CN114558115B - Use of ELABELA in improving adipose-derived stem cell survival and migration - Google Patents

Use of ELABELA in improving adipose-derived stem cell survival and migration Download PDF

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CN114558115B
CN114558115B CN202210225561.6A CN202210225561A CN114558115B CN 114558115 B CN114558115 B CN 114558115B CN 202210225561 A CN202210225561 A CN 202210225561A CN 114558115 B CN114558115 B CN 114558115B
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CN114558115A (en
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王彤
刘欣
李霜梅
许岱诗
侯静雨
符佳颖
张康龙
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Eighth Affiliated Hospital of Sun Yat Sen University
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
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Abstract

The invention belongs to the technical field of medicines, and particularly relates to an application of ELABELA (ELA) in improving survival and migration of adipose-derived stem cells (ADSCs). In order to improve survival of ADSCs, reduce apoptosis in ischemic and anoxic microenvironment and improve migration capacity, ELA is used to improve survival and migration of ADSCs. In studies of ELA improving survival and migration of ADSCs, ELA was found to promote survival of ADSCs and inhibit apoptosis of ADSCs under ischemic and hypoxic conditions, while promoting migration of 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 effect of stem cells in the treatment of ischemic heart disease and vascular injury. The invention not only develops new application of ELA, but also finds new and improved strategies for regenerative medicine and cell therapy application of ADSCs.

Description

Use of ELABELA in improving adipose-derived stem cell survival and migration
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to an application of ELABELA in improving survival and migration of adipose-derived stem cells.
Background
Adipose stem cells (Adipose DERIVED STEM CELLS, ADSCs) are promising regenerative medicine and cell therapy substitutes due to their self-renewal, multipotency, proliferative capacity, abundant sources, availability, low immune rejection, etc. Studies have shown that ADSCs can transplant and survive in an infarcted myocardial environment and have a positive impact on the structure and function of the cardiovascular system. ADSCs are therefore the primary choice in myocardial repair, cardiac tissue engineering and cell regeneration therapies. However, ADSCs have poor viability, and are particularly susceptible to apoptosis in adverse environments such as hypoxia and ischemia, rendering the host environment a number of unique barriers to cell transplantation. Whereas survival, retention and localization of ADSCs in affected tissues can affect the efficacy of cell therapy, these problems are particularly apparent in the field of cardiac tissue regeneration following myocardial infarction. Therefore, improving the viability and migration ability of ADSCs, while reducing apoptosis in hypoxic and ischemic microenvironments, is an important issue to be addressed.
The polypeptide small molecule hormone ELABELA (ELA) is a polypeptide consisting of 32 amino acids, and has the sequence: QRPVNLTMRRKLRKHNCLQRRCMPLHSRVPFP. ELA is a novel endogenous peptide ligand for the G protein-coupled receptor APJ (i.e., the angiotensin receptor AT 1-related receptor protein), playing an important role in a variety of pathophysiological processes in embryonic and adult stages. Recent studies have shown that ELA can protect the cardiovascular system by promoting angiogenesis, regulating cardiac and vascular functions, etc. However, no use of ELA polypeptides for improving survival of ADSCs is seen.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention provides the application of ELA in improving the survival of ADSCs, and the research shows that the ELA has the capability of improving the survival of ADSCs cells and improves the application effect of stem cells in treating ischemic heart diseases, vascular injuries and other diseases.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
the invention provides an application of ELA in preparing a medicament for improving survival of ADSCs.
Preferably, the improvement of the survival of the ADSCs means promotion of the proliferation of the ADSCs. The ELA can be further prepared into a medicament for promoting ADSCs proliferation for application.
Preferably, the improvement of the survival of the ADSCs refers to the improvement of the cell viability of the ADSCs. The ELA can be further prepared into a medicament for improving the activity of ADSCs cells for application.
Preferably, the improvement of ADSCs survival refers to inhibition of apoptosis of adipose stem cells. The ELA can be further prepared into a medicine for inhibiting ADSCs apoptosis for application.
Preferably, the improvement of ADSCs migration refers to promotion of migration ability of ADSCs. The ELA can be further prepared into medicines for promoting ADSCs migration for application.
According to the research, the ELA can improve the viability of ADSCs cells and the migration capacity of the ADSCs by promoting proliferation, improving activity and resisting apoptosis, and is expected to be used as 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 ischemic heart diseases, vascular injuries and other diseases.
The invention also provides a medicament for improving survival of ADSCs, the medicament comprising ELA.
Preferably, the medicament further comprises other pharmaceutical ingredients capable of acting synergistically with ELA.
Preferably, the medicament further comprises a pharmaceutically acceptable carrier or excipient.
Further, the carrier or excipient comprises diluents, binders, wetting agents, disintegrants, lubricants, glidants, and the like as known in the art. Diluents include, but are not limited to, starches, dextrins, sugars, dextrose, 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, dextrose solution, acacia slurry, gelatin slurry, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, polyethylene glycol, and the like; disintegrants include, but are not limited to, dry starch, microcrystalline cellulose, low substituted hydroxypropyl cellulose, polyvinylpyrrolidone, croscarmellose sodium, sodium carboxymethyl starch, sodium dodecyl sulfonate, 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, drop pills, emulsions, solutions, patches, ointments and injections. Pharmaceutical formulations may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically), and if some 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 the apoptosis in the anoxic and ischemic microenvironment, the application of the ELA in improving the survival of the ADSCs is found by research, and the ELA can promote the survival and migration of the ADSCs and inhibit the apoptosis of the ADSCs under the anoxic and ischemic condition. These results indicate that ELA can be used as a promising stem cell treatment method for prolonging the life of ADSCs and improving the effect of stem cells in the treatment of ischemic heart diseases and vascular injury. The invention not only develops new application of ELA, but also finds new and improved strategies for regenerative medicine and cell therapy application of ADSCs.
Drawings
FIG. 1 shows the effect of ELA on ADSCs proliferation under ischemic and hypoxic conditions (A is OD450, B is cell viability);
FIG. 2 shows the results of flow cytometry validation of ELA effect on apoptosis of ADSCs under ischemic and hypoxic conditions (A is the results of flow detection, B is the statistics of apoptotic cell numbers based on flow detection);
FIG. 3 shows the results of protein validation of ELA affecting ADSCs apoptosis under ischemic and hypoxic conditions (A is a trace of Bcl-2, bax and beta-actin proteins; B is a statistical chart of Bcl-2/Bax; C is a trace of CLEAVED CASPASE-3 and GAPDH; D is a statistical chart of CLEAVED CASPASE-3/GAPDH);
FIG. 4 shows the effect of ELA on ADSCs migration under ischemic and hypoxic conditions (A is the crystal violet staining result, B is the migrated cell count).
Detailed Description
The following describes the invention in more detail. The description of these embodiments is provided to assist understanding of the present invention, but is not intended to limit the present invention. In addition, the technical features of the embodiments of the present invention described below may be combined with each other as long as they do not collide with each other.
The experimental methods in the following examples, unless otherwise specified, are conventional, and the experimental materials used in the following examples, unless otherwise specified, are commercially available.
Example 1 effect verification of ELABELA (ELA) on improving adipose Stem cell survival
(1) ELA (QRPVNLTMRRKLRKHNCLQRRCMPLHSRVPFP), synthesized by Shanghai Jier Biometrics. ELA powder has a purity of 95.31%, is stored at-20deg.C, is dissolved in PBS before use, and is sterilized with 0.22 μm filter.
(2) Isolation and culture of ADSCs
ADSCs were isolated from inguinal fat pads of male SD rats. Adipose tissues were washed 3 times with PBS buffer containing 1% of diabody (penicillin/streptomycin) under sterile conditions to remove adherent blood cells. Adipose tissue was then minced and the tissue fragments incubated with 0.1% type I collagenase, digested for 1h with shaking in a constant temperature water bath at 37 ℃, and the digestion was stopped by adding the same volume of low sugar DMEM medium containing 10% fetal bovine serum as 0.1% type I collagenase and centrifuged to separate the floating mature adipocytes from the granular stromal vascular fraction. Finally, the tissue suspension is washed 3 times by PBS buffer containing 1% of double antibody, filtered through a 200-mesh cell line and centrifuged to obtain ADSCs cells.
The ADSCs obtained were cultured in low-sugar DMEM medium containing 10% Fetal Bovine Serum (FBS) and 1% diabody, and placed under normoxic conditions (20% O 2,5％CO2). 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 they were used for the subsequent experiments at passage 3.
(3) Establishment and treatment of ADSCs hypoxia ischemia model
A total of 7 groups are arranged according to different treatment modes: (1) control group: ADSCs were cultured under normoxic conditions (20% O 2,5％CO2) as negative controls; (2) H/I group: ADSCs were cultured in low-sugar DMEM medium and anoxic conditions (1%O 2、94％N2 and 5% CO 2) in an anoxic incubator for 24 hours; (3) ELA group: ADSCs were cultured in low-sugar DMEM medium containing 20. Mu.M ELA in an anoxic incubator for 24 hours; (4) siAPJ +ela group: ADSCs were transfected with siRNA-APJ and then treated with 20. Mu.M ELA (i.e., inoculated in low-sugar DMEM medium containing 20. Mu.M ELA) and incubated in an anaerobic incubator for 24h; (5) siAPJNC +ela group: ADSCs were transfected siRNA-APJNC and then treated with 20. Mu.M ELA (i.e., inoculated in low-sugar DMEM medium containing 20. Mu.M ELA) and incubated in an anaerobic incubator for 24h.
Wherein APJ silencing by small interfering RNAs (siRNAs), siRNA-APJ (SEQ ID NO: GCCTCAGCTTTGACCGATA) and negative controls for siRNAs were synthesized by Sharp, guangzhou, china. ADSCs were transfected with Lipofectamine RNAiMax reagents (Thermo Fisher, USA) according to the procedure described, siRNA-APJ or siRNA-APJNC. During this time, ADSCs were incubated in medium without diabody for 6-8h.
(4) Cell viability assay:
Cell viability was determined using cell counting kit 8 (CCK-8). After the prescribed treatment, 100. Mu.L of the cell suspension (4X 10 3 cells per well) was inoculated into a 96-well plate and cultured for 24 hours, followed by addition of 10. Mu.L of CCK-8 reagent and culture at 37℃for 2 hours. Next, absorbance at 450nm was measured using a microplate reader. The percentage of cell viability was then calculated by the average Optical Density (OD) in each group. Cell viability = (experimental well-blank well)/(control well-blank well) ×100%.
(5) Cell migration assay
The migration of cells was examined using a Transwell chamber with a pore size of 8 μm, and the Transwell chamber was placed in a 24-well plate. ADSCs (density of 1X 10 5 cells per well) with 200. Mu.L of low-sugar DMEM in the indicated treatment (7 treatments of step (2)) were inoculated in the upper chamber, and 600. Mu.L of low-sugar DMEM containing 10% FBS was added to the lower chamber. The 24-well plate was placed in an incubator at 37℃for 12 hours. Cells on the lower surface of the upper chamber were gently rinsed 3 times with PBS and then fixed with 4% paraformaldehyde for 30min at room temperature. Finally, the upper chamber was placed in 0.1% crystal violet dye to stain the cells, and then the cells that did not migrate to the bottom layer were removed with a cotton swab. Five photographs were taken randomly for each group and the cell number was calculated.
(6) Apoptosis assay
Referring to the instructions, the Annexin V-FITC/PI apoptosis detection kit was used to assess apoptosis of ADSCs. First, ADSCs treated (7 treatments of step (2)) were obtained 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 1X bindingbuffer. Add 5. Mu. LAnnexinV-FITC, mix gently, incubate at 4℃for 15min in the dark, add 5. Mu.LPI, mix gently, incubate at 4℃for 5min in the dark. Then, 400. Mu.L of 1X bindingbuffer was added to each group. Finally, the cell samples were examined by flow cytometry in one hour.
(7) Western blot
ADSCs treated in the 7 treatment groups described above were washed 1 pass with PBS and lysed on ice with RIPA lysate containing 10uL/mL protease and 10uL/mL phosphatase inhibitor for 30 min. The respective sets of mixed solutions were then recovered, centrifuged at 12,000Xg for 20min, and the respective sets of supernatants were collected and assayed for protein concentration by the BCA assay kit. After mixing with SDS loading buffer, the collected proteins were heated at 100℃for 10min, then protein samples of the same mass were separated by 12% SDS-PAGE and transferred to 0.2 μm PVDF membranes, the membranes were blocked with blocking solution (1 XTBE containing 5% skim milk) for 1h at room temperature and incubated overnight at 4℃with primary antibodies including APJ、Bcl-2、cleaved Caspase-3,phospho-p44/42MAPK(p-ERK1/2),p44/42MAPK(ERK1/2),phospho-p38 MAPK,p38MAPK,phospho-SAPK/JNK,SAPK/JNK,phospho-p53,p53,β-actin and GAPDH. The next day the membranes were washed 3 more times with 1 XTBE for 10min each, followed by incubation of the membranes with anti-rabbit secondary antibodies or anti-mouse secondary antibodies for 1h at room temperature. Finally, the film was washed 3 times with 1 XTBST for 10min each and the chemiluminescent reagent-treated strips were detected with an exposure instrument.
(8) Experimental results
In FIG. 1, the OD450 and cell viability of ADSCs cells were significantly reduced after APJ was silenced by siRNA and under hypoxic conditions, but after ELA was added to the medium under hypoxic conditions, the OD450 and cell viability of ADSCs cells were comparable to that of normal culture, indicating that ELA promoted proliferation of ADSCs and increased viability of cells under ischemic and hypoxic conditions.
In FIG. 2, ADSCs cells undergo substantial apoptosis after silencing APJ under hypoxic conditions and siRNA, but after ELA is added to the culture medium under hypoxic conditions, the number of apoptosis is significantly reduced, indicating that ELA can reduce apoptosis of ADSCs under ischemic and hypoxic conditions.
In FIG. 3, bcl-2,Bax,cleaved Caspase-3 (cleaved cysteine aspartate proteolytic enzyme-3) and GAPDH (glyceraldehyde 3-phosphate dehydrogenase) are important apoptosis-related proteins, of which 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. The expression level of Bcl-2/Bax and CLEAVED CASPASE-3/GAPDH of ADSCs cells after silencing APJ under the anoxic condition and siRNA shows to be increased, but the corresponding expression level is obviously reduced after ELA is added into a culture medium under the anoxic condition, which further indicates that the ELA can reduce apoptosis of ADSCs under the anoxic condition.
In FIG. 4, ADSCs cells showed a significant decrease in cell migration after silencing APJ under hypoxic conditions and siRNA, but showed a significant increase in migration after addition of ELA to the medium under hypoxic conditions, indicating that ELA promoted migration of ADSCs under ischemic conditions
The analysis shows that ELA can improve the viability of ADSCs cells and the migration capacity of ADSCs by promoting proliferation, improving activity and resisting apoptosis, and can be used for prolonging the service life of ADSCs and improving the application effect of stem cells in treating ischemic heart diseases, vascular injuries and other diseases.
The embodiments of the present invention have been described in detail above, 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 to these embodiments without departing from the principles and spirit of the invention, and yet fall within the scope of the invention.
Sequence listing
<110> Eighth Hospital affiliated to university of Zhen Futian (Shenzhen)
Use of <120> ELABELA to improve adipose stem cell survival and migration
<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 (4)

1. An application of ELABELA protein in promoting proliferation of adipose-derived stem cells under ischemia and hypoxia conditions for non-disease diagnosis and treatment.
2. An application of ELABELA protein in improving the survival of adipose-derived stem cells under the condition of ischemia and hypoxia for the purpose of non-disease diagnosis and treatment.
3. An application of ELABELA protein in inhibiting fat stem cell apoptosis under ischemia and anoxia condition for non-disease diagnosis and treatment.
4. An application of ELABELA protein in promoting migration of adipose-derived stem cells under ischemia and hypoxia conditions for the purpose of non-disease diagnosis and treatment.
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KR102035716B1 (en) * 2017-12-01 2019-10-23 주식회사 엠디뮨 Pharmaceutical composition for preventing or treating of pulmonary disease comprising mesenchymal stem cell-derived artificial nanosomes

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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
CN110960671A (en) * 2019-12-25 2020-04-07 广州中医药大学(广州中医药研究院) New application of Elabela polypeptide and medicine thereof

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Peptide hormone ELABELA promotes rat bone marrow-derived mesenchymal stem cell proliferation and migration by manipulating the cell cycle through the PI3K/AKT pathway under the hypoxia and ischemia microenvironment;Xuxiang Chen等;《Stem Cell Research & Therapy》;第13卷(第32期);摘要、第4页左栏第1段 *
PI3K/Akt通路在低氧诱导脂肪干细胞增殖和向内皮细胞分化中的作用;殷令妮等;《中国组织工程研究》;第24卷(第19期);第3004页摘要 *

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