CN112773803A - Application of small molecule in preparation of medicine for promoting skin wound healing - Google Patents

Application of small molecule in preparation of medicine for promoting skin wound healing Download PDF

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Publication number
CN112773803A
CN112773803A CN202110100910.7A CN202110100910A CN112773803A CN 112773803 A CN112773803 A CN 112773803A CN 202110100910 A CN202110100910 A CN 202110100910A CN 112773803 A CN112773803 A CN 112773803A
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stem cells
epidermal stem
promoting
chir99021
small molecule
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Inventor
张建明
陈露
李云齐
孙晓明
崔文国
田强
程林
张余光
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Ruinjin Hospital Affiliated to Shanghai Jiaotong University School of Medicine Co Ltd
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Ruinjin Hospital Affiliated to Shanghai Jiaotong University School of Medicine Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like

Abstract

The invention provides an application of a small molecule in preparing a medicine for promoting skin wound healing, wherein the small molecule is CHIR99021, the concentration of the small molecule acting on epidermal stem cells is 1.0-5.0 mu mol/L, and the in vivo application concentration is 0.1-0.5 mu mol/L. When the small molecules are prepared into a medicament for promoting the healing of skin wounds, the effect of efficiently promoting the proliferation of epidermal stem cells can be shown. The micromolecule has the effect of inducing epidermal stem cell proliferation for a long time, can obviously shorten the time for wound healing, has the effects of promoting epidermal stem cell dryness maintenance and epidermal stem cell proliferation, does not induce pathological scar formation, can efficiently repair scars and induce tumor formation, and is safe and effective to use. The risks of long treatment time and uncertain curative effect caused by the separation culture and the in vivo transplantation of the epidermal stem cells can be effectively avoided. The molecular structural formula of CHIR99021 is shown as the formula (I):
Figure DDA0002915876730000011

Description

Application of small molecule in preparation of medicine for promoting skin wound healing
Technical Field
The invention belongs to the technical field of medical drugs, and particularly relates to application of small molecules in preparation of a drug for promoting skin wound healing.
Background
The skin is the outermost organ of the human body and also an effective protective barrier of the body, and plays a role in resisting external injury. However, under the stimulation of various external physical and chemical factors, the skin is often damaged, and wounds, burns, chronic wounds and the like are common skin injuries. The exposure of a large-area wound for a long time often causes the problems of serious inflammatory reaction, systemic infection, imbalance of homeostasis and the like, and seriously threatens the appearance and life safety of patients. In order to maintain the body homeostasis and restore the human body barrier, the skin needs to rapidly start a self-repair mode in time, and once the skin is damaged, a series of intracellular and intercellular mechanisms are triggered to repair the tissue damage. The wound healing of the skin is a complex process influenced by various factors and participated by various cells, and needs to go through an inflammatory reaction phase, a proliferation phase, a remodeling phase and the like.
Epidermal stem cells play a crucial role in the repair of skin. The epidermal stem cells are positioned at the bottom layer of the epidermis and are tightly connected with the basement membrane. A large number of epidermal stem cells are usually in a dormant state on a normal epidermal basement membrane, and when the epidermis is wounded to the skin defect, an organism can automatically awaken the stem cells, so that the stem cells are continuously proliferated and differentiated into various normal epidermal cells through cell division, the damaged wound surface is subjected to tissue filling, and re-epithelialization and tissue structure remodeling are finally realized. The epidermal stem cells have the capabilities of self-renewal and proliferation and differentiation, can proliferate and differentiate into various epidermal cells, and have the effects of maintaining epidermal self-renewal, keeping normal epidermal structures, promoting wound repair and the like. The proliferation and differentiation of the cells can be regulated by a plurality of factors, and the factors for promoting the proliferation of the epidermal stem cells and the factors for inhibiting the proliferation of the cells are more common. In the process of wound healing, epidermal stem cells migrate to the center of a wound and continuously proliferate to fill the epidermal defect and restore the normal skin barrier. Therefore, it is important to maintain the dryness of epidermal stem cells and promote the proliferation of epidermal stem cells, and to promote the wound healing process mediated by epidermal stem cells.
After the epidermis forms the wound surface, the wound surface is quickly sealed, so that not only can scar hyperplasia be well prevented, but also the risk of infection of the wound surface can be reduced, and the obvious curative effect is brought to a large-area epidermis injury patient in the aspects of improving the life quality and the survival rate. When the wound surface is small and superficial, the human body can realize wound surface healing through regeneration of epidermal stem cells and migration of adjacent epidermal cells. However, when a large area of skin defect occurs, the self-repair of the skin is difficult due to limited ability of epidermal cell regeneration, infection, and the like.
Based on the important function of the epidermal stem cells, at present, a treatment mode of separation, culture and transplantation of autologous epidermal stem cells is clinically used for rapidly restoring the epidermal barrier of a patient with large-area burn. However, this method has problems of long in vitro amplification time, low survival rate of implanted cells, etc., and cannot restore the epidermal barrier rapidly as desired. In addition, recombinant human epidermal growth factor has also been used in various products for promoting wound healing. Although the recombinant human epidermal growth factor has a remarkable effect of promoting epidermal cell proliferation, the epidermal growth factor as a bioactive protein has the disadvantages of complex preparation process, high production cost, strict requirement on storage conditions and difficulty in large-scale popularization and application.
Although there are many clinically applicable treatment schemes for chronic difficult-to-heal wounds, many new problems often occur during the treatment process, and the overall treatment effect is not ideal at present. The common problems are as follows: when a patient has large-area skin defect, the autologous skin supply area cannot meet the requirement of transplantation; damage to the autologous donor area; multiple epidermal graft failures; the immune system rejects the allogeneic skin tissue transplantation and the like. Most clinical skin injuries such as burns, wounds and the like are easy to scar even after the skin heals, so that the living quality and health of patients are greatly influenced due to the hyperplasia of the scar after the wound under most conditions even if the wound surface heals due to the morphological or functional abnormality of the trunk and the limbs. With the pursuit of people for quality of life and disease prognosis, the expectation value is higher and higher along with the rapid development of the economic level, the pursuit of beauty is higher and higher, and scars caused by skin injury can influence the beauty, thereby causing psychological disorders of different degrees. Therefore, the healing method of the scar is a focus of attention of many scholars, but the treatment effect is still not ideal so far.
The molecular weight of the small molecular compound is often lower than 1000, and the small molecular compound is easy to synthesize and store. In addition, the small molecular compound can directly act on protein targets in cells, effectively regulates the biological effect of the cells and has great potential in various diseases. If a small molecular compound capable of effectively promoting the proliferation of epidermal stem cells can be developed, a novel treatment measure of the medicine for promoting wound healing with low cost and definite curative effect is expected to be developed.
Yan Ying[1]The small molecule CHIR99021 of the Wnt pathway activator is used for the human induced pluripotent stem cell, and is found to be capable of promoting the differentiation of the human induced pluripotent stem cell into the myocardial cell when being combined with the Wnt pathway inhibitor IWP4, which indicates that the small molecule CHIR99021 does not have a good function of maintaining the dryness when acting on the stem cell.
Chengming Fan[2]It is reported that small molecules CHIR99021 and FGF1 can activate the cell cycle of cultured human induced pluripotent stem cell-derived cardiomyocytes, increase proliferation and reduce apoptosis, and the small molecules CHIR99021 are used for inducing human induced pluripotent stem cells to differentiate into cardiomyocytes, and the research does not show that the small molecules CHIR99021 have the function of maintaining the stem cell dryness.
Sugiyama-Nakagiri[3]Small molecule CHIR99021 is reported to be useful for generating pluripotent stem cells from humansThe reconstructible skin-derived precursor cells and the differentiation into nerve cells and mesoderm cells indicate that the small molecules can induce the proliferation and differentiation of stem cells, but do not have the function of maintaining the dryness.
Chinese patent document CN110804593A, entitled "small molecule compound combination for inducing skin fibroblasts to transdifferentiate directly to neurons and use" describes that the small molecule composition includes CHIR99021, and the research result shows that the composition exhibits the ability to induce skin fibroblasts to transdifferentiate directly to neurons, indicating that small molecules are likely to cause cell differentiation when treating human skin fibroblasts.
In order to repair damaged skin, it is necessary to proliferate a large amount of epidermal stem cells and maintain the dryness of epidermal stem cells for promoting the reconstruction of tissues related to epidermal stem cells, and therefore, it is medically desirable that the proliferation of epidermal stem cells for repairing wounds in skin be maintained well without causing differentiation of epidermal stem cells into other cells. However, the small molecules studied at present, including CHIR99021, have not been found to be effective in maintaining the dryness of stem cells.
On the other hand, in the current skin injury treatment process, the commonly used repair substances do not show a good repair effect on scars, and the repair of the scars cannot be quickly and effectively realized, which is a problem that is difficult to solve in the skin wound healing process.
Therefore, how to find a small molecular compound which can effectively promote the proliferation of the epidermal stem cells and well maintain the dryness of the epidermal stem cells, can prevent the differentiation of the epidermal stem cells, and has a quick and efficient repairing effect on scars formed when the skin is damaged becomes a technical problem to be solved urgently.
The references are as follows:
[1] yan glu. Experimental study of stem cells and tissue engineering combined regulation of Wnt and BMP signal pathways to promote differentiation of human-derived induced pluripotent stem cells into cardiomyocytes [ J ]. China J.J.J.repair and reconstruction surgery, 2020, 9 th, Vol.37, 9 th.
[2]Chengming Fan.CHIR99021 and fibroblast growth factor 1enhance the regenerative potency of human cardiac muscle patch after myocardial infarction in mice[J].Journal of Molecular and Cellular Cardiology.2020.
[3]Sugiyama-Nakagiri.Induction ofSkin-Derived Precursor Cells from Human Induced Pluripotent Stem Cells[J].PLoS One.2016.
Disclosure of Invention
The invention aims to solve the technical problems, and finds a small molecular compound capable of promoting skin wound healing, so that effective treatment on clinical skin injury can be realized. Therefore, the invention provides an application of a small molecule in preparing a medicament for promoting skin wound healing. The small molecule can effectively promote the proliferation of epidermal stem cells and well maintain the dryness of the cells when promoting the healing of skin wounds, and simultaneously has the function of efficiently repairing scars formed after the skin wounds.
The invention provides an application of a small molecule in preparing a medicine for promoting skin wound healing, wherein the small molecule is CHIR99021, and the molecular structural formula of the small molecule is shown as the formula (I):
Figure BDA0002915876710000061
further, the concentration range of the CHIR99021 acting on the epidermal stem cells is 1.0-5.0 mu mol/L, and the optimal concentration is 3.3 mu mol/L; the in vivo application concentration is 0.1-0.5 μmol/L, and the optimal application concentration is 0.33 μmol/L.
Furthermore, when the CHIR99021 is used for promoting the healing of skin wounds, no pathological scar formation is induced, and the scar can be quickly and efficiently repaired.
As shown by the research results of the embodiment of the invention, the small molecular compound CHIR99021 for promoting wound healing, which is provided by the invention, is used as a medicine for epidermal wound healing, shows the function of well maintaining the dryness of epidermal stem cells, and effectively promotes the proliferation of the epidermal stem cells. The optimal concentration of the medicine acting on epidermal stem cells is 3.3 mu mol/L, and the effective concentration in vivo application is 0.33 mu mol/L. In addition, the small molecular compound does not induce the formation of pathological scars, and can quickly and efficiently repair the scars.
The inventor of the present patent application found that when the small molecule compound CHIR99021 was allowed to act on 90000/mL epidermal stem cells, cell viability of different groups was examined after three days, and found that the in vitro proliferation promoting effect was significant at a concentration of 3.3 μmol/L, and the proliferation fold was 1.8 times that of the control group. And the differentiation promoting drug ATRA acts on 90000/mL of epidermal stem cells, and the in vitro proliferation promoting effect is shown to be only 1.5 times of that of the control group after three days under the optimal acting concentration of ATRA under the same conditions. The small molecular compound provided by the invention has better in-vitro proliferation promoting effect compared with the differentiation promoting drug ATRA.
The in vitro clone formation experiment of the medicine further shows that: the cloning result after 15 days shows that CHIR99021 with the concentration of 3.3 mu mol/L can obviously promote the cloning of epidermal stem cells relative to a control group, and the cloning number is about 2 times that of the control group; the number of ATRA group clone formation is 0, which proves that the differentiation promoting drug ATRA has no effect of inducing the proliferation of the epidermal stem cells for a long time, while the small molecular compound CHIR99021 of the invention has the effect of inducing the proliferation of the epidermal stem cells for a long time.
The in vivo application effect of the medicament shows that: the healing time of the wound of the control group is 12 days, while the healing time of the CHIR99021 drug group is only 9 days, and the hair of the drug group is rapidly regenerated after the wound is healed. Under the action of the differentiation promoting drug ATRA, the wound healing speed is obviously slower than that of the control group.
The results of the immunohistochemistry in vivo application of the medicine show that: the thickness of the epidermis of the CHIR99021 drug group is increased, and more epidermal stem cell related proteins such as Keratin15, Integrin-beta 1, Collagen17 and the like are expressed in the epidermis; and under the action of the differentiation-promoting drug ATRA, the epidermal stem cell related protein is reduced, and the promotion effect of CHIR99021 on the dryness maintenance of the epidermal stem cells and the proliferation of the epidermal stem cells is proved. In addition, the collagen deposition in the dermal layer of the drug group has no obvious change compared with the control group, and the effect of CHIR99021 on inducing pathological scarring is shown.
The repair experiment of scars after skin injury shows that: the medicine group for CHIR99021 can inhibit scar formation. After the wound is healed, no obvious scar is locally seen.
The safety performance research result of the medicine shows that: the appearance of the skin treated by CHIR99021 is normal, the secondary structure of the cortex under the microscope is clear, and abnormal tumor masses are not formed. Therefore, CHIR99021 has no effect of inducing tumor formation in the process of promoting wound healing, and is safe and effective.
The invention has the following beneficial effects:
the invention provides an application of a small molecule in preparing a medicine for promoting skin wound healing, and compared with other small molecules, the small molecule CHIR99021 has the most obvious effect of promoting epidermal stem cell proliferation. The small molecule CHIR99021 has an obvious in-vitro proliferation promoting effect with the concentration of 3.3 mu mol/L, and the proliferation multiple is 1.8 times that of a control group and is 1.5 times higher than that of an ATRA (differentiation promoting drug); the small molecule has the effect of inducing the proliferation of the epidermal stem cells for a long time, and the differentiation promoting drug ATRA has no effect of inducing the proliferation of the epidermal stem cells for a long time; the in vivo application results of the small molecule show that: it can significantly shorten the time for wound healing, while the differentiation promoting drug ATRA can not shorten the time for wound healing; the micromolecule CHIR99021 has the effects of maintaining the dryness of the epidermal stem cells and promoting the proliferation of the epidermal stem cells, and the differentiation promoting medicine ATRA does not have the effect of maintaining the dryness of the epidermal stem cells; CHIR99021 has no effect of inducing pathological scar formation, has good repairing effect on the existing scar, has no effect of inducing tumor formation, and is safe and effective to use. The micromolecule CHIR99021 provided by the invention can effectively avoid the risks of long treatment time and uncertain curative effect caused by the separation culture and in-vivo transplantation of epidermal stem cells.
Drawings
FIG. 1 is a graph of drug-sieving drug proliferation data (the original graph is in color, and shows that CHIR99021 is located at the top of the right scale, and shows the best effect of promoting epidermal stem cell proliferation);
FIG. 2 is a graph of the effect of concentration gradient of the drug CHIR99021 in vitro;
FIG. 3 is a graph of the in vitro clonogenic effect of the drug ATRA;
FIG. 4 is a graph of the in vitro clonogenic effect of a drug;
FIG. 5 is a graph showing the effect of the drug on the in vivo effect;
FIG. 6 is a graph of immunohistochemical staining of the effect of drugs in vivo.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more clearly understood, the present invention is described in detail below with reference to the following embodiments, and it should be noted that the following embodiments are only for explaining and illustrating the present invention and are not intended to limit the present invention. The invention is not limited to the embodiments described above, but rather, may be modified within the scope of the invention.
Example 1
In this embodiment, based on a small molecule compound drug library that can effectively act on stem cells, 80 common stem cell-related small molecule compounds are screened, the proliferation promoting effect of the stem cells is determined, and a small molecule compound CHIR99021 that can significantly promote the proliferation of the stem cells of the epidermis is screened, and the screening result is shown in fig. 1. FIG. 1 shows that: compared with other small molecule compounds, the compound CHIR99021 screened by the invention has the optimal effect of promoting the proliferation of epidermal stem cells.
The drug screening method comprises the following steps: epidermal stem cells are isolated and cultured from foreskin tissue. The effect of the existing stem cell related small molecule compound (shown in figure 1) of the national center for transformation medicine (Shanghai) on epidermal stem cells is screened. Epidermal stem cells were seeded in 96-well plates at a concentration of 4500/well, with different small molecule compounds added at a concentration of 0.2. mu. mol/L per well. Each medicine is provided with 4 compound holes, and 64 compound holes of a control group without medicine are arranged at the same time. After 3 days of constant-temperature culture in an incubator at 37 ℃, the proliferation activity of the cells in each well is detected. And (3) screening out a small molecular compound CHIR99021 with the most obvious effect of promoting the proliferation of the epidermal stem cells according to the proliferation activity.
Example 2
In vitro concentration gradient experiment of medicine
(one) CHIR99021 was diluted to a concentration gradient of 10. mu. mol/L, 3.3. mu. mol/L, 1.1. mu. mol/L, 0.36. mu. mol/L, 0.12. mu. mol/L, 0.04. mu. mol/L, 0.013. mu. mol/L, 0.004. mu. mol/L, respectively, and it was applied to 90000/mL of epidermal stem cells, and cell viability of different groups was examined after three days, and the results are shown in FIG. 2. The in vitro proliferation promoting effect was found to be significant at a concentration of 3.3. mu. mol/L, with a fold proliferation of 1.8 fold compared to the control treated with medium without any drug.
(II) selecting the differentiating medicine ATRA as comparison: ATRA was diluted to a concentration gradient drug of 10. mu. mol/L, 3.3. mu. mol/L, 1.1. mu. mol/L, 0.36. mu. mol/L, 0.12. mu. mol/L, 0.04. mu. mol/L, 0.013. mu. mol/L, 0.004. mu. mol/L, and applied to 90000/mL of epidermal stem cells, and cell viability of different groups was examined after three days, and the results are shown in FIG. 2. The concentration of less than 3.3 mu mol/LATRA is found to have obvious in-vitro proliferation promoting effect on epidermal stem cells, wherein the in-vitro proliferation promoting effect is the best after the concentration of 0.36 mu mol/LATRA acts for three days, and the proliferation multiple is 1.5 times of that of a control group.
The results of the in vitro concentration gradient experiment show that: although ATRA showed a significant effect on epidermal stem cell proliferation in its early stages of action in vitro experiments, its proliferative effect was inferior to CHIR99021 at the optimal in vitro acting concentration.
Example 3
In vitro drug cloning experiments
The epidermal stem cells were seeded in 6-well plates at a concentration of 2000 cells/well, and CHIR99021 at a concentration of 3.3 μmol/L was allowed to act on the epidermal stem cells, and after 15 days, the colony formation results were observed, and it was found that CHIR99021 at a concentration of 3.3 μmol/L significantly promoted the colony formation of epidermal stem cells compared to the control group without any drug treatment, and the number of colonies was about 2 times that of the control group (see fig. 3). On the other hand, the colony formation number of the group treated with ATRA at a concentration of 0.36. mu. mol/L was 0 (see FIG. 4), demonstrating that ATRA, a differentiation-promoting drug, has no effect of inducing the proliferation of epidermal stem cells for a long period of time.
The above research results show that: CHIR99021 has the effect of inducing the proliferation of epidermal stem cells for a long time, while ATRA (differentiation promoting drug) has no effect of inducing the proliferation of epidermal stem cells for a long time.
Example 4
Test of in vivo Effect of drugs
A full-thickness skin excision model of the back of the mouse was prepared, with a back wound diameter of about 6 mm. CHIR99021 drug group CHIR99021 was applied daily to the back at a concentration of 0.33. mu. mol/L, approximately 20. mu.L per application, and wound healing was observed every 3 days. The ATRA group applied ATRA to the back at a concentration of 0.036. mu. mol/L per day, about 20. mu.L per application, and the wound was observed to heal every 3 days, as shown in FIG. 5. As can be seen from fig. 5, the wound healing time of the control group was 12 days, whereas the healing time of the drug group was only 9 days, and the hair was rapidly regenerated after the wound of the drug group healed. Under the action of the differentiation promoting drug ATRA, the wound healing speed is obviously slower than that of the control group.
The above research results show that: CHIR99021 was able to shorten wound healing time, whereas the differentiation-promoting drug ATRA was unable to shorten wound healing time.
Example 5
Immunohistochemical assay for in vivo application of drugs
Immunohistochemical staining was performed on the skin at the wound margins on day 9, and the results are shown in FIG. 6, and it was found that the thickness of the epidermis was increased in the CHIR99021 drug group, and more epidermal stem cell-associated proteins such as Keratin15, Integrin-beta 1, Collagen17 and the like were expressed in the epidermis; and under the action of the differentiation-promoting drug ATRA, the epidermal stem cell related protein is reduced, and the promotion effect of CHIR99021 on the dryness maintenance of the epidermal stem cells and the proliferation of the epidermal stem cells is proved. In addition, the collagen deposition in the dermal layer of the drug group has no obvious change compared with the control group, and the effect of CHIR99021 on inducing pathological scarring is shown. Combining gross observations and in vitro experimental results, this study demonstrated the effectiveness of compound CHIR99021 in promoting wound healing in maintaining epidermal stem cell dryness and promoting epidermal stem cell proliferation.
Example 6
Scar inhibition assay
The observation of the scars of the skin wounds after the medicine is applied for 12 days in the medicine application group shows that no visible scars exist after the medicine is applied for 12 days in the medicine application group, which indicates that the medicine can inhibit the formation of scars.
Example 7
Drug safety test
The general appearance of the medicine group and the appearance under an HE staining microscope are comprehensively observed, the appearance of the skin treated by the CHIR99021 is normal, the secondary structure of the skin layer under the microscope is clear, and abnormal tumor masses are not formed. Therefore, CHIR99021 has no effect of inducing tumor formation in the process of promoting wound healing, and is safe and effective.
In conclusion, the result of comparing CHIR99021 with the differentiation promoting drug ATRA is as follows: although ATRA shows a remarkable effect on the proliferation of the epidermal stem cells in the early stage of the action in vitro experiments, in vitro clonogenic experiments and in vivo immunohistochemical staining show that ATRA has the effect of promoting the proliferation of the epidermal stem cells and also remarkably promotes the differentiation of the epidermal stem cells. Therefore, it is necessary to promote the stem cell-related tissue reconstruction and simultaneously promote the stem cell proliferation and maintain the stem cell dryness. CHIR99021 can promote the proliferation of epidermal stem cells and maintain the dryness of the epidermal stem cells at the same time, and is an ideal novel medicine for promoting the healing of the skin related to the epidermal stem cells.

Claims (5)

1. The application of a small molecule in preparing a medicine for promoting skin wound healing is characterized in that the small molecule is CHIR99021, and the molecular structural formula of the small molecule is shown as the formula (I):
Figure FDA0002915876700000011
2. the use of claim 1, wherein the concentration of CHIR99021 acting on epidermal stem cells is in the range of 1.0-5.0 μmol/L.
3. The use of claim 2, wherein the optimal concentration of CHIR99021 acting on epidermal stem cells is 3.3 μmol/L.
4. The use of claim 1 or 2, wherein CHIR99021 is used in vivo at a concentration of 0.1-0.5 μmol/L.
5. The use of claim 1 or 2, wherein CHIR99021 is used in vivo at an optimal concentration of 0.33 μmol/L.
CN202110100910.7A 2021-01-26 2021-01-26 Application of small molecule in preparation of medicine for promoting skin wound healing Pending CN112773803A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116236456A (en) * 2023-02-28 2023-06-09 上海交通大学医学院附属第九人民医院 Targeting endothelial cell delivery vehicle and application thereof in promoting wound healing

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012065065A1 (en) * 2010-11-12 2012-05-18 Follica, Inc. Methods and compositions for modulating hair growth, wound healing and scar revision

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012065065A1 (en) * 2010-11-12 2012-05-18 Follica, Inc. Methods and compositions for modulating hair growth, wound healing and scar revision

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116236456A (en) * 2023-02-28 2023-06-09 上海交通大学医学院附属第九人民医院 Targeting endothelial cell delivery vehicle and application thereof in promoting wound healing

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Application publication date: 20210511