with fibrin fibres, platelets, and fibronectin.
2 Leucocytes migrate through intact vessel walls; polymorphs attacking the few bacteria and monocytes removing cell debris and fibrin. (The inflammatory response and agents involved in it, e.g., affecting capillary permeability and the migration of leucocytes, will be studied in pathology and pharmacology.)
3 Fibroblasts in CT become active, proliferate, migrate into the clot, and lay down new collagen fibres, glycoproteins, and proteoglycans, in the construction of granulation tissue.
4 Endothelial cells of cut capillaries concurrently proliferate and move into the clot, rebuilding the capillary network.
5 Continued activity along these several lines results in the rapid formation of a new lamina propria. Meanwhile,

3 In the epithelium
l Epithelial cells at the cut margins migrate out as a thin layer, penetrating the fibrin, and replacing the temporary substrate of fibronectin and tenascin with basal lamina as a robust and permanent support.
2 While the epithelial surface is being restored as a thin sheet, its cells start to multiply and differentiate, to restore the original thickness and variety of specialized cells of the epithelium.
3 Since the new epithelium has to grow in from the edges, the degree of gaping of the cut determines the distance over which the cells must migrate, and hence the time needed for healing. The cut margins of the wound should therefore be drawn into apposition by sutures. The sooner the epithelium is restored, the earlier is the underlying tissue protected from invasion by pathogenic organisms.
The above describes the smooth, progressive sequence of healing by first intention.
4 The surviving deep part of exocrine glands can provide a source of regenerative epithelial cells to replace the surface epithelium, in addition to the lost part of the gland. Significant examples are:
(i) in the physiological restitution of the uterine lining from the basal layer of the endometrium after menstruation;
(ii) the replacement of epidermis from the sweat glands (and hair follicles), after a second-degree burn has killed the more superficial epithelial cells.

Although the regenerations of epithelium and CT have been treated separately, in life these processes, and, indeed, their normal day-to-day working, are tightly coordinated by cytokines and cell-matrix interactions.

In general, repair can restore both epithelium and its lamina propria of connective tissue to almost as good a condition as before. When there is pathological delay, cytokines are being tried in order to speed up epithelial events and to boost construction of the lamina propria.

C GLANDULAR REPAIR

D MUSCULAR REGENERATION

2 Smooth and cardiac muscle
l Radioautographic studies indicate that smooth muscle cells, e.g., in the gut, are capable of some proliferation to replace damaged cells and partially restore continuity in a muscular tunic.
2 Cardiac muscle is at a disadvantage, because it cannot relax and rest for a period to permit cell division and muscle reorganization; and there may be an early and unfavourable response from its CT.
Lung, likewise, is prevented by its elasticity and motion, and other factors, from effective regeneration, despite its epithelial content.
3 Cuts into cardiac muscle fill quickly with collagenous CT, but muscle fibres injured by infections can regenerate.
In general then, a large lesion in muscle will be filled with C.T. Only a little new muscle tissue forms to replace that lost or to fill gaps. Surviving muscle fibres may hypertrophy in an attempt to restore the power of the muscle as a whole.

E BONE AND CARTILAGE