Regeneration and Repair Part I Flashcards
Regeneration leads to
restoration of lost/damaged tissue and return to normal state
Repair
restore original tissues but results in architectural changes and deposition of fibrous scar
what types of cells undergo regeneration
tissues with high proliferative capacity:
- hematopoietic cells
- skin
- GI epithelium
regeneration is dependent on the presence of what type of cells
pluripotent stem cells
repair combines regeneration of native tissue with
scar formation/fibrosis
the extent of repair is dependent on
the type and degree of injury
inflammation contributes to scar formation through production of
growth factors and cytokines
what is the function of ECM components (ie. collagen)
provides a framework needed for cell migration, angiogenesis and repair
cell numbers are controlled by balancing
- proliferation
- differentiation
- death
proliferation
physiologic or pathologic stimuli regulate cellular proliferation and tissue growth
differentiation
terminally differentiated cells are incapable of replication. After death, new cells may be generated by stem cells
cell death/apoptosis
genetically determined cell destruction required for tissue homeostasis
what are the 3 different proliferative activity of tissue
- liable (continuously dividing)
- stable (quiescent)
- permanent (non-dividing)
liable tissue
rapid replication allows replacement of dead cells with newly formed ones
examples of liable tissues
surface epithelium GI and GU tract, hematopoietic cells
stable tissues
limited replication under normal homeostasis (quiescent, Go) may replication in response to stimuli
examples of stable tissue
parenchymal cells of liver, kidneys and pancreases; mesenchymal cells
what are parenchymal cells
functional tissue o an organ as distinguished from the connective and supporting tissue
what is quiescent
in a state or period of inactivity or dormancy
permanent tissues
cannot undergo mitotic divisions
examples of permanent tissues
neurons, skeletal and cardiac muscle cells. Injured cells are replaced by system supportive elements (ie. glial cells in CNS) or scarring (fibrosis)
what are stem cells
cells capable of self-renewal and differentiation
what are the 2 mechanisms that stem cells maintain their number
- obligatory asymmetric replication
2. stochastic differentiation
what is obligatory asymmetric replication
-with each stem cell division, one daughter cell retains its self-renewing capacity (new stem cell) while the other enters a differentiation pathway
what is stochastic differentiation
-each stem cell division generates EITHER two self-renewing stem cells OR two cells that will undergo lineage differentiation
what are the 2 types of stem cells
- embryonic stem cells
2. adult (somatic) stem cells
embryonic stem cells are induced by
pluripotent stem cells
where do embryonic stem cells reside
in the inner cell mass of blastocysts during the early stages of embryonic development
embryonic stem cells regenerate what kind of tissue
any/all tissues of the body (Pluripotent)
as embryonic stem cells differentiate they give rise to
multipotent stem cells and differentiated cells of the 3 embryonic layers
how do you prevent embryonic stem cell rejection
immune rejection can be prevented if stem cells contain the patient’s genetic material
describe the process of embryonic stem cell treatment
- transfer of cell nucleus to enucleated oocyte
- induced pluripotent stem cells (iPS cells):
- adult cells undergo activation of genes responsible for pluripotency
what is the purpose of stem cell therapy
use cells to replace damaged or genetically defective cells (sickle cell anemia)
function of adult (somatic) stem cells
-allow regeneration (and homeostasis) in liable tissues (ie. bone marrow, skin, GI tract)
adult (somatic) stem cells give rise to what type of cells
progenitor cells which are lineage restricted and no longer have the ability to self-renew
where do adult (somatic) stem cells residue
in special micro environments (niches) that support transmission of regulatory stimuli that directs stem cell self-renewal and generation of daughter cells
where do hematopoietic stem cells (HSC) generate all cell lineages
in the bone marrow
after disease, radiation or chemotherapy —– cells are able to repopulate all blood elements
hematopoietic stemm cells (HSC)
what is the most important clinical use of hematopoietic stem cells
- in the treatment of leukaemia/lymphoma
- stem cell transplantation
where are skin stem cells present
in the hair follicle bulge, interfollicular areas of the surface epidermis and sebaceous glands
function of skin stem cells
replenish the surface epidermis after skin wounding
epidermal stem cells are tightly regulated by what
growth factors and cytokines
function of cell cycle and replication
allows tissues to maintain homeostasis and to replenish cells during tissue regeneration and repair
Phases of Cell Cycle
G1 (presynthetic)
S (DNA synthesis)
G2 (premitotic)
M (mitotic)
what phase are quiescent cells in
remain in Go (not entered the cell cycle)
what are check points
prevent errors/maintain tissue homeostasis by halting the cell cycle if DNA is damaged
G1 entrance
transition into G1 (from Go or M) induced by growth factors
G1/S checkpoint
- the restriction point, is a rate-limiting step
- monitors DNA integrity BEFORE replication
G2/M checkpoint
monitors DNA AFTER replication and allows entry into M phase
what cells are key players in the checkpoint system
cyclins and cyclin-depdent kinases (CDKs)
function of cyclins and CDKs
they phosphyorylate target proteins which in turn stimulate transcription of cell cycle genes –> CELL CYCLE PROGRESSION
how do cyclins and CDKs gain catalytic activity
by forming complexes
function of growth factors
bind cell surface receptors and regulate key physiologic processes (such as proliferation, cell survival, locomotion, angiogenesis)
what begins the intracellular signalling cascade of
formation of ligand-receptor complex
what are the 3 signalling mechanisms among cells
- autocrine
- paracrine
- endocrine
autocrine
cells secrete their own ligand (autocrine loop)
paracrine
one cell type produces a ligand that binds to receptors on adjacent target cells
endocrine
hormones are synthesized by endocrine cells and travel through the circulation to distant target cells
the type of cellular receptors determines the mechanisms of
signal transduction
what are the different types of cellular receptors
- receptors with intrinsic tyrosine kinase activity
- receptors lacking intrinsic tyrosine kinase activity that recruit kinases
- G protein-coupled receptors
- Steroid hormone receptors
where do receptors with kinase activity reside
on the cel surface
what activates the receptor tyrosine kinase
ligand binding which induces dimerization and tyrosine phosphorylation
function of the active kinase
phosphorylates downstream effector molecules that transmit the signal to the cell nucleus
receptors with kinase activity used by
most growth factors (EGF, TGF-a, HGF, PDGF, VEGF, FGF)
GF signalling…think kinase receptors!!!!
describe receptors without kinase activity
- ligand-receotor binding recruits extrinsic kinase (ex. JAK)
- JAKs bind the receptors, activate signal transducers (STATs) through phosphorylation
- STATs enter the nucleus and activate gene transcription by directly binding DNA
receptors without kinase activity used by
- interleukins
- interferons
- growth hormone
what are G-protein coupled receptors
composed of seven transmembrane alpha helices that signal through GTP-binding proteins
function of p53
inhibit cell cycle progression (TUMOR SUPPRESSOR GENE = growth inhibiting)
G-proteins get activated by
guanine nucleotide exchange factor (GEF)
GDP –> GTP
G protein coupled receptors are the largest family of
plasma membrane receptors
G protein coupled receptors are common — targets
pharmaceutical targets
where do steroid hormone receptors reside
in cell, in cytoplasm of nucelus
steroid hormone receptors function as
ligand-depdent transcription factors
ligand activated receptors bind to
- specific DNA sequences (hormone response elements) in target genes
- interact with other transcription factors
steroid hormone receptors bind to
- estrogen
- thyroid hormone
- Vit D
growth hormones induce activity of
transcription factors
function of transcription factors
bind to DNA and allow transcription of adjacent genes
what are the important transcription factors that regulate cell proliferation
c-MYC and c-JUN
P53
function of c-MYC and c-JUN
induce cell cycle (ONCOGENE = growth promoting)
extensive regeneration of the liver only occurs if
the basic connective tissue framework is uninjured
partial hepatectomy triggers
cytokine signaling that forces the remaining hepatocyte to reenter the cell cycle and proliferate
when is the liver able to regernate
after partial hepatectomy (up to 60% can be removed)
which parenchumal organ does not have a limited regeneration capacity
liver
function of p53
inhibit cell cycle progression (TUMOR SUPPRESSOR GENE = growth inhibiting)
function of the active kinase
phosphorylates downstream effector molecules that transmit the signal to the cell nucleus
