CN114558115A - Application of ELABELA in improving survival and migration of adipose-derived stem cells - Google Patents
Application of ELABELA in improving survival and migration of adipose-derived stem cells Download PDFInfo
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- CN114558115A CN114558115A CN202210225561.6A CN202210225561A CN114558115A CN 114558115 A CN114558115 A CN 114558115A CN 202210225561 A CN202210225561 A CN 202210225561A CN 114558115 A CN114558115 A CN 114558115A
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Abstract
The invention belongs to the technical field of medicines, and particularly relates to application of ELABELA (ELA) in improvement of survival and migration of adipose-derived stem cells (ADSCs). In order to improve the survival of the ADSCs, reduce apoptosis in an ischemia-hypoxia microenvironment and improve migration capacity of the ADSCs, the ELA is applied to improve the survival and migration of the ADSCs. In the research of improving the survival and migration of the ADSCs by the ELA, the ELA promotes the survival of the ADSCs and inhibits the apoptosis of the ADSCs under the condition of ischemia and hypoxia, and simultaneously promotes the migration of the ADSCs. These results indicate that ELA can be used as a promising stem cell treatment method for prolonging the life of ADSCs and improving the application effect of stem cells in treating diseases such as ischemic heart disease and vascular injury. The invention not only develops the new application of ELA, but also finds a new improvement strategy for the regenerative medicine and the cell therapy application of ADSCs.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to application of ELABELA in improvement of survival and migration of adipose-derived stem cells.
Background
Adipose-derived stem cells (ADSCs) are promising alternatives for regenerative medicine and cell therapy due to their advantages of self-renewal, pluripotency, proliferative capacity, abundant sources, availability, and low immunological rejection. Studies have shown that ADSCs can be transplanted and survive in the infarcted myocardium environment and have a positive impact on the structure and function of the cardiovascular system. Therefore, ADSCs are the primary choice in myocardial repair, cardiac tissue engineering, and cell regeneration therapy. However, ADSCs have poor viability and are particularly susceptible to apoptosis in adverse environments such as hypoxia and ischemia, so that the host environment presents many unique obstacles to cell transplantation. Survival, retention and localization of ADSCs in affected tissues can affect the efficacy of cell therapy, and these problems are particularly evident in the area of cardiac tissue regeneration following myocardial infarction. Therefore, the improvement of the activity and the migration capability of the ADSCs and the reduction of the apoptosis in hypoxic and ischemic microenvironments are important problems to be solved urgently.
The polypeptide small molecular hormone ELABELA (ELA) is a polypeptide consisting of 32 amino acids, and has the sequence: QRPVNLTMRRKLRKHNCLQRRCMPLHSRVPFP are provided. ELA is a novel endogenous peptide ligand of the G-protein coupled receptor APJ (i.e. the angiotensin receptor AT 1-related receptor protein) and plays an important role in a variety of pathophysiological processes in embryonic and adult stages. A number of recent studies have shown that ELA can protect the cardiovascular system by promoting angiogenesis, regulating cardiac and vascular function, etc. However, the use of the ELA polypeptide in improving the survival of ADSCs is not found.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides the application of the ELA in improving the survival of the ADSCs, and researches show that the ELA has the capability of improving the survival of the ADSCs and improves the application effect of stem cells in treating diseases such as ischemic heart diseases, vascular injury and the like.
In order to achieve the purpose, the invention adopts the technical scheme that:
the invention provides an application of ELA in preparing a medicine for improving the survival of ADSCs.
Preferably, the improving survival of the ADSCs means promoting proliferation of the ADSCs. The ELA can be further prepared into the medicine for promoting the proliferation of the ADSCs for application.
Preferably, the improving the survival of the ADSCs means increasing the cell viability of the ADSCs. The ELA can be further prepared into a medicine for improving the cell viability of the ADSCs for application.
Preferably, the improvement of survival of the ADSCs means inhibition of apoptosis of the adipose stem cells. The ELA can be further prepared into the medicine for inhibiting the apoptosis of the ADSCs for application.
Preferably, the improvement of migration of the ADSCs refers to promoting the migratory ability of the ADSCs. The ELA can be further prepared into a medicine for promoting the migration of ADSCs for application.
According to research, the ELA can improve the survival capability of ADSCs cells and improve the migration capability of the ADSCs by promoting proliferation, improving activity and resisting apoptosis, and is expected to be a promising stem cell treatment method for prolonging the service life of the ADSCs and improving the application effect of the stem cells in treating diseases such as ischemic heart diseases, vascular injury and the like.
The invention also provides a medicament for improving the survival of ADSCs, which comprises ELA.
Preferably, the medicament further comprises other pharmaceutical ingredients that act synergistically with the ELA.
Preferably, the medicament further comprises a pharmaceutically acceptable carrier or excipient.
Further, the carrier or excipient includes diluents, binders, wetting agents, disintegrants, lubricants, glidants and the like well known in the art. Diluents include, but are not limited to, starch, dextrin, sugar, glucose, lactose, mannitol, sorbitol, xylitol, dibasic calcium phosphate, and the like; wetting agents include water, ethanol, isopropanol, and the like; binders include, but are not limited to, starch slurry, dextrin, syrup, honey, glucose solution, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, ethylcellulose, polyethylene glycol, and the like; disintegrants include, but are not limited to, dry starch, microcrystalline cellulose, low substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, sodium carboxymethyl starch, sodium lauryl sulfate, and the like; lubricants and glidants include, but are not limited to, talc, silicon dioxide, polyethylene glycol, and the like.
Preferably, the medicament of the present invention can be formulated into several dosage forms, including tablets, sachets, granules, dripping pills, emulsions, liquids, patches, ointments and injections. Pharmaceutical formulations may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically), and if certain drugs are unstable under gastric conditions, they may be formulated as enteric coated tablets.
Compared with the prior art, the invention has the beneficial effects that:
in order to improve the activity and migration capability of ADSCs and reduce apoptosis in hypoxic and ischemic microenvironments, the application of the ELA in improving the survival of ADSCs is found through research, and the ELA can promote the survival and migration of ADSCs and inhibit the apoptosis of ADSCs under the hypoxic and ischemic conditions. These results indicate that ELA can be used as a promising stem cell treatment method for prolonging the lifespan of ADSCs and enhancing the application effect of stem cells in treating ischemic heart diseases, vascular injuries and other diseases. The invention not only develops the new application of ELA, but also finds a new improvement strategy for the regenerative medicine and the cell therapy application of ADSCs.
Drawings
FIG. 1 shows the effect of ELA on the proliferation of ADSCs under hypoxic-ischemic conditions (A is OD450, B is cell viability);
FIG. 2 shows the flow cytometric results of the apoptosis of ADSCs influenced by ELA under ischemia and hypoxia conditions (A is the flow detection result, B is the statistical result of the number of apoptotic cells based on flow detection);
FIG. 3 is the result of protein verification that ELA affects the apoptosis of ADSCs under the conditions of ischemia and hypoxia (A is the blot of Bcl-2, Bax and beta-actin proteins; B is the statistical chart of Bcl-2/Bax; C is the blot of cleaned caspase-3 and GAPDH; D is the statistical chart of cleaned caspase-3/GAPDH);
FIG. 4 shows the effect of ELA on the migration of ADSCs under hypoxic-ischemic conditions (A is crystal violet staining results and B is the number of migrated cells).
Detailed Description
The following further describes the embodiments of the present invention. It should be noted that the description of the embodiments is provided to help understanding of the present invention, but the present invention is not limited thereto. In addition, the technical features involved in the embodiments of the present invention described below may be combined with each other as long as they do not conflict with each other.
The experimental procedures in the following examples were carried out by conventional methods unless otherwise specified, and the test materials used in the following examples were commercially available by conventional methods unless otherwise specified.
Example 1 demonstration of the Effect of ELABELA (ELA) on improving the survival of adipose-derived stem cells
(1) ELA (QRPNLTMRRKLRKHNCLQRCMPLHSRVPFP), synthesized by Shanghai Gill biosciences. The ELA powder was 95.31% pure, stored at-20 deg.C, dissolved in PBS and sterilized with a 0.22 μm filter before use.
(2) Isolation and culture of ADSCs
ADSCs were isolated from inguinal fat pad of male SD rat. The adipose tissues were washed 3 times with PBS buffer containing 1% diabody (penicillin/streptomycin) under sterile conditions to remove adherent blood cells. Then, the adipose tissues were minced, and the tissue fragments were incubated with 0.1% collagenase type I, digested by shaking in a thermostatic water bath at 37 ℃ for 1 hour, then added with the same volume of low sugar DMEM medium containing 10% fetal calf serum as the 0.1% collagenase type I to terminate the digestion and centrifuged, and the floating mature adipocytes were separated from the granular matrix vascular fraction. And finally, washing the tissue suspension for 3 times by using PBS (phosphate buffer solution) containing 1% double antibody, filtering by using a 200-mesh cell net, and then centrifuging to obtain the ADSCs.
The obtained ADSCs were cultured in low-sugar DMEM medium containing 10% Fetal Bovine Serum (FBS) and 1% double antibody and placed under normoxic conditions (20% O)2，5％CO2) And (5) culturing. After 2 days of culture, the medium was first changed to remove non-adherent cells, then changed every 2 days until the cell density reached about 80% confluence and the ADSCs were passaged at a ratio of 1:2 until passage 3 for subsequent experiments.
(3) Establishment and treatment of ADSCs hypoxia ischemia model
And 7 groups are set according to different processing modes: (1) control group: ADSCs in normoxic condition (20% O)2，5％CO2) Lower culture as negative control; (2) H/I group: ADSCs in low-sugar DMEM medium and under anoxic conditions (1% O)2、94％N2And 5% CO2) Then, culturing for 24 hours in an anoxic incubator; (3) ELA group: culturing ADSCs in low-sugar DMEM culture medium containing 20 μ M ELA in an anoxic incubator for 24 h; (4) siAPJ + ELA group: transfecting ADSCs with siRNA-APJ, treating with 20 μ M ELA (namely inoculating in low-sugar DMEM medium containing 20 μ M ELA), and culturing in an anoxic incubator for 24 h; (5) siAPJNC + ELA group: the ADSCs were transfected with siRNA-APJNC and then treated with 20. mu.M ELA (i.e., inoculated in low-sugar DMEM medium containing 20. mu.M ELA) and cultured in an anoxic incubator for 24 h.
Wherein APJ silencing is performed by small interfering RNA (siRNA), siRNA-APJ (sequence: GCCTCAGCTTTGACCGATA) and negative control of siRNA are synthesized by Ruibo, Guangzhou, China. According to the protocol, the ADSCs are transfected with siRNA-APJ or siRNA-APJNC using Lipofectamine RNAiMax reagent (Thermo Fisher, USA). During this period, the ADSCs are incubated in the medium without the double antibody for 6-8 h.
(4) Cell viability assay:
cell viability was determined using cell counting kit 8 (CCK-8). After each group had been subjected to the prescribed treatment, 100. mu.L of cell suspension (per well) was added4×103Cell density) were inoculated in a 96-well plate and cultured for 24 hours, then 10. mu.L of CCK-8 reagent was added and cultured at 37 ℃ for 2 hours. Next, absorbance at 450nm was measured using a microplate reader. Subsequently, the percentage of cell viability was calculated by the mean Optical Density (OD) in each group. Cell viability ═ 100% x (experimental-blank)/(control-blank).
(5) Cell migration assay
Cell migration was detected using a Transwell chamber with a pore size of 8 μm and placed in a 24-well plate. ADSCs (1X 10 per well) with prescribed treatment (7 treatments of step (2)) of 200. mu.L Low sugar DMEM5Density of individual cells) was seeded in the upper chamber, and 600 μ L of low-sugar DMEM containing 10% FBS was added to the lower chamber. The 24-well plate was incubated at 37 ℃ for 12 hours. Cells on the lower surface of the upper chamber were gently washed 3 times with PBS and then fixed with 4% paraformaldehyde at room temperature for 30 min. Finally, the upper chamber was placed in 0.1% crystal violet dye to stain the cells, and then cotton swabs were used to remove cells that did not migrate to the bottom layer. Five pictures were taken at random for each group and the cell number was calculated.
(6) Apoptosis assay
And (3) evaluating the apoptosis of the ADSCs by using an Annexin V-FITC/PI apoptosis detection kit according to the instruction. First, the treated (7 treatments of step (2)) ADSCs were harvested with 0.25% trypsin (EDTA-free) and centrifuged at 1000rpm for 5 minutes. Subsequently, the ADSCs were washed 3 times with cold PBS and resuspended in 100. mu.L of 1 × biningbuffer. Adding 5 μ LannexinV-FITC, mixing, incubating at 4 deg.C in dark for 15min, adding 5 μ LPI, mixing, and incubating at 4 deg.C in dark for 5 min. Then 400. mu.L of 1 XBindingbuffer was made up and mixed into each group. Finally, the cell samples were examined by flow cytometry within one hour.
(7) Western blot
The treated ADSCs in the 7 treatment groups were washed 1 time with PBS and lysed on ice for 30 minutes using RIPA lysate containing 10uL/mL protease and 10uL/mL phosphatase inhibitor. The mixtures of each group were then recovered, centrifuged at 12,000 Xg for 20min, and the supernatants of each group were collected and assayed for protein concentration by BCA assay kit. After mixing with SDS loading buffer, the collected proteins were heated at 100 ℃ for 10min, and then samples of the same mass of proteins were separated by 12% SDS-PAGE and transferred to 0.2 μm PVDF membranes, which were blocked with blocking solution (1 XTST containing 5% skim milk) for 1h at room temperature and incubated overnight at 4 ℃ with primary antibodies including APJ, Bcl-2, cleared past case-3, phospho-p44/42MAPK (p-ERK1/2), p44/42MAPK (ERK1/2), phospho-p38 MAPK, p38MAPK, phospho-SAPK/JNK, phospho-p53, p53, β -actin and GAPDH. The next day the membrane was washed 3 times with 1 × TBST for 10min each, and then the membrane was incubated with anti-rabbit secondary antibody or anti-mouse secondary antibody for 1h at room temperature. Finally the membrane was washed 3 times with 1 × TBST for 10min each and the chemiluminescent reagent treated bands were detected with an exposure instrument.
(8) Results of the experiment
In fig. 1, after the ADSCs cells are subjected to hypoxia condition and siRNA silenced APJ, the OD450 and cell survival rate of the ADSCs cells are significantly reduced, but after ELA is added to the culture medium under hypoxia condition, the OD450 and cell survival rate of the ADSCs cells are equivalent to those of normal culture, which indicates that ELA can promote proliferation of the ADSCs and improve cell viability under ischemia hypoxia condition.
In fig. 2, the apoptosis of ADSCs cells under hypoxic condition and after siRNA silenced APJ is largely reduced, but the number of apoptosis of the cells is significantly reduced after ELA is added to the culture medium under hypoxic condition, which indicates that ELA can reduce the apoptosis of ADSCs under ischemic and hypoxic condition.
In FIG. 3, Bcl-2, Bax, cleared Caspase-3 (cleaved cysteine aspartate proteinase-3) and GAPDH (glyceraldehyde-3-phosphate dehydrogenase) are important apoptosis-related proteins, where Bcl-2 and Bax are two important members of the Bcl-2 family of apoptosis-regulating genes, which can regulate apoptosis by forming homo-or heterodimers. After APJ is silenced by the siRNA and the ADSCs are under the anoxic condition, the expression level of Bcl-2/Bax and cleaned caspase-3/GAPDH is increased, but after ELA is added into the culture medium under the anoxic condition, the corresponding expression level is obviously reduced, and the fact that the ELA can reduce the apoptosis of the ADSCs under the ischemia-anoxic condition is further illustrated.
In FIG. 4, the migration number of ADSCs cells is significantly reduced under the hypoxic condition and APJ silenced by siRNA, but the migration number is significantly increased after ELA is added into the culture medium under the hypoxic condition, which indicates that ELA can promote migration of ADSCs under the ischemic and hypoxic condition
The above analysis shows that ELA can improve the viability of ADSCs cells and enhance the migration ability of ADSCs by promoting proliferation, enhancing activity, resisting apoptosis, and can be used for prolonging the life of ADSCs and enhancing the application effect of stem cells in treating ischemic heart diseases, vascular injury, etc.
The embodiments of the present invention have been described in detail, but the present invention is not limited to the described embodiments. It will be apparent to those skilled in the art that various changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, and the scope of protection is still within the scope of the invention.
Sequence listing
<110> Zhongshan university affiliated eighth Hospital (Shenzhen Futian)
Application of <120> ELABELA in improving survival and migration of adipose-derived stem cells
<160> 2
<170> SIPOSequenceListing 1.0
<210> 1
<211> 32
<212> PRT
<213> ELABELA(Artificial Sequence)
<400> 1
Gln Arg Pro Val Asn Leu Thr Met Arg Arg Lys Leu Arg Lys His Asn
1 5 10 15
Cys Leu Gln Arg Arg Cys Met Pro Leu His Ser Arg Val Pro Phe Pro
20 25 30
<210> 2
<211> 19
<212> DNA/RNA
<213> siRNA-APJ(Artificial Sequence)
<400> 2
gcctcagctt tgaccgata 19
Claims (9)
- The application of ELABELA in preparing the medicine for improving the survival and migration of adipose-derived stem cells.
- 2. The use according to claim 1, wherein the improvement of the survival of the adipose-derived stem cells is the promotion of the proliferation of the adipose-derived stem cells.
- 3. The use of claim 1, wherein the improvement of adipose stem cell survival is an increase in the survival rate of adipose stem cells.
- 4. The use of claim 1, wherein the improvement in survival of adipose stem cells is inhibition of apoptosis of adipose stem cells.
- 5. The use according to claim 1, wherein the improvement of the migration of the adipose-derived stem cells is the promotion of the migration ability of the adipose-derived stem cells.
- 6. A medicament for improving survival and migration of adipose stem cells, wherein the medicament comprises elabel.
- 7. The medicament for improving survival of adipose-derived stem cells of claim 6, further comprising other pharmaceutical ingredients that can act synergistically with ELABELA.
- 8. The medicament for improving survival of adipose-derived stem cells as claimed in claim 6, wherein the medicament further comprises a pharmaceutically acceptable carrier or excipient.
- 9. The drug for improving the survival of adipose-derived stem cells, according to claim 6, wherein the drug comprises tablets, sachets, granules, dripping pills, emulsions, liquids, patches, pastes and injections.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103969442A (en) * | 2013-02-01 | 2014-08-06 | 上海交通大学医学院附属第九人民医院 | Method for promoting stem cell adhesion, migration, homing and angiogenesis |
| US20190167587A1 (en) * | 2017-12-01 | 2019-06-06 | Mdimune Inc. | Pharmaceutical composition for prevention or treatment of pulmonary disease including mesenchymal stem cell-derived artificial nanosomes |
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