Friday, March 12, 2010
Heparin Nanofibers Loaded with VEGF and FGF Mimic Stem Cells
In previous articles, I have emphasized the mediation of extracellular signaling by heparan sulfate proteoglycans (HSPGs, polysaccharides attached to proteins) and heparin (HS fragments, oligosaccharides) and the sensitivity of HSPG expression and HS degradation by inflammation. I return to that subject, spurred on by reading two articles that together show both the significance of heparin-mediated growth factors in general and in the specific case of symptom development in rosacea.
FGF Receptor Inhibitors Cause Symptoms Like Rosacea
Fibroblast growth factors stimulate the development of cancers, and antibodies against FGF receptors block cancer growth (see ref.) FGF receptor inhibiting antibodies are now being used to stop cancers. Unfortunately, FGFR antibodies (e.g. cetuximab, panitumumab) also cause symptoms in the skin (telangiectasia, acneiform eruption) similar to the facial inflammation of rosacea. Similarly, in knock-out mice, that lack the ability to produce FGFR, there are related symptoms. It appears that lack of some FGF signaling may produce the symptoms of visible blood vessels and pus-filled (though lacking bacteria) follicles of rosacea.
FGF Mediated by HSPG
FGF binds to the heparan sulfate of membrane bound HSPG in pairs and these FGF dimer/heparan sulfate complexes activate a pair of FGF receptors. The result is activation of protein phosphorylation activity (tyrosine kinase) and normal skin development. HSPG synthesis is modified by inflammation and heparanase activity is increased. This suggests that inflammation will decrease FGF signaling and could lead to symptoms of rosacea.
Growth Factors (VEGF, FGF) Bind to Heparin Nanofibers that Mimic Stem Cells
Stem cells produce lots of different growth factors and when stem cells are introduced into damaged cardiovascular tissue, more healing results (see ref.) To determine if the growth factors produced by the transplanted stem cells was sufficient for the improved healing, fibers made of heparin were dipped into stem cell cultures and the resulting growth factor-coated fibers were injected into damaged tissue. The heparin-binding growth factors were just as effective at enhancing healing as were the stem cells in previous experiments. This demonstrated that heparin-binding growth factors were the key to normal repair/revascularization and function.
Rosacea Results from Inflammation and Aberrant Vascularization
Rosacea is poorly understood and is probably numerous diseases that have related symptoms and complex development. As I indicated in previous articles, neurotransmitters from stimulated facial nerves, enzymes (kallikrein) and cytokines from intestinal interactions with gut flora, mast cell products (heparin, protease) and modified antimicrobial peptides (cathelicidins), as well as cryptic bacteria in facial tissues, may all be involved. Inflammation in the skin of the face and in the intestines is involved. Vitamin D, omega-3 fatty acids and anti-oxidants have a variety of responses (sometimes paradoxical) that differ from individual to individual and at different stages in the development of the disease. Facial inflammation leads to abnormal development of blood vessels (telangiectasia) and in accumulation of lymphocytes and neutrophils (papulopustular rosacea).
Facial Inflammation May Depress HSPG Production and Disrupt FGF Function
One of the key ramifications of persistent facial inflammation may be the depletion of of HSPGs that normally coat cells. HSPGs are continually produced, reabsorbed and degraded. The half-life for HSPGs, even those that surround the cells that produce cartilage in connective tissue, is six hours. HSPGs are also the source of heparin, that is produced as a counter ion bound to histamine and proteases in the secretory granules released by activated mast cells. Thus, inflammation-based depression of HSPG production, which is also accompanied by heparanase activation, will remove the HSPG coating of cells. This HSPG coating is needed for normal growth factor function. Lack of an HSPG matrix on the surface of cells will also result in the migration of growth factors away from where they are normally functional and into adjacent tissue where they may stimulate aberrant development of blood vessels. This may explain telangiectasia.
Is Topical Heparin a Rosacea Treatment?
Topical heparin does penetrate the skin. It would appear to be a logical treatment, if HSPG depletion is contributing to symptom development in rosacea. The length of the heparin fragments may be important. I am unaware if anyone has tried the heparin lotions that are available for treatment of wounds to minimize scarring, on rosacea. Heparin may be useful in combination with vitamin D3 and remediation of gut flora in a general scheme to treat rosacea.
Segaert S, Van Cutsem E. Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibitors. Ann Oncol. 2005 Sep;16(9):1425-33. Epub 2005 Jul 12.
Webber MJ, Han X, Prasanna Murthy SN, Rajangam K, Stupp SI, Lomasney JW. Capturing the stem cell paracrine effect using heparin-presenting nanofibres to treat cardiovascular diseases. J Tissue Eng Regen Med. 2010 Mar 10. [Epub ahead of print]