What you should know about cell proliferation

Tissue renewal & cell proliferation

Research in the area of regenerative medicine has established hope in the use of stem cells to develop least diving cells. Tissue renewal can be defined by how they can regenerate or repair themselves after damage.

Regeneration is the proliferation of cells to completely replace damaged structures. Repair is the formation of scars in combination with cell proliferation to replace damaged structures. Cells proliferate due to the action of hormones & stimulating agents. E.g. action of estrogen on uterus during menstruation. Tissues are divided by their proliferative capacity: Labile, quiescent, & permanent tissues.

Labile tissues have continuously dividing cells which include: Epidermis, epithelium of oral cavity, vagina, and cervix; columnar epithelium of uterus, G.I tract; excretory ducts of pancreas, salivary gland, & biliary tract; transitional epithelium of the urinary tract; bone marrow cells & hematopoietic stem cells.

Quiescent tissues have least dividing cells, but can replicate to normal size in response to injury. They include: Liver; pancreas; kidney, endothelium, leukocytes; fibroblast; smooth muscle cell; adipocytes, osteocytes; chondrocytes. E.g., regeneration of liver after partial hepatectomy. Permanent tissues are incapable of dividing in the adult life. E.g. Skeletal muscle; cardiac muscle; neurons. If any regenerative capacity, it could by help of complementary cell such as satellite cell in skeletal muscle

Stems cells and cell cycle

Stem cells are self-replicating cells that can differentiate into different cells lineages. To ensure their continuity throughout life, they must either be involved in an obligatory asymmetric proliferation or stochastic differentiation.

In an obligatory asymmetric replication, dividing stem cells keep one daughter cell for self-renewable purposes, while allowing others to differentiate into cell lineages. Stochastic differentiation ensures dividing stem cell to either keep 2 self-renewing cells or 2 cells that will differentiate.

Examples of adult stem cells: Hematopoietic and Mesenchymal stem cells of the bone marrow; oval stem cells of the liver; bulge stem cells & interfollicular stem cells of the skin; intestinal stem cells; satellite cells of the skeletal muscle; limbic stromal cell of the cornea.  

In normal homeostatic conditions, epidermis replicates every 4 wks. HSC is obtained from bone marrow, umbilical cord blood, & peripheral blood of patients receiving granulocyte-monocyte colony-stimulating factor.

Cell cycle is a well-regulated sequence of events to enable a successful cell division. It includes: G0 (quiescent phase); G0/G1 (transition phase); G1(DNA pre-synthesis); G1/S checkpoint; S (DNA duplication); G2 (pre-mitosis); G2/M checkpoint; M (mitosis). 

The G0 phase is basically for quiescent tissues. Labile tissues go directly from Mitosis to G1 phase. G1/S check-point monitors damaged DNA before they duplicate. G2/M check-point monitors damaged or unduplicated DNA before they divide. Activated cyclin-dependent kinases activates a transcription factor “E2F” which stimulates gene transcriptions that maintains the cycle.  

Growth factors

Important growth factors with their corresponding receptors include:

1. Epidermal Growth Factor- EGF/EGFR: Among other cells, it is produced by keratinocytes for cell division in epithelial cells, hepatocytes and fibroblasts.
2. Transforming Growth Factor Alpha- TGFα/EGFR: Also produced by macrophages, enables hepatocytes & epithelial cells proliferation.
3.  Hepatocyte Growth Factor- HGF/c-MET: Produced by mesenchymal cells, it enables proliferation of hepatocytes & epithelial cells of lungs, kidneys.
4. Platelet Derived Growth Factor- PDGF/PDGFR: Made from platelets and stimulates migration & proliferation of fibroblasts.
5. Vascular Endothelial Growth Factor-VEGF/VEGFR-2: Produced by many cells, this enables vasculogenesis and angionesis in wound healing.
6.  Fibroblast Growth Factor- FGF/FGFR: Produced from fibroblast, this enables fibroblast & keratinocyte proliferation with angiogenesis.
7.  Transforming Growth Factor Beta- TGFβ/TGFR: Among other cells, it is produced by the endothelium, macrophages. It inhibits epithelial cells proliferation & also attracts fibroblasts for wound healing.

The plasma membrane receptors

Growth factors are known for how they act on their target organ receptors. Common signaling patterns include: Autocrine (self), paracrine (adjacent) & endocrine (distant) signaling. Ligands bind to receptors such as: Tyrosine kinase; G-protein, & steroid hormone receptors and others. These ligands cause synthesis and activation of transcription factors such as: JUN, FOS & STAT.

Growth factors & vaso-peptide insulin hormone activate tyrosine kinase receptors by phosphorylation. Their activation triggers downstream effector molecules such as: mitogen-activated protein kinase (MAP kinase); phospholipase Cγ (PLCγ); inositol triphosphate (IP3); phosphatidyl inositol-3 kinase; & protein kinase C (Akt).

Together, these effector molecules cause the production of transcription factors needed for cell proliferation and survival.

The G-protein coupled receptors are the largest family of membrane receptors. Chemokines, vaso-peptide mediators, vasopressin, rhodopsin ligand (11-cis retinal), corticotropin, glucagon, parathyroid hormones activate this receptor.

Their activation produces cyclic adenosine monophosphate (cAMP) which causes multiple effects including transcription. Inherited defects in signal transduction results in retinitis pigmentosa, corticotropin deficiency and hyperparathyroidism.

Steroid hormones, thyroid hormones, retinoid & vit D activate steroid hormone receptors in the nucleus. Their activation results in their binding to specific DNA sequences.

Ligands such as cytokines (IL-2, IL-3), growth hormones, prolactin, interferon γ, erythropoietin act on specialized JAK-coupled receptors. These receptors are connected with Janus Kinase (JAK) family of proteins. They then activate a transcription factor called, signal transducer & activation of transcription (STAT) that acts on DNA.