Tissue renewal and Repair. Nisamanee Charoenchon, PhD Department of Pathobiology, Faculty of Science

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1 Tissue renewal and Repair Nisamanee Charoenchon, PhD Department of Pathobiology, Faculty of Science

2 Topic Objectives 1. Describe processes of tissue repair, regeneration and their molecular mechanisms 2. Describe roles and components of the extracellular matrix (ECM) in tissue repairing processes 3. Differentiate between regeneration and healing 4. Differentiate between normal aspects of tissue and pathologic aspects of tissue repair

3 Checklist 1. Overview and definition of tissue renewal and repair 2. Cell and tissue regeneration 3. Scar formation 4. Factors that influence tissue repair 5. Selected clinical examples of tissue repair and fibrosis

4 Leading questions How is importance of tissue renewal and repair? What are the key proteins related to tissue renewal and repair?

5 1. Overview and definition of tissue renewal and repair

7 Definitions Regeneration = proliferation of cells and tissues to replace lost or damaged cells and tissue. Normal structure is restored Repair or healing = response to injury involving both regeneration and scar formation (fibrosis). Normal structure is permanently altered

8 REPAIR Scar formation; Organization of exudate

9 Response after injury Regeneration or renewal Scar formation Both processes involve the proliferation of various cells and close interactions between cells and the ECM. Ref: Robbins Basic Pathology (9th Edition)

10 Regeneration Some tissues are able to replace the damaged cells and essentially return to a normal state Occurs by proliferation of residual (uninjured) cells that retain the capacity to divide, and by replacement from tissue stem cells. Ref: Robbins Basic Pathology (9th Edition)

11 Scar formation If the injured tissues are incapable of degeneration, or if the supporting structures of the tissue are severely damaged, repair occurs by the laying down of connective (fibrous) tissue, a process that results in scar formation. Ref: Robbins Basic Pathology (9th Edition)

12 2. Cell and tissue regeneration

13 Cell and tissue regeneration 1. The control of cell proliferation 2. Proliferation capacity of tissue 3. Associated cells and signals 1. Stem cells 2. Growth factors 3. ECM 4. Role of generation in tissue repair

14 The control of cell proliferation

15 Proliferation capacity of tissue Mechanisms regulating cell populations. Cell numbers can be altered by increased or decreased rates of stem cell input, cell death by apoptosis, or changes in the rates of proliferation or differentiation. Ref: Robbins Basic Pathology (9th Edition)

16 Proliferation capacity of tissue Labile (continuously dividing) tissues Stable tissues Permanent tissues

17 Labile Cells of these tissues are continuously being lost and replaced by maturation from stem cells and by proliferation of mature cells.

18 Stable tissues Cells of these tissues are quiescent and have only minimal replicative activity in their normal state. However, these cells are capable of proliferating in response to injury or loss of tissue mass.

19 Permanent tissues The cells of these tissues are considered to be terminally differentiated and nonproliferative in postnatal life.

20 Principles of cell proliferation Several cell types proliferate during tissue repair. The remnants of the injured tissue restore normal structure Vascular endothelial cells create new vessels that provide the nutrients needed for the repair process), Ref:

21 Principles of cell proliferation (cont.) Fibroblasts the source of the fibrous tissue that forms the scar to fill defects that cannot be corrected by regeneration Ref: _08_01_archive.html

22 Associated cells and signals 1. Stem cells 2. Growth factors 3. ECM

23 Stem Cells Stem cells are characterized by two important properties: Selfrenewal capacity and asymmetric replication. Ref:

24 Ref:

Adult stem cells also called tissue stem cells, are less undifferentiated than ES cells and are found among differentiated cells within an organ or tissue.

26 Adult stem cells also called tissue stem cells, are less undifferentiated than ES cells and are found among differentiated cells within an organ or tissue. Although, like ES cells, they also have selfrenewal capacity, this property is much more limited. Ref:

Stem cell niches Have been identified in many

27 Stem cell niches Have been identified in many organs.- brain, skin, cornea Furthermore, they occur in specialized microenvironments within the organ = stem cell niches. Apparently, signals from other cells in such niches keep the stem cells quiescent and undifferentiated.

28 Mesenchymal stem cells Hematopoietic stem cells, the bone marrow also contains a somewhat distinctive population of tissue stem cells, often called mesenchymal stem cells. Ref:

29 These cells can give rise to a variety of mesenchymal cells, such as chondroblasts, osteoblasts, and myoblasts. Hence, there is great interest in their therapeutic potential. chondroblasts osteoblasts myoblasts

30 Growth factors (MITCHELL, et al. 2016)

31 Ref: Robbins Basic Pathology (9th Edition) p. 62

32 Role of the Extracellular Matrix in Tissue Repair ECM occurs in two basic forms: 1. interstitial matrix and 2. basement membrane Ref:

33 Extracellular matrix Ref :

34 ECMs 1. Collagen 2. Elastin 3. Proteoglycan and Hyaluronan 4. Adhesive glycoproteins and adhesion receptors 1. Fibronectin 2. Laminin 3. Integrin

35 Ref: Robbins Basic Pathology (9th Edition) p. 63

36 Collagen Image adapted from Ricard-Blum 2011 and Chung and Uitto 2010

37 The categories of collagen families classified by the their supramolecular structure. (a) Distinct collagens form different type of assembly. (b) Systematic relation among some various forms of collagen at DEJ.

39 Elastin

40 Proteoglycan and Hyaluronan Ref:

Structure of Proteoglycan Ref: http://www.buzzle.

41 Structure of Proteoglycan Ref:

42 Adhesive glycoproteins and adhesion receptors Ref:

43 1. Fibronectin (a large (450-kDa) Tissue fibronectin forms fibrillar aggregates at wound healing sites; plasma fibronectin binds to fibrin within the blood clot that forms in a wound, providing the substratum for ECM deposition and re-epithelialization.

44 2. Integrins (leukocyte adhesion to endothelium) main cellular receptors for ECM components, such as fibronectins and laminins some of the integrins as leukocyte surface molecules that mediate firm adhesion and transmigration across endothelium at sites of inflammation, and we shall meet them again when we discuss platelet aggregation

45 3. Laminin Ref:

46 Ref:

47 3. Laminin (820-kDa, is the most abundant glycoprotein in basement membrane) connects cells to underlying ECM components such as type IV collagen and heparan sulfate. Besides mediating attachment to basement membrane, laminin can also modulate cell proliferation, differentiation, and motility.

48 Functions of ECMs 1. Mechanical support 2. Control of cell proliferation 3. Scaffolding for tissue renewal. 4. Establishment of tissue microenvironments.

49 3. Scar formation

50 Processes I. Formation of new blood vessels (angiogenesis) II. Migration and proliferation of fibroblasts and deposition of connective tissue III. Maturation and reorganization of the fibrous tissue (remodeling)

51 Steps in repair by scar formation Injury to a tissue that has limited regenerative capacity first induces inflammation Ref: Robbins Basic Pathology (9th Edition)

52 Clears dead cells and microbes, if any. This is followed by formation of vascularized granulation tissue and then deposition of ECM to form the scar. ECM, extracellular matrix. Ref: Robbins Basic Pathology (9th Edition)

53 Angiogenesis Angiogenesis is the process of new blood vessel development from existing vessels, primarily venules. Angiogenesis involves sprouting of new vessels from existing ones and consists of the following steps Vasodilation occurring in response to NO and increased permeability induced by VEGF Separation of pericytes from the abluminal surface Migration of endothelial cells toward the area of tissue injury

driven outgrowth of residual endothelium, sprouting of new

54 Mechanism of angiogenesis. In tissue repair, angiogenesis occurs mainly by growth factor driven outgrowth of residual endothelium, sprouting of new vessels, and recruitment of pericytes to form new vessels. Ref: Robbins Basic Pathology (9th Edition)

55 Growth factors Involved in Angiogenesis The VEGF family of growth factors includes VEGF-A, -B, -C, -D, and -E and placental growth factor (PlGF) The FGF family of growth factors has more than 20 members; the best characterized are FGF-1 (acidic FGF) and FGF-2 (basic FGF). Angiopoietins Ang1 and Ang2 are growth factors that play a role in angiogenesis and the structural maturation of new vessels.

56 Growth factors Involved in ECM Deposition Transforming growth factor-β (TGF-β) Functions.- 1. stimulates the production of collagen, fibronectin, and proteoglycans, and it inhibits collagen degradation 2. an anti-inflammatory cytokine that serves to limit and terminate inflammatory responses

57 Growth factors Involved in ECM Deposition Platelet-derived growth factor (PDGF) causes migration and proliferation of fibroblasts and smooth muscle cells and may contribute to the migration of macrophages Cytokines may also function as growth factors and participate in ECM deposition and scar formation.

58 4. Factors that influence tissue repair

59 Important influences Infection Nutrition Glucocorticoids (steroids) Mechanical variables Poor perfusion, Foreign bodies The location of the injury Aberrations of cell growth

60 5. Selected clinical examples of tissue repair and fibrosis

61 Healing of Skin Wounds Healing by First Intention Healing by Second Intention

62 Steps in wound healing by first intention (left) and second intention (right). In the latter case, note the large amount of granulation tissue and wound contraction. Ref: Robbins Basic Pathology (9th Edition)

63 Ref: Robbins Basic Pathology (9th Edition)

65 References 1) Mitchel et al Engineering growth factors for regenerative medicine applications. Acta Biomater, 30, ) Ricard-Blum, S., The collagen family. Cold Spring Harb Perspect Biol, (1): p. a ) Urciuolo, A., et al., Collagen VI regulates satellite cell self-renewal and muscle regeneration. Nat Commun, : p

66 Media The overview: Tissue Repair Mg5E Scar Tissue Formation Wound Healing

Tissue repair. (3&4 of 4)

Tissue repair. (3&4 of 4) Tissue repair (3&4 of 4) What will we discuss today: Regeneration in tissue repair Scar formation Cutaneous wound healing Pathologic aspects of repair Regeneration in tissue repair Labile tissues rapid