Tissue Repair and Healing: Understanding Cell Regeneration Process

1. Chapter Ⅳ. Repair 修复 injured cells and tissue  repair   parenchyma实质 connective tissue间质 regenerationhealing (scar, fibrosis) (Regeneration refers to the proliferation of cells and tissues to replace lost structures)

2. Ⅰ. Control of Normal Cell Proliferation and Tissue Growth (1). The activity of cell proliferation (增生能力) Labile cells (continuously dividing tissues ) Surface epithelia, cells of bone marrow hematopoietic tissues Stem cells Stable cells (Quiescent tissues ) Parenchyma cells of liver, kidneys, and pancreas endothelial cells, lymphocytes, leukocytes Permanent cells (Nondividing tissues) Neurons, cardiac muscle, skeletal muscle

3. Cell-cycle 细胞周期 A Cyclins-CDKs C、D、E B

4. Embryonic stem cells Stem cells Sequamous cell of skin Gene 2012 Nobel Prize for the discovery that adult cells can be transformed back into embryo-like stem cells that may one day regrow tissue in damaged brains, hearts or other organs.

5. (2).The effect of Growth factors • EGF:mitogenicfor keratinocytes and Fb • PDGF:chemotacticfor PMNs, MΦ, Fb, SMC;stimulatesproduction of MMPs, Fn, HA, angiogenesis and wound contraction • bFGF:chemotacticfor Fb, mitogenic for Fb and keratinocytes,stimulateskeratinocyte migration, angiogenesis, matrix deposition • HGF: stimulatesproliferation of epithelial and endothelial cells • KGF: stimulateskeratinocyte migration, proliferation and differentiation • TGF-: chemotacticfor PMNs, MΦ, Lymphocytes, Fb, SMC;stimulatesTIMP synthesis, keratinocyte migration, angiogenesis andfibroplasia; inhibitsproduction of MMPs and keratinocyteproliferation • IL-1: chemotacticfor PMNs; stimulationof MMP-1 synthesis • TNF:activatesMΦ, regulates other cytokines

6. (3).Cell surface receptors and signal transduction system General patterns of intercellular signaling

7. Ⅱ. Extracellular matrix, ECM 细胞外基质

8. Major components of ECM： 1.fibrous structural proteins： collagen 胶原蛋白 elastin 弹性蛋白 2.adhesive glycoproteins： fibronectin 纤连蛋白 laminin 层连蛋白 3.proteoglycans and hyaluronan glycosaminoglycan：粘多糖 heparan sulfate、dermatan sulfate

9. ECM occurs in two basic forms: interstitial matrix and basement membrane.

10. Roles of the ECM • Mechanical support for cell anchorage • Control of cell growth • Maintenance of cell differentiation • Scaffolding for tissue renewal • Establishment of tissue microenvironments • Storage and presentation of regulatory molecules

11. Ⅲ. Repair by Healing with connective tissue 结缔组织修复 The formation of granulation tissue is the critical stape in healing (1).granulation tissue 肉芽组织 Newly formed capillaries Proliferation of Fibroblast Inflammaroty cells

12. New small blood vessels (新生的小血管) Proliferation of Fb (成纤维细胞) Inflammaroty cells

13. 2.The process of granulation tissue formation • Angiogenesis • from pre-existing vessels

14. Angiogenesis from endothelial precursor cells

15. b) Granulation tissue formation and development Granulation tissue Fibrous tissue Scar

16. c. ECM and tissue remodeling The outcome of repair process is a balance between the synthesis and degradation of ECM ECM degradated by Matrix metalloproteinase (MMPs,) ①interstitial collagenase ( MMP1, MMP5) Col and ColⅢ ②gelatinases (MMP2,MMP9) ColⅣ and ColⅤ in BM ③stromelysin (MMP3,MMP10, MMP11) proteoglycans fibronectin, Laminin, others MMPs are inhibited by Tissue inhibitor of matrix metalloproteinase (TIMPs) TIMP1, TIMP2;

17. （2）基质金属蛋白酶/基质金属蛋白酶组织抑制因子（2）基质金属蛋白酶/基质金属蛋白酶组织抑制因子 matrix metalloproteinases MMPs主要分三类： （1）间质胶原酶如MMP-1、MMP-5，降解 Ⅰ型和Ⅲ型胶原； （2）明胶酶，包括MMP-2、MMP-9，降解 Ⅳ型胶原和Ⅴ型胶原； （3）间质溶解素，如MMP-3、MMP-10及基质水解蛋白等， 主要作用于ECM成分的糖蛋白，如FN、LN等。 基质金属蛋白酶组织抑制因子（tissue inhibitor of matrix metalloproteinases， TIMPs）是MMPs特异性的抑制剂， 主要有TIMP-1、TIMP-2、TIMP-3三类。

18. Ⅳ. wound healing 创伤愈合 Inflammation Granulation Tissue Reepithelialization Cutaneous Wound Healing Healing by first/second intention 一期愈合、二期愈合

19. Healing processes: • Induction of inflammation process • (remove damaged and dead tissue) • Proliferation and migration of parenchyma • and connective tissue cells • Formation of new blood vessels and granulation • tissue • Synthesis of ECM proteins and collagen deposition • Tissue remodeling • Wound contraction • Acquisition of wound strength

21. Healing by first intention • Operative incision • Cut surface is neat and tidy • Less infection • Invaded and linked by less granulation tissue and covered by new epithelial cell

22. Healing by second intention • Large wound, abscess, ulceration • Infection or foreign body existing • More inflammation • Clear the wound by debridement • Large amounts of granulation tissue • Scar formation

24. Ⅴ. Factors that influence wound healing影响修复的因素 Systemic factors： nutrition(营养) Metabolic sttus(代谢状况) Circulatory sttus(循环状况) Hormones(激素) Local factors： Infection(感染) Mechanical factors(机械磨擦) Foreign bodies(异物) Size, location and type of wound (大小、部位、伤口类型）

25. Complications in cutaneous wound healing （并发症）： Deficient scar formation瘢痕形成不足 Wound dehiscence(伤口裂开) Ulceration（溃疡） Excessive formation of the repair components瘢痕形成过度 keloid（瘢痕疙瘩） aggressive fibromatoses （侵袭性纤维瘤病） Formation of contractures挛缩 Deformities of the wound and the surrounding tissue

26. keloid（瘢痕疙瘩）

27. 1 2 3

30. Thank you for your attention ！