Transcript 學習目標
Tissue Renewal, Regeneration, and Repair 病理學科暨研究所 彭奕仁 醫師 [email protected] 分機 24977 1 Regeneration and Repair 再生 Stem cells 修復 ECM 學習目標 1. Control of normal cell proliferation and tissue growth 2. Cell cycle and the regulation of cell replication 3. Mechanisms of tissue and organ regeneration 4. Extracellular matrix and cell-matrix interaction 5. Healing by repair, scar formation and fibrosis 3 Control of normal cell proliferation and tissue growth • Homeostasis Control of normal cell proliferation and tissue growth • Tissue proliferative activity – Continuously dividing tissues (時時更新) – Quiescent tissues (後勤部隊) – Nondividing tissues (成熟後無法有絲分裂) • Neuron： replaced by glial cells • Skeletal muscle： satellite cells • cardiac muscle：followed by scar formation Stem cells 1. Self-renewal properties 2. Capacity to generate differentiated cell lineages Stem cells (SC) • 全能性幹細胞（Totipotent stem cell） • 多功能性幹細胞（Pluripotent stem cell） • 多潛能性幹細胞（Multipotent stem cell） 外滋養層細胞 Adult stem cells (somatic stem cells) Stem cells in tissue hemeostasis: niches • • • • • • Skin: the hair follicle bulge Liver: canals of Hering Intestinal epithelium: crypts Skeletal muscle: satellite cells Cornea: limbal stem cells Brain: – subventricular zone, – dentate gyrus of the hipocampus Reprogramming of differentiated cells induced pluripotent stem cells (iPS) • Tanscriptional Factors: – Oct3/4, Sax2, c-myc, Klf4 – Oct3/4, Sax2, Nanog, Lin28 • Stem cell therapy • ES cells without embryos Regeneration and Repair 再生 Stem cells 修復 ECM 學習目標 1. Control of normal cell proliferation and tissue growth 2. Cell cycle and the regulation of cell replication 3. Mechanisms of tissue and organ regeneration 4. Extracellular matrix and cell-matrix interaction 5. Healing by repair, scar formation, and fibrosis 13 Cell Cycle Landmarks 品管機制 品質保證 Cyclins, CDKs, CDK inhibitors G0: quiescent G1: Pre-synthetic S: DNA synthesis G2: pre-mitotic M: mitosis The regulation of cell replication • Growth factors (Keys and locks) • Signaling from ECM components through integrins • Signaling mechanisms in cell growth – Receptors and signal transduction pathways – Transcription factors Models of signaling • Autocrine • Paracrine • Endocrine Signaling transduction Ligand Receptor integrin Reaction and Response Transcriptional factor DNA RNA Protein Central dogma Main types of cell surface receptors and their principal signal transduction pathways Growth factors • 名字 • 接受器，重要下游 • 作用細胞，功能 • 與腫瘤的關聯性 名字：TGF-β • Isoform TGF-β (1, 2, 3) • 接受器：TGF-β receptor type I and II. • 重要下游：Smad • 作用細胞，功能： Pleiotropic agent – Growth inhibitor for most epithelial cells – A potent fibrogenic agent 纖維化 – A strong anti-inflammatory effect 抗發炎 名字 接受器 重要下游 Growth factors and cytokines involved in regeneration and wound healing • GF vs. embryonic development vs. cancer • EGFR (EGFR1 or ERB B1)： – EGF, TGF-α, HB-EGF, amphiregulin； – cancers of the lung, H&N, breast, glioblastoma. • ERB B2 (HER-2 or HER2/Neu)：breast cancer. • HGF：c-MET (receptor). scatter factor. • To promote cell scattering and migration. • Renal and thyroid papillary carcinoma. Transcriptional factors • Transfer information to the nucleus and modulate gene transcription 各式各樣的訊息傳遞方式 • Heterodimerization: c-FOS+c-JUNAP-1 • Phosphorylation: STATs • Release of inhibition: NF-κB • Release from membranes by proteolytic cleavage: Notch receptor Regeneration and Repair 再生 Stem cells 修復 ECM 學習目標 1. Control of normal cell proliferation and tissue growth 2. Cell cycle and the regulation of cell replication 3. Mechanisms of tissue and organ regeneration 4. Extracellular matrix and cell-matrix interaction 5. Healing by repair, scar formation, and fibrosis 26 Capacity of regeneration • Urodele amphibians vs. mammals –Absence of blastema formation –Rapid fibroproliferation. • • Wnt/β-catenin pathway Liver regeneration after partial hepatectoomy Compensatory growth or Compensatory hyperplasia (HGF, TGFα, HB-EGF) (TGFα, TNF, IL-6) • TGF-β and activins may be involved in terminating hepatocyte replication. • Intrahepatic stem or progenitor cells do not play a role in the compensatory growth that occurs after partial hepatotectomy. 學習目標 1. Control of normal cell proliferation and tissue growth 2. Cell cycle and the regulation of cell replication 3. Mechanisms of tissue and organ regeneration 4. Extracellular matrix and cell-matrix interaction 5. Healing by repair, scar formation, and fibrosis 30 Regeneration and Repair 再生 Stem cells 修復 ECM Components of ECM • Fibrous structural proteins: collagens, elastins • Adhesive glycoproteins • Proteoglycans and hyaluronan Extracellular matrix Functions • Control of cell growth: integrin • Maintenance of cell differentiation: integrin • Mechanical support • Scaffolding for tissue renewal • Establishment of tissue microenvironments • Storage and presentation of regulatory molecules: FGF, HGF Collagen Structure: Primary sequence : Gly-X-Y (X,Y: other than cysteine or tryptophan) Monomer( alpha chain)=> left handed helix, 3 a.a. per turn Trimer: coiled-coil => stabilized by H-bond, crosslink between triple helixes(disulfide bond) Function: Provide tensile strength Collagen Osteogenesis imperfecta • • • • 俗名：玻璃娃娃、成骨不全症 症狀：骨骼不夠堅硬、發育不全 病因：遺傳疾病造成collagen不足或不全 Osteogenesis imperfecta(II) Ehlers-Danlos syndrome Ehlers-Danlos syndrome (EDS) refers to a group of inherited disorders that affect your connective tissues — primarily your skin, joints and blood vessel walls. 一般症狀 • Loose, unstable joints • Highly elastic, velvety skin Scurvy(壞血病) • Vitamin C is required for the hydroxylation of procollagen, a requirement that explains the inadequate wound healing in scurvy ECM and GF activate signaling pathway Glycosaminoglycans(GAGs), and proteoglycans Extracellular matrix Functions • Control of cell growth: integrin • Maintenance of cell differentiation: integrin • Mechanical support • Scaffolding for tissue renewal • Establishment of tissue microenvironments • Storage and presentation of regulatory molecules: FGF, HGF 學習目標 1. Control of normal cell proliferation and tissue growth 2. Cell cycle and the regulation of cell replication 3. Mechanisms of tissue and organ regeneration 4. Extracellular matrix and cell-matrix interaction 5. Healing by repair, scar formation and fibrosis 43 Regeneration and Repair 再生 Stem cells 修復 ECM Healing by repair： Scar formation and Fibrosis • • • • • Inflammation Angiogenesis Migration and proliferation of fibroblasts Scar formation Connective tissue remodeling Angiogenesis (capillary growth) • Vasodilation: NO, VEGF • Degradation of BM: MMPs, plasminogen activator • Migration of endothelial cells • Proliferation of endothelial cells • Maturation of endothelial cells • Recruitment of peri-endothelial cells Angiogenesis (EPC) • EPC: endothelial precursor cells • Stem cell markers and endothelial cell markers (VEGFR-2 and vascular endothelial-cadherine) • Increased number of EPC greatly in patients with ischemic conditions EPC: endothelial precursor cells Growth factors and receptors Notch signaling and VEGF, Delta-like ligand Phases of cutaneous wound healing Sequence of events in healing • • • • • • • Formation of blood clot Formation of granulation tissue Cell proliferation and collagen deposition Scar formation Wound contraction Connective tissue remodeling Recovery of tensile strength ECM proteins as regulators of angiogenesis • Integrins: αvβ3 • Matricellular proteins: thrombospondin 1, SPAEC, tenascin C • Proteinases: plasminogen activators, MMPs. Factors that influence wound healing Pathologic aspects of repair • Deficient scar formation • Excessive formation of the repair components • Formation of contractures Development of fibrosis Inquiries • How to regulate the cell proliferation and tissue growth in normal cell cycle and regeneration? • The mechanism of regeneration in liver. • The mechanism of repair in cutaneous wound. • Why did happen the complications in wound healing, such as keloid and contracture? 61 References • Robbins and Cortran’s Pathologic Basis of Disease, 8th edition. P.79-110 62 • Gly-X-Y