Lecture 4.1 - Regeneration and Repair PDF

Stem cells: ◦Stem cell definition/properties: ‣ A stem cell is an undifferentiated cell that can: Continuously divide Differentiate into various other kind(s) of cell ◦Stem cell characteristics: ‣ Self-renewal - capable of dividing...

Stem cells: ◦Stem cell definition/properties: ‣ A stem cell is an undifferentiated cell that can: Continuously divide Differentiate into various other kind(s) of cell ◦Stem cell characteristics: ‣ Self-renewal - capable of dividing and renewing themselves, to keep the source of regrowth ‣ Potency - the capacity to differentiate into specialised cell types for development and regeneration Stem cell properties: ◦Self-renewal - by asymmetric replication, one daughter cell remains as stem cell ◦Potency - by direct differentiation or after further proliferation Potency of the stem cells - hierarchy: ◦Totipotent - fertilised egg and the cells produced by the first few divisions. They can differentiate into embryonic and extraembryonic cell types (placenta). They can construct a baby (IVF). ◦Pluripotent - the descendants of totipotent cells (embryonic stem cell ESC) and can differentiate into cells derived from any of the three germ layers or tissues of the body (but not placenta). ◦Multipotent - can produce a family of cells in a tissue (e.g. haematopoietic stem cells, HSC, into blood cells); neural stem cells, NSC, into neurons and glial cells). Sub-level: oligopotent (lymphoid) ◦Unipotent - can produce (differentiate) only one cell type (lineage specific), but have the property of self-renewal (germ line, epidermal) ◦Classification of stem cells based on their differentiation potential  Types of stem cells (where and when): ◦Embryonic stem cells (ESC) that exist only at the earliest stages of development - pluripotent ◦Adult (or tissue-specific) stem cells that appear after foetal development and remain in our bodies throughout life - multipotent and unipotent ◦Induced pluripotent stem cell (iPSC) (from body to in dish) - pluripotent ◦Cord blood (umbilical) stem cells, rich in mesenchymal stem cells (MSC) and HSC - multipotent Roles of adult stem cells in regeneration: ◦"Regeneration' or replacement - the adult stem cells constantly replace the used cells ◦Healing (regeneration/repair) - the adult stem cells regrow for the regeneration and repair Adult stem cells in different tissues-role in healing: ◦Bone marrow-derived stem cell: ‣ Bone marrow produces multipotent haematopoietic stem cells (labile) ‣ Other stem cells from bone marrow - EPC, MSC ◦Stem cells have the potential to regenerate in physiological conditions and regrow cell/tissue in healing Regenerative capacity of cells - labile, stable permanent: Regenerative capacity of tissues: ◦3 groups of cells/tissues based on proliferative activity and the link to their stem cells. ◦1. Labile tissues - continuously dividing tissues e.g. skin epithelia, epithelia GI tract, haematopoietic tissue: ‣ Normal state is active cell division: G1 - M - G1  ‣ Usually rapid proliferation for regeneration from active stem cells ◦2. Stable tissues - quiescent tissue e.g. hepatocytes, osteoblasts, fibroblasts: ‣ Resting state - G0 (quiescent mature and stem cells) ‣ Speed of regeneration variable ◦3. Permanent tissues - non-dividing tissue e.g. neurones, cardiac myocytes: ‣ Unable to divide - G0 (terminally differentiated cells and no effective stem cells) ‣ No effective regeneration Fibrous repair/organisation: ◦Regeneration, or return of a tissue to a normal state following injury, is essential for restoration of full functionality and a ‘normal’ appearance to the injured tissue. ◦If, however, the collagen framework of a tissue is destroyed, if there is on-going chronic inflammation or if there is necrosis of specialised parenchymal cells that cannot be replaced then fibrovascular connective tissue will grow into the area, this is called fibrous repair or organisation. ◦Fibrous repair involves the following processes: ‣ Phagocytosis of necrotic tissue debris ‣ Proliferation of endothelial cells which results in small capillaries that grow into the area (angiogenesis) ‣ Proliferation of fibroblasts and myofibroblasts that synthesise collagen and cause wound contraction (the repair tissue at this stage is called granulation tissue) ‣ The granulation tissue becomes less vascular and matures into a fibrous scar The scar matures and shrinks due to contraction of fibrils within myofibroblasts. ◦The synthesis of collagen is essential to the fibrous repair process. Collagen is the most common protein in the animal world and 27 different types are known. It provides the extracellular framework for all multicellular organisms. Type I (fibrillar) collagen is the most common type in the body and is present in hard and soft tissues (bones, tendons, ligaments, skin, sclera, cornea, blood vessels and hollow organs). ◦Collagen consists of a triple helix of three polypeptide alpha chains with gly-x-y repeating sequence. Collagen is synthesised by fibroblasts and myofibroblasts in the following way: ‣ Preprocollagen is produced in the cell. This is modified to procollagen which takes on the triple helix form and is secreted from the cell. ‣ Procollagen is then cleaved to produce fibrillar collagen. There is considerable cross-linking between molecules which produces the tensile strength of collagen. ◦There are a number of diseases that you should be aware of that are due to defects in collagen synthesis: ‣ Scurvy – due to vitamin C deficiency. Vitamin C is required for hydroxylation of procollagen. People with scurvy are unable to heal wounds adequately and have a tendency to bleed as capillaries are fragile. ‣ Ehlers-Danlos syndrome – a heterogeneous group of six inherited disorders where the collagen fibres lack adequate tensile strength. Skin is hyperextensible, fragile and susceptible to injury and joints are hypermobile. Wound healing is poor and patients have a predisposition to joint dislocation. Because the collagen in internal organs is also affected, patients can suffer from rupture of the colon and, in some forms, large arteries. Corneal rupture and retinal detachment can also be seen. ‣ Osteogenesis imperfecta – also called brittle bone disease. Patients have too little bone tissue and hence extreme skeletal fragility. They also have blue sclerae as there is too little collagen in the sclerae making them translucent. They can also have hearing impairment and dental abnormalities. ‣ Alport syndrome – usually an X-linked disease. Type IV collagen is abnormal and this results in dysfunction of the glomerular basement membrane, the cochlea of the ear and the lens of the eye. Patients, usually male, present with haematuria as children or adolescents. This progresses to chronic renal failure. They also have neural deafness and eye disorders. Regeneration and repair in organs and tissues (local factors):  Factors controlling regeneration and repair- the mechanisms: ◦Cell to cell communication via: ‣ Local mediators (e.g. cytokines, growth factors - soluble signals) ‣ Systemic hormones (e.g. growth hormone) ‣ Direct cell to cell or cell to stroma contact ◦Growth factors are particularly important in wound healing: ‣ Polypeptides (local mediators and hormones) that act on cell surface receptors, stimulate transcription of genes that regulate cell proliferation and other effects. ◦Produced mostly by macrophages and other cells (local hormones) ‣ Epidermal growth factor (EGF) - mitogenic for epithelial cells and fibroblasts ‣ Vascular endothelial growth factor (VEGF) - induces angiogenesis ‣ Platelet derived growth factor (PDGF) - causes migration and proliferation of fibroblasts ‣ Tumour necrosis factor (TNF) - induces fibroblast migration, fibroblast proliferation and collagenase secretion. Cell-to-cell and cell-to-stroma and contact: ◦Signalling through adhesion molecules: ‣ Connexion and cadherins bind cells to each other ‣ Integrins bind cells to the extracellular matrix ◦Effect-contact inhibition - inhibits cell proliferation Applications of stem cells and regenerative medicine: ◦Regenerative medicine - a process of replacing, engineering or regeneration cells, tissues or organs to restore or establish normal function.  ◦Cell therapy: ‣ Original cells (blood transfusion) ‣ Lab (ex vivo) expanded cells ---> healing? ◦Stem cell therapy: ‣ Stem cells from embryo (e.g. cord blood) ---> from adult (bone marrow) ‣ Induced stem cells from adult Clinical application of stem cells for regeneration and repair: ◦Skin tissue regeneration for burn injury ◦Further applications - similar principle for other cell types Cord blood stem cells and potential application to regeneration and repair: ◦Functions of MCS and other stem cells (when transplanted to the body): ‣ Differentiate and replace the cells ‣ Promote other cells regeneration ‣ Rejuvenate aged stem cells Induced pluripotent stem cells (iPSC) and potential applications: ◦Personalised medicine/precision medicine ◦Overcome tissue rejection issue Clinical applications of stem cells: ◦Pros: ‣ Medical benefits-regeneration and repair ‣ Diseases curing (including gene correction) ‣ Research for human disease  ‣ Drug testing on human cells ◦Cons: ‣ Uncertainty of long term effect-need research ‣ Potential tumour growth ‣ Tissue rejection ‣ Ethical and legal aspects Wound healing in control: ◦Beneficial factors: ‣ Healing wound: Cell proliferative capacity (labile) Growth factors (controlling) Clean and small wound (local) Young (systemic) Nutrition, Vc (systemic) ◦Negative factors: ‣ Chronic wound: Permanent cell Cell-to-cell contact (controlling) Infection Large wound Aged Drug