As the largest organ of the human body, the skin protects the human body from harmful substances from the outside. But because of this, the skin is also the most vulnerable part. Every year, 300,000 people worldwide die from skin wounds. Most of these people die from wounds that are difficult to heal and infect shock. Wound healing relies on basal keratinocytes, but such cells are often extremely absent from the wound. A new study published in the journal Nature found a solution: reprogramming other cells at the wound ulcer into stem-like cells to help the wound heal and re-grow new skin.
Large areas of skin ulcers pose a serious threat to life. For surgical incisions, ulcers caused by burns, and long-term chronic ulcers, wound healing ability is closely related to survival. The healing rate of the wound determines the patient’s secondary infection, physiological pain, call scar and other conditions; compared with acute ulcers, cases of chronic skin ulcers are also rising sharply, including pressure ulcers and diabetes-derived foot ulcers, affecting the global billion The quality of life of people.
The illustration shows the process of skin damage healing, from the wound stage (A) → inflammatory phase (B) → proliferative phase (C) → remodeling phase (D); this process requires a large number of primary keratinocytes involved in skin regeneration.
Current treatments for ulcers include relying on autologous intact skin grafts, which require secondary trauma to the patient and can be stretched when the ulcer surface is too large. Another method is to use the in vitro cultured skin stem cells for combined transplantation, but the skin rate is low, and the patient’s healing level is different. When the skin is not finished, the patient is infected by the ulcer surface. The medical community has also tried to accelerate wound healing and skin growth by applying epidermal growth factor (EGF) to the affected area, but the ulcer is often accompanied by a large inflammatory reaction, and these single-factor components are easily inactivated or cleared by the autoimmune system.
“Grows new skin in areas without skin”
Professor Juan Carlos of the Salk Institute of the United States has extensive clinical experience. He said that the most critical factor in the recovery of wounds is the efficiency of the transfer of keratinocytes to the wound. These cells have stem cell characteristics that can differentiate into different skin cell precursors and proliferate to cover the wound. However, a slightly larger area of ulcer does not have this condition because the cell is almost absent from the ulcer. Even if the wound heals, it will produce a large inflammatory response and will not maintain normal skin function. Therefore, there is a need for a method that can quickly and efficiently promote wound healing.
This week, a study led by Juan Carlos boarded the international top journal Nature. The paper pointed out that by simply transferring four epidermal growth-related factor combinations at the wound, other cells can be transformed into stem cell-like cells to achieve natural non-invasive healing of the wound, and the new skin function is the same as normal skin function. The first author of the article, Masakazu Kurita, called it: “Growing new skin in areas without skin.”
Traditional wound treatment (Up); reprogramming mediated wound treatment (below)
The research team selected four skin growth-related factors and introduced them into skin tissue through large-scale screening. Under the action of the combination factor, reprogramming of the mesenchymal cells at the wound can be achieved in the mouse, and then new skin tissue is re-grown at the wound to cover the ulcer wound. In the process, some of these factors can restore cells to a state similar to stem cells, while others are responsible for initiating cell proliferation and differentiation toward skin cells. This is many times stronger than the single factor growth factor addition.
“Our experiments have demonstrated for the first time the feasibility of recreating three-dimensional structures in vitro,” said Professor Juan Carlos. “This discovery not only contributes to skin damage repair, but can also serve as an example and can be replicated in other areas. In vivo tissue regeneration. For example, in the process of aging, tissue self-repairing ability has been impaired to achieve tissue regeneration.”
Four magical factors
So what are these four magical factors? The study called this combination DGTM factor, which contains four single factors: DNP63A, GRHL2, TFAP2A, and MYC. Among them, DNP63A and GRHL2 can reprogram skin mesenchymal cells into skin cell precursors; MYC can improve reprogramming efficiency and promote cell proliferation and stratification; TFAP2A is responsible for accelerating the aggregation of small skin cell masses. These four factors are carefully selected. The researchers analyzed 55 reprogramming factors associated with skin production and 31 microRNA molecules, and finally decided to adopt DGTM based on protein expression and growth performance at the cellular level. The combination.
The best combination of skin regeneration can be achieved with four combinations of factors: the number of animals that produce new skin (left), and the area of newborn skin (right).
To simulate skin rupture, the researchers performed a surgical procedure on the back of the mouse to install a nested ring that isolates the normal skin tissue of the ulcer surface and prevents natural healing. After that, the selected DGTM combination factor was introduced into the ulcer surface, and only 18 days later, the ulcer surface began to grow new skin tissue mass, and the new skin tissue expanded over time until it covered the entire ulcer surface.
After starting the new skin tissue on the back of the mouse, the researchers removed the nesting ring and observed the direction of the new skin tissue. The results showed that the new skin tissue was successfully connected to the surrounding normal epidermis, indicating that the new tissue can help the wound heal. In addition, through tissue section analysis and other means, it is also determined that the new skin tissue induced by DGTM has the same function as the normal skin structure and has no tumorigenic risk.
Whether a technology is important depends on its future clinical value. The study found that DGTM has a positive effect on skin regeneration, and in order to make it more clinically useful, the researchers have refined the means of delivery. Finally, collagen gel was selected for transport of DGTM factor. This gel can be applied directly to the wound without irritation and is therefore more clinically useful than bioinjection or vaccination.
More importantly, the gel means that subsequent treatments can be combined with traditional means. At present, the clinically used ulcers are treated with fibroblast growth factor 2 (FGF2). FGF2 and DGTM are mixed and applied to the rupture site by gel, which can accelerate the skin growth and healing process. The ulcer surface wound can be only 2-2.5 weeks. A new skin tissue is grown.
After using in combination with the traditional treatment FGF, the rate of skin healing is greatly enhanced.
Of course, more experiments are needed in the future to prove its clinical feasibility, including the role of the human immune system in DGTM factors, and the differences in the effects of DGTM factors on different stages and types of wounds. However, the use of four factors to achieve reprogramming of stem cells in living animals has been a huge technological breakthrough. This technology has unprecedented significance for accelerating the skin regeneration of wounds and solving the excessive time and energy problems required for routine wound repair. This is currently not possible with clinical surgery. Therefore, this technology has no prospects for the future of regenerative treatment for human skin damage repair.
The research team is currently trying to apply this technology to different wound models. Kurita said: “Before entering clinical use, we need to do more research to ensure its long-term safety, and to increase its efficiency to a new level.”