nemoci-sympt/DERMATOLOGIE/jizvy-hojeni/redukce-jizveni
Inhibice YAP proteinu
- Stanford scientists genetically tweaked mice to not express the YAP protein in fibroblasts. Those mice (middle and bottom rows) regenerated skin, including hair follicles and sweat glands.
MASCHARAK ET AL., SCIENCE 2021 -www.statnews.com/2021/04/22/scientists-unlock-key-to-scar-free-skin-healing/
- Scar-producing cells actually arise from another population of fibroblasts that don’t produce engrailed-1, and instead regenerate healthy skin. It’s only when the animal gets wounded that the gene flips on. Longaker, a pediatric plastic surgeon who directs the program in regenerative medicine at Stanford, said the group hypothesized that the trigger might be mechanical — the force of the skin splitting apart.
So the group studied how fibroblasts responded to a variety of different mechanical cues. When they were grown in soft substrates they didn’t flip on engrailed-1. The researchers also messed with the tension of wounds in mice and found the same thing. And they noticed that as they applied more tension, the fibroblasts produced more of a protein called YAP. They wondered if maybe it was the key chemical signal for kicking off scarring.
To test that, they blocked YAP a few different ways: first, by genetically modifying mice to not express it in their fibroblasts, and then, with a YAP-disrupting chemical called verteporfin. In both cases, the cells that flooded into each mouse’s wound weren’t the scar-producing EPFs, but the other kind of fibroblast, the one that tells the skin to regenerate, not just repair. “Discovering that YAP starts the fibrotic response, that was the last piece of the puzzle,” said Longaker.
Mice treated with the YAP-blocker not only grew back hair follicles and glands within 30 days, their new skin also recovered normal collagen structure. And when tested for mechanical breaking strength, it was comparable to normal skin.
Related: Experimental vaccine patch embeds invisible dots under the skin, leaving record of immunizationWashington State’s Driskell sees the discovery as more of a beginning than the end. “If we want to get to full regeneration we have to understand how all these sub-populations of fibroblasts work together to rebuild the tissues properly,” he said. While Longaker’s group catalogued the return of some skin structures, it wasn’t a complete list. More work will need to be done to see if YAP-blockers can turn on all the signals needed to regrow everything healthy skin needs to function, such as temperature- and pressure-sensing nerves. “There’s always more to it,” said Driskell. “But I think it’s definitely worthwhile to move to the next step and try some clinical trials.”
Over the last decade, several companies have sought to commercialize wound-healing therapies — spray-on skins and living sheets of stem cells. But none has yet achieved scar-free healing. Verteporfin, if it works in humans, would be the first. It’s already on the market, sold under its brand name Visudyne. The U.S. Food and Drug Administration approved it in 2000 for treating age-related macular degeneration. That should make it easier to move from testing it in pigs to human trials.
Longaker envisions a time when doctors will be able to inject a bit of verteporfin around a laceration or incision as they stitch it up, encouraging the wound to repair itself slowly, carefully, and completely. That’s scar prevention. But Longaker said the drug might be able to erase old scars too. It would require some minor surgery to cut the damaged tissue out and inject the verteporfin in. But for particularly disfiguring or painful scars that limit people’s mobility, the procedure might be an attractive option.
It’s this future that got Atit so excited she began bombarding her children with fibroblast chat over breakfast this week. “I told them, ‘Guys, this means you will not have scars in your lifetime,’” she said.
Scars are more than just disfiguring. You lose sweat glands and nerves and other critical ways of sensing and responding to the world around you. “Right now the best we can offer people is little bits of skin, but there’s nothing in it — no hair follicles, no blood vessels, no nerve endings,” said Atit. “To be able to give people the ability to regenerate their own skin, which is where this is heading, it’s really just beyond exciting.”
About the AuthorReprintsMegan MolteniMegan MolteniScience Writer
Megan Molteni reports on discoveries from the frontiers of genomic medicine, neuroscience, and reproductive tech. She joined STAT in 2021 after covering health and science at WIRED.
Megan.molteni@statnews.com
@MeganMolteni
Successful human scar regeneration by topical iodine: a case report: an interim (3.5 year) summary
Case Reports Med Hypotheses, 2009 May;72(5):553-61. doi: 10.1016/j.mehy.2008.11.038. Epub 2009 Jan 24., David M Derry 1, PMID: 19168293 DOI: 10.1016/j.mehy.2008.11.038
- 1997, topical Lugol's iodine solution applied daily for 3 days to a 50 year old facial scar
- Lead to hyperemic scar tissue
- Author proposed topical iodine could initiate, control and complete human scar regeneration
- 2005, after collecting three more surgical scars, topical iodine applications began
- Within 3 days all four scars started regenerating
- Stopping topical iodine halted the process
- Within a week an appropriate adult scar formed
- Digital cameras recorded events
- Appearance depends on whether scar is covered with plastic or open
- Topical iodine induces hair growth in and around scars
- Hair is regeneration's workhorse, moving purposefully in all directions under arrector pili muscle power delivering regenate material accurately to scar tissues and coordinating centers
- Hair repeatedly self amputates possibly strengthening regenerating tissues
- Two types of regenate material show under plastic wrap: white and globular
- White regenate appears and behaves somewhat like snow, but can be yellow, green or brown depending iodine content
- The globular form of regenate material maybe derived from white regenate material with hair's help
- Globular regenate material is larger, nondescript, variable in size and color (depends on iodine content) and seemed usually associated with hair.
- There are two centrally placed coordinating centers 5 mm apart on major scars
- Wrist centers have a palpable, but not visible ridge, between them whereas abdominal centers do not.
- Wrist centers lasted through all regeneration of the wrist scar, whereas abdominal centers were only present for about 18 months before falling off.
- This paper summarizes and adds to previous preliminary reports.
- The 50 year old scar regenerated completely 2 years ago.
- Small experiments on regeneration are possible because it is a slow process and more importantly can be stopped and started at will
- These results support the proposed hypothesis topical iodine initiates, controls, and completes human scar regeneration.
Topical Lugol's iodine solution
- Applied daily for 3 days to a 50 year old facial scar
- Lead to hyperemic scar tissue
- Author proposed topical iodine could initiate, control and complete human scar regeneration
- 1997
- 2005, after collecting three more surgical scars
- Topical iodine applications Within 3 days all four scars started regenerating
- Stopping topical iodine halted the process
- Within a week an appropriate adult scar formed
- Digital cameras recorded events
- Regeneration is complex and slow
- no visible signs detectable changes from oral iodine on regeneration
- Topical iodine induces hair growth in and around scars
- Hair is regeneration's workhorse
- Delivering regenate material accurately to scar tissues and coordinating centers
- Hair repeatedly self amputates possibly strengthening regenerating tissues
- Under plastic wrap: white and globular.
- The white regenate appears somewhat like snow
- Can be yellow, green or brown depending iodine content
- Globular form of regenate material
- Maybe derived from white regenate material with hair's help
- Larger, nondescript, variable in size and color usually associated with hair
- 50 year old scar regenerated completely 2 years ago
- The scar tissue was white. Its appearance had not changed in 50 years.
- Even after on and off trials of treatments this regeneration took about a year or so to complete but the author continued to apply iodine to the area.
- Terminally all visible and palpable evidence of scar tissue disappeared
Facial Plast Surg Clin North Am. 2011 Aug;19(3):481-9. doi: 10.1016/j.fsc.2011.06.004. PMID: 21856536 Review. pubmed.ncbi.nlm.nih.gov/19168293/
- In 1993 Ghent and Eskin
- Treatment for fibrocystic breast disease with oral iodine
- Treated patient’s with fibrocystic disease successfully using Lugol’s iodine solution
- 1997
- Applied Lugol’s iodine daily topically to a 50 year old facial scar
- Unchanged since removal of a large birth mole by a plastic surgeon
- Three days of iodine applications had no visible effects but on day 4 – white scar tissue became hyperemic
- During 8 years between iodine applications, the author had three surgical interventions for diverticulitis resulting in three more scars
- 2005 there were four scars to try Lugol’s iodine on
- Lugol’s iodine contains three chemical species of iodine
- Free iodine (elemental),
- Iodide and tri-iodide
- Henri Lugol discovered free iodine
- Barely soluble in water
- Can be made soluble if iodide is added
- Lugol’s contains:
- 5% free iodine
- 10% potassium iodide in water
Triamcinolone acetonide (TA) has a regulatory effect on TGF-ß1 in keloids by decreasing fibrotic gene expression and down-regulating pro-fibrotic genes and extracellular matrix (ECM) regulators such as TGF-ß1, collagens, and integrins [4]. Intralesional injection of TA in combination with 5-fluorouracil (5-FU) interrupts the differentiation trajectory of fibroblasts towards pro-fibrotic subtypes, possibly inhibiting the FGF signaling pathway in intercellular communication [1]. Additionally, TA reduces collagen synthesis, alters extracellular matrix components, and increases pro-inflammatory mediators, ultimately affecting the expression of ß-fibroblast growth factor (ß-FGF) [2]. Furthermore, a study comparing TA alone to a combination of TA and 5-FU found that the combination therapy was superior in improving various parameters of keloids, indicating the effectiveness of TA in conjunction with other agents in keloid treatment [3].
