Home » The secret of longevity is in the genes (Part 2)-PanSci

The secret of longevity is in the genes (Part 2)-PanSci

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“Doctor, does this leave scars?” Presumably this is one of the most concerned issues for many people after trauma and surgery. After all, the appearance of scars is obviously different from the original skin. If it is not handled well, it is easy to attract people’s attention.Therefore, how to effectively remove scars has always been an important challenge in wound care, and it was recently published in Science The above research provides a real possibility of removing scars1

What happened when we were injured physically?

If you want to remove scars, you must first understand how the scars come from. To know where the scars come from, you must start with wound healing.

When the integrity of human tissue is damaged by various external forces (such as cutting, puncture, etc.), wounds will be caused.When the human tissue has a wound, it will initiate the complex physiological process of wound healing, which involves the coordination of various cells and physiological reactions.2. Wound healing can be divided into three stages:

(1) Inflammation stage: inflammation and scab.

When the wound is produced, the cells in the wound will immediately produce various cytokinesCause inflammation, Attracting immune cells to fight the infection of foreign bacteria. At the same time, due to the rupture of blood vessels in the injured part, platelets will go to the wound to promote the formation of thrombus and seal the wound to reduce the wound from more injury and infection.

(Two) proliferative periodGranulation tissue fills the wound

At this stage, the wound is filled by the growth of “granulation tissue”.

The granulation tissue is composed of newly formed capillaries, fibroblasts, various immune cells, and collagen secreted by fibroblasts.After the granulation tissue is covered with new “epidermal cells”, That is, after the wound has closed its contact with the outside world, it will enter the next stage.

After injury, the process of wound healing can be roughly divided into three stages. Photo/Pixabay

(3) Remodeling period: collagen and fibrocytes form scars

Although the appearance of the wound has healed at this stage, there is still a lot of work on the granulation tissue inside the wound.

At this time, the microvessels and immune cells in the granulation tissue will gradually decrease, and the fibroblasts will gradually differentiate into fibroblasts. These actions can make the vacancies in the granulation tissues and provide more space for the collagen secreted by the fibroblasts.

Collagen and fibrous cells will also restructure and arrange in the tissue to make the tissue firmer, further shrink the wound while increasing the ability to resist external forces, and this new tissue is what we call the “scar.”

The three stages of wound healing: (a) inflammatory period (b) proliferative period (c) remodeling period. Figures/References 2

Scars have no hair follicles, sweat glands, and elasticity

Both the appearance and the inside of the scar are different from the original tissue.

Take skin as an example. Normal skin must contain hair follicles, sweat glands and other accessory organs, but these scars are all absent. In addition, because the arrangement of collagen and fiber cells inside scars is different from that of normal skin, the elasticity and strength of scars are not as good as normal skin. For example, large scars on joints such as knees and elbows often make it difficult to bend.

It should be noted that scars are a natural product of wound healing and cannot be avoided!

Although many small abrasions of the skin only damage the epidermal layer, after healing, it looks like the original skin, but in fact, it still produces scars.It’s just that these scars don’t fill the wound much and are not obvious, so we will “misunderstand” that there is no scarHowever, when our body has deep wounds such as the “dermis”, the filling of the wound by scar tissue is obvious.

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Scar removal products are not true “scar removal”

therefore,All kinds of scar removal products and methods on the market can only make the scars closer to the surrounding skin tissues in the “appearance”, but can not really eliminate the scars.! Scar removal in the true sense must be done at the stage of wound healing so that scar tissue will not form.

If you want to have no scars, you must deal with it properly during the healing period! Figure/Wikipedia

However, as mentioned earlier, wound healing is a very complex physiological response, and it is not until these few years that we have a deep understanding of the molecular mechanism.2.The recent article published by the research team of Stanford University not only reveals the key molecular mechanism behind scar formation, but also provides the possibility of wound healing without leaving scars.1

Fibroblasts: the key to scar formation

It can be seen from the three processes of wound healing that “fibroblasts” occupy a key position.

In addition to being responsible for the formation of granulation tissue, fibroblasts also secrete a large amount of collagen during the remodeling phase of the wound. At the same time, they also differentiate into fibroblasts. The remodeling of collagen and fibroblasts makes scar tissue more Tight.

In 2015, the team published a study showing that there are two types of fibroblasts involved in the wound healing process, which are the expression of Engrailed-1 (EN-1) and the non-expression of Engrailed-1 (EN-1).Note 1 Protein fibroblasts:

  1. Cells that do not express Engrailed-1 (Engrailed-1 Negative Fibroblasts, ENFs)
  2. Cells that express Engrailed-1 (Engrailed-1 Positive Fibroblasts, EPFs).

Among them, the EPFs that express Engrailed-1 areThe main cells that form scars3

First, the research team found that ENFs in mouse wounds would be converted into EPFs during wound healing, producing more EPFs.

There are both ENFs and EPFs in mouse skin, but in the stage of wound healing, ENFs will be converted into EPFs. Figure/Reference 1

Why would ENFs become EPFs? It’s an external force!

After knowing the source of EPFs, they then wanted to understand what “factors” stimulated the conversion of ENFs into EPFs.

Since one of the functions of fibroblasts in the organism is to sense various mechanical external forces, and after feeling the external forces, change the gene expression of the cells to cope with the external forces, so the research team speculates:

The factor that stimulates the conversion of ENFs into EPFs in the wound isThe “mechanical external force” caused by the change in elasticity of the skin after injury」。

In order to confirm this idea, they purified ENFs and cultured them in three different experimental environments with different mechanical external forces. The results showed that fibroblasts not only can sense different mechanical external forces, but also under different external forces, the cells behave differently:

  1. Under low mechanical external forces, ENFs will not be converted into EPFs
  2. Under high mechanical external forces, ENFs will be transformed into EPFs
  3. After blocking the mechanical external force signal in ENFs, ENFs will not be transformed into EPFs even under high mechanical external force
ENFs will not be converted to EPFs under low mechanical force culture (3D Hydrogel); they will be converted to EPFs under high mechanical force (TCPS), and this conversion can be reversed by the mechanical signal blocker (Y-27632). Figure/Reference 1

Scientists have also obtained similar results in mice experiments. When tension is applied to the wounds of mice, the number of EPFs in the wounds healed will increase. At the same time, the scar tissues of the mice will also be thicker. This result can also be The mechanical signal blocker reverses.

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Cut off the signal!Not telling cells that the wound is stressed

The above experiment confirmed that mechanical tension can stimulate fibroblasts to express Engrailed-1 and promote scar formation. If the transmission of the mechanical tension signal is blocked, can scar formation be prevented?

Following this idea, the researchers found a drug Verteporfin approved by the US FDA for the treatment of eye diseasesNote 2, Verteporfin can block key proteins that cells use to sense mechanical signals, and achieve the ability to block the transmission of mechanical signals.

Experiments in mice have shown that adding Verteporfin to the wound is “very effective” for wound healing!

As mentioned earlier, scars do not produce skin appendages such as hair follicles and sweat glands, and their elasticity and strength are also poor. But after adding Verteporfin, the healed wound can not only grow hairs, but also sweat glands can function normally, and its elasticity and strength are equivalent to normal skin. When observed under a microscope, it is impossible to distinguish the difference between the healed wound and the original skin.

In addition, from the molecular level, the number of EPFs in healing wounds without Verteporfin is much higher than that of healing wounds with Verteporfin, showing that Verteporfin can indeed inhibit the expression of Engrailed-1 in fibroblasts.

Verteporfin can make hair grow from healed wounds. Figure/Reference 1

Based on the above results, the research team sorted out the molecular mechanisms and factors that affect scar formation:

The large number of Engrailed-1 in fibroblasts is a key factor in scar formation. The mechanical tension at the wound can stimulate fibroblasts to express Engrailed-1 in large quantities. As long as the stimulation of this mechanical tension is inhibited, the performance of Engrailed-1 can be effectively inhibited and the mice can achieve “scar-free healing” at the wound.

The research team revealed the molecular pathways and factors that influence scar formation. Figure/Reference 1

How to heal without leaving scars?Researching problems for thirty years

The host of the research team, Professor Michael T. Longaker, is a plastic surgeon. In 1987, when Longaker was still in the fetal surgery operating room, his mentor gave him an assignment: Why can the wound on the fetal skin leave no scars? Healing, but the skin of children and adults can’t do it?

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“I thought about this question for a year, then it became four years, and then it became a few decades later. Since then, in order to answer this question, my research has expanded to many other areas. I always want to know how scars are formed Yes!” Professor Longaker said4

By studying the results of this article, we can now get a glimpse of the possibilities:The fetal skin is not as elastic as children and adults, so the skin will not produce mechanical tension due to changes in elasticity after injury. In the absence of external mechanical stimulation, the fibroblasts in the fetal wound will naturally not express Engrailed-1, and scarless healing can be achieved.

In the future, scars may be rare!

If the findings of this study can be applied to other tissues, medical wound treatment will bring a very big breakthrough. After all, scars in other tissues are also “different from” the original tissue, and too many scars will seriously affect The function of tissues and even organs, such as the fibrosis of the heart and liver after damage. If scar-free healing can be achieved through this mechanism, it will be the gospel for many patients!

However, before entering clinical trials, more tests must be carried out in animal experiments, and the research team also stated that they have begun research in this area.

Perhaps in the future, leaving no scar on the wound is the standard process of wound care. Scars are no longer something that needs to be covered. Scars may be a cool and rare thing!

Annotation

  1. Engrailed-1: This protein is currently believed to be related to growth and development, and is involved in the development of nerves, bones, and limbs.
  2. Verteporfin: It is a drug for the treatment of typical or latent subfoveal choroidal angiogenesis caused by macular degeneration. Simply put, it is a drug that inhibits abnormal angiogenesis.

Reference

  1. Mascharak S, desJardins-Park HE, Davitt MF, Griffin M, Borrelli MR, Moore AL, Chen K, Duoto B, Chinta M, Foster DS, Shen AH, Januszyk M, Kwon SH, Wernig G, Wan DC, Lorenz HP, Gurtner GC, Longaker MT. Preventing Engrailed-1 activation in fibroblasts yields wound regeneration without scarring. Science. 2021 Apr 23;372(6540).
  2. Gurtner, G., Werner, S., Barrandon, Y. et al. Wound repair and regeneration. Nature 453, 314–321 (2008).
  3. Rinkevich, Yuval et al. Skin fibrosis. Identification and isolation of a dermal lineage with intrinsic fibrogenic potential. Science flight. 348.6232 (2015): aaa2151.
  4. http://med.stanford.edu/news/all-news/2021/04/drug-enables-healing-without-scarring.html

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