CN117398427B - Application of pharmaceutical composition containing iPS induced directional differentiation into myocardial cells in treatment of heart failure - Google Patents
Application of pharmaceutical composition containing iPS induced directional differentiation into myocardial cells in treatment of heart failure Download PDFInfo
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- CN117398427B CN117398427B CN202311713715.7A CN202311713715A CN117398427B CN 117398427 B CN117398427 B CN 117398427B CN 202311713715 A CN202311713715 A CN 202311713715A CN 117398427 B CN117398427 B CN 117398427B
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- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 229960000103 thrombolytic agent Drugs 0.000 description 1
- 230000002537 thrombolytic effect Effects 0.000 description 1
- 208000037816 tissue injury Diseases 0.000 description 1
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- 229920001664 tyloxapol Polymers 0.000 description 1
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Abstract
The invention relates to the use of a pharmaceutical combination comprising iPS-induced committed differentiation into cardiomyocytes for the treatment of heart failure. The application can effectively treat heart failure, and further has better effect of treating myocardial infarction after the myocardial cells obtained by induction and differentiation are used together with the salvia miltiorrhiza injection, and the myocardial cells and the salvia miltiorrhiza injection can be effectively used for preparing a medicine combination for heart failure after being combined for use, so that the application prospect is better.
Description
Technical Field
The present application relates to the field of biology, in particular to the use of a pharmaceutical combination comprising iPS induced committed differentiation into cardiomyocytes for the treatment of heart failure.
Background
The iPS cells are very similar to ES cells in terms of cell morphology, growth characteristics, stem cell marker expression and the like, are almost identical to ES cells in terms of DNA methylation mode, gene expression profile, chromatin state, chimeric animal formation and the like, have strong self-renewal capacity and high differentiation capacity. At present, the iPS cells can be induced to generate all 210 cells forming a human body in vitro, and have infinite disease treatment prospect. In theory, when tissues or organs cultured by the iPS cells are transplanted back into the body of the original patient, the attack problem of an autoimmune system can be avoided, and meanwhile, the ethical problem generated by the prior ES cells can be radically solved. Therefore, iPS cells become an important cell source of interest in regenerative medicine. Stem cell technology has subverted the idea of medical treatment, and future therapeutic drugs are not various chemical compositions, but are in the form of cells, and the problem cells holding the cells are solved, and substances with activities such as small molecular proteins, antibodies, stem cells and the like are sent into the body, so that the diseases are treated. Induced pluripotent stem cells (iPS stem cells), which function to differentiate and constitute various cells of the body, can be produced in a very small amount of skin fragments or blood. The mountain extension of the japanese stem cell scientist is due to the successful reversion of adult cells to iPS cells, which gave great acceptance of the nobel biomedical prize in 2012.
The existing iPS treatment is a very hot stem cell type, and comprises 9 diseases such as cornea transplantation, parkinson's disease, macular degeneration, heart disease, spinal cord disease, transfusion disease, arthritis, type I diabetes and leukemia, and the use of the iPS stem cells is possible in clinical treatment in the next few years.
In recent years, the use of IPS cells has made some progress in the field of treatment of severe chronic ischemic heart failure. A research team of cardiovascular surgery at University of Osaka, japan, used clinical treatment studies of induced pluripotent stem cells (IPS) for ischemic cardiomyopathy, obtained conditional approval by japanese regulatory authorities recently. The international clinical application of IPS has been studied for a few but the japan is in the leading position. In recent years, a team led by the advanced acronym (Masayo Takahashi) institute of RIKEN, japan, first began clinical studies in patients with ophthalmic macular degeneration using IPS cells. Conventionally, cell therapy for heart failure has been mainly performed by: bone marrow cells, vascular endothelial precursor cells, skeletal muscle cells, mesenchymal stem cells or cardiac stem cells. University of osaka japan announced that a myocardial membrane has been successfully transplanted for patients with cardiac insufficiency, and that this membrane was cultured using iPS cells. In short, patients with severe myocardial infarction or even heart failure in the future can rescue the heart with stem cells without relying on artificial hearts or donation of an inexhaustible organ. The use of IPS-induced differentiated cardiomyocytes in heart disease patients is still the first innovative work.
The clinical test application of the 'human iPSC-derived myocardial cell injection' product (HiCM-188) which is independently developed in China is approved, and the product is prepared by utilizing myocardial cells differentiated from IPS cells. It can be used for treating severe chronic ischemic heart failure by intravenous injection. Compared with the traditional treatment method, the treatment method is safer, and the heart function and the life quality of the patient can be obviously improved. The development of chemical induction methods further enriches the methods of somatic "reprogramming". By using some small chemical molecules, somatic cells can be promoted to become stem cells with multipotency again, and then differentiate into cardiomyocytes. The method has the advantages of simple and convenient operation and high efficiency, and can avoid ethical problems possibly brought by using a gene editing technology to carry out cell transformation. In addition, iPS cells formed by processing the patient's own cells, the tissue or organ cultured from the iPS cells will be considered as autologous tissue after being transplanted again into the patient, and thus can avoid the attack of the immune system. The method has the advantages of avoiding immune rejection reaction, thereby improving the safety and effectiveness of treatment.
In conclusion, the technology of differentiating IPS cells into myocardial cells has a broad application prospect in the field of heart failure treatment. In the future, as related researches are advanced, the technology is expected to bring good news to more patients. However, there is currently insufficient research on differentiation of IPS cells into cardiomyocytes, and the provision of alternative products is not yet mature enough.
Disclosure of Invention
The invention provides a method for treating heart failure by combining induced myocardial cells with red sage root injection against the defects of the prior art.
The cardiomyocytes are specifically prepared by the method well described in the prior patent application (application number: CN 202311628005.4) of the applicant.
Specifically, the preparation method of the myocardial cells comprises the following steps: regulating cell number of skin fibroblast to 1×10 6 Adding 3 mu l of reprogramming factors in an Epi5 (TM) Epicomal iPSC reprogramming kit into 100 mu l of electrotransfection buffer solution, inoculating conventional electrotransfected cells into a 6-well plate coated with matrigel according to 2 ml/well, and culturing in an incubator; the ReproTeSRTM reprogramming culture medium is used for changing liquid every other day, cells are digested and re-inoculated on a feeder layer made of 5 th generation mouse fibroblasts on 8 th day after transfection, the culture is carried out for 18 days, typical clones seen by iPSCs are observed, ips clones are re-inoculated in a 6-hole plate coated by matrigel, the 6-hole plate is placed in an incubator for culture, and mTESRTM culture medium is used for continuous culture; preparing a myocardial differentiation complete culture medium I, II and a solution III according to the description of a CardioEasy human myocardial cell differentiation kit, sucking the stock solution when the prepared iPSCs grow to 80% fusion, cleaning by using PBS, adding 2mL of myocardial differentiation I solution which contains 200 mug/mL of SKP2-3F2 monoclonal antibody, sucking old solution after 48 hours, and adding the myocardial differentiation II solution which contains 200 mug/mL of SKP2-3F2 monoclonal antibody according to claim 1 after cleaning by using PBS; changing into myocardial differentiation III solution containing 200 mug/mL of SKP2-3F2 monoclonal antibody after 48h, continuously culturing in a 5% CO2 incubator at 37 ℃ and changing the culture solution every 48h, wherein each changing culture solution contains 200 mug/mL of SKP2-3F2 monoclonal antibody until cell pulsation is observed, thus obtaining differentiated myocardial cells. The variable region sequence of the light chain of the SKP2 monoclonal antibody is shown as SEQ ID NO:1, the heavy chain variable region sequence is shown as SEQ ID NO: 2. The affinity of the monoclonal antibody is 5.63×10 9 M -1 Can specifically recognize and inhibit the function of SKP2 protein. The monoclonal antibody is a monoclonal antibody prepared by hybridoma technology after mice are immunized by SKP2 recombinant protein, and is specifically described in the prior patent application (application number: CN 202311628005.4) of the applicant.
Furthermore, the invention provides a pharmaceutical composition for treating heart failure, which consists of the myocardial cells induced to differentiate and the salvia miltiorrhiza injection.
In particular, the inventionThe amount of myocardial cells transplanted was about 1X10 6 ～5×10 6 And each.
The dosage of the red sage root injection is 1-10 g/(kg.d).
Furthermore, the myocardial cells in the pharmaceutical composition of the invention comprise a pharmaceutically acceptable carrier.
Examples of suitable pharmaceutically acceptable excipients include one or more polymers, wetting agents or surfactants, pH adjusting agents, isotonicity adjusting agents, preservatives, buffers and chelating agents, or any combination thereof.
Examples of suitable pharmaceutically acceptable pH adjusting agents include, but are not limited to, sodium hydroxide, citric acid, hydrochloric acid, boric acid, acetic acid, phosphoric acid, succinic acid, sodium hydroxide, potassium hydroxide, ammonium hydroxide, magnesium oxide, calcium carbonate, magnesium carbonate, aluminum magnesium silicate, malic acid, potassium citrate, sodium phosphate, lactic acid, gluconic acid, tartaric acid, 1,2,3, 4-butane tetracarboxylic acid, fumaric acid, diethanolamine, monoethanolamine, sodium carbonate, sodium bicarbonate, triethanolamine, or any combination thereof. In one embodiment, the pharmaceutically acceptable pH adjusting agent is present in an amount of about 0.01% to about 2.0% (w/v), preferably about 0.05% to about 1% (w/v).
Examples of suitable pharmaceutically acceptable preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride and cetylpyridinium chloride, benzyl bromide, benzyl alcohol, disodium EDTA, phenylmercuric nitrate, phenylmercuric acetate, sodium ethylmercaptide, thimerosal, acetate and phenylmercuric borate, polymyxin B sulfate, chlorhexidine, methyl and propyl p-hydroxybenzoates, phenethyl alcohol, quaternary ammonium chloride salts, sodium benzoate, sodium propionate, stabilized oxy chloride complex (stabilized oxychloro complex), sorbic acid, or mixtures thereof. Preferred pharmaceutically acceptable preservatives include disodium EDTA (disodium edetate) and benzalkonium chloride or mixtures thereof. In one embodiment, the pharmaceutically acceptable preservative is present in an amount of about 0.01% to about 2.0% (w/v), preferably about 0.05% to about 1% (w/v).
Examples of suitable pharmaceutically acceptable buffers include, but are not limited to, sodium chloride, dextrose, lactose, and Phosphate Buffered Saline (PBS) or any combination thereof. Other suitable pharmaceutically acceptable buffers include, but are not limited to, disodium succinate hexahydrate, borates, citrates, phosphates, acetates, physiological saline, tris-HCl (tris (hydroxymethyl) aminomethane hydrochloride), HEPES (N-2-hydroxyethylpiperazine-N' -2-ethanesulfonic acid (N-2-hydroxyethyl piperazine-N1-2-ethane sulfonic acid)), sodium phosphate, sodium borate, physiological saline, citrates, carbonates, phosphates, and/or mixtures thereof to achieve the desired osmolarity (osmoticity). In one embodiment, the pharmaceutically acceptable buffer is present in an amount of about 0.01% to about 2.0% (w/v), preferably about 0.05% to about 1% (w/v).
Examples of suitable pharmaceutically acceptable chelating agents include, but are not limited to, ethylenediamine tetraacetic acid (EDTA), disodium EDTA and derivatives thereof, citric acid and derivatives thereof, nicotinamide and derivatives thereof, sodium deoxycholate and derivatives thereof, or mixtures of these chelating agents. In one embodiment, the pharmaceutically acceptable chelating agent is present in an amount of about 0.01% to about 2.0% (w/v), preferably about 0.05% to about 1% (w/v).
Examples of suitable pharmaceutically acceptable polymers include, but are not limited to, cellulose derivatives (e.g., hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methylcellulose, methylcellulose polymers, hydroxyethyl cellulose, sodium carboxymethyl cellulose, carboxymethyl hydroxyethyl cellulose, and carboxymethyl hydroxyethyl cellulose (carboxymethylene and carboxymethyl hydroxyethylcellulose) or any combination thereof), acrylates (e.g., acrylic acid, acrylamide, and maleic anhydride polymers, copolymers, or mixtures thereof), and mixtures thereof. Polymer blends may also be used. A preferred pharmaceutically acceptable polymer is hydroxyethylcellulose. In one embodiment, the pharmaceutically acceptable polymer is present in an amount of about 0.01% to about 5.0% (w/v), preferably about 0.05% to about 2% (w/v), more preferably about 0.1% to about 1.0% (w/v), for example about 0.1%, 0.2%, 0.5% or 1.0% (w/v).
Examples of suitable pharmaceutically acceptable wetting agents or surfactants include, but are not limited to, amphoteric, nonionic, cationic or anionic molecules. Suitable surfactants include, but are not limited to, polysorbate, sodium dodecyl sulfate (sodium lauryl sulfate), dodecyldimethylamine oxide, docusate sodium, cetyltrimethylammonium bromide (CTAB), polyethoxylated alcohols, polyoxyethylene sorbitan, octoxynol, N, N-dimethyldodecylamine-N-oxide, cetyltrimethylammonium bromide, polyoxyethylene (10) lauryl ether, surfactants (vegetable oil-based fatty alcohol polyoxyethylene ethers derived from lauryl alcohol, cetyl alcohol, stearyl alcohol and oleyl alcohol), bile salts (e.g., sodium deoxycholate and sodium cholate), polyoxyethylene castor oil, nonylphenol ethoxylates, cyclodextrins, lecithins, benzalkonium chloride, carboxylates, sulfonates, petroleum sulfonates, alkylbenzenesulfonates, naphthalene sulfonates, olefin sulfonates, alkyl sulfates, sulfated natural oils and fats, sulfated esters, sulfated alkanolamides, alkylphenols (ethoxylated and sulfated), ethoxylated fatty alcohols, polyoxyethylene surfactants, carboxylic acid esters, polyethylene glycol esters, sorbitan esters and ethoxylated derivatives thereof, fatty acid glycol esters, carboxamide, monoalkanolamides, polyoxyethylene acid condensate, polyoxyethylene amide, N-3-ethyl-3-amino-2-N-3-hydroxyethyl-aminopropionate, N-3-hydroxyethyl amide, and 3-hydroxyethyl-3-aminopropionic amine substituted by-N-3-alkyl amine, N-3-hydroxyethyl amide, N-3-alkyl-N-alkyl sulfate, N-polyoxyethylene ether, disodium N-tallow-3-iminodipropionate (N-tallow 3-iminodipropionate disodium salt), N-carboxymethyl-N, N-dimethyl-N-9-octadecenylammonium hydroxide (N-carboxymethyl N dimethyl N-9octadecenyl ammonium hydroxide), N-cocoamidoethyl-N-hydroxyethyl glycine sodium salt and the like, polyoxyethylene, sorbitan monolaurate and stearate, (polyethoxylated castor oil), (ethylene oxide/12-hydroxystearic acid), polysorbate, tetrabutyl phenol aldehyde, and any combinations thereof. Preferred pharmaceutically acceptable surfactants include tyloxapol and (sorbitan monooleate) or mixtures thereof.
The invention further provides a method of treating a heart condition comprising administering an induced cardiomyocyte of the invention. In some embodiments, the heart condition or disease is selected from pediatric cardiomyopathy, age-related cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, chronic ischemic cardiomyopathy, perinatal cardiomyopathy, inflammatory cardiomyopathy, other cardiomyopathy, myocarditis, myocardial ischemia reperfusion injury, ventricular dysfunction, heart failure, congestive heart failure, coronary artery disease, end-stage heart disease, atherosclerosis, ischemia, hypertension, restenosis, angina pectoris, rheumatic heart disease, arterial inflammation, or cardiovascular disease.
The method comprises administering a composition comprising a therapeutically effective amount of any of the isolated, engineered differentiated cardiomyocytes described herein. In some embodiments, the composition further comprises a therapeutically effective carrier. In some embodiments, administering comprises implanting cardiac tissue of the patient, intravenous injection, intra-arterial injection, intra-coronary injection, intramuscular injection, intraperitoneal injection, intramyocardial injection, endocardial injection, epicardial injection, or infusion.
In some embodiments, the vascular condition or disease is selected from the group consisting of vascular injury, cardiovascular disease, vascular disease, ischemic disease, myocardial infarction, congestive heart failure, hypertension, ischemic tissue injury, limb ischemia, stroke, neuropathy, and cerebrovascular disease.
In some embodiments, the cardiac drug is also administered to a patient administered differentiated cardiac cells. Illustrative examples of cardiac drugs suitable for combination therapy include, but are not limited to, growth factors, polynucleotides encoding growth factors, angiogenic agents, calcium channel blockers, hypotensive agents, antimitotics, inotropic agents, anti-atherosclerosis agents, anticoagulants, beta blockers, antiarrhythmic agents, anti-inflammatory agents, vasodilators, thrombolytics, cardiac glycosides, antibiotics, antiviral agents, antifungal agents, protozoan inhibiting agents, nitrates, angiotensin Converting Enzyme (ACE) inhibitors, angiotensin II receptor antagonists, brain Natriuretic Peptides (BNP); antitumor agents, steroids, etc.
Advantageous effects
The invention provides a method for improving induction differentiation of ips cells into myocardial cells by single monoclonal antibody treatment. The myocardial cells obtained by the induced differentiation and the red sage root injection have better effect of treating myocardial infarction after being used together, and the myocardial cells and the red sage root injection can be effectively used for preparing a medicine combination for heart failure after being combined for use, thus having better application prospect.
Drawings
FIG. 1 comparison of results of echocardiographic LVFS examinations of groups after cell injection
FIG. 2 comparison of results of the echocardiographic LVEF examinations of groups after cell injection
Description of the embodiments
Specific embodiments of the present invention will be described in more detail below with reference to the accompanying drawings. While specific embodiments of the invention are shown in the drawings, it should be understood that the invention may be embodied in various forms and should not be limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.
Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the presently described subject matter belongs.
EXAMPLE 1 preparation of ips cells by dermal fibroblasts
The skin of the children foreskin isolated after the operation was taken about 0.3cm×0.3cm, and after repeated rinsing in HBSS containing penicillin (100 kU/L) and streptomycin (100 mg/L), subcutaneous fat was removed. The skin was cut to 1mm with an ophthalmic scissors in a 60mm dish 2 Size, placed in 3ml of DMEM/F12 (1:1) solution containing penicillin (100 kU/L) and streptomycin (100 mg/L) at 37℃in a volume fraction of 5% CO 2 95% air, saturation humidityThe incubator was left overnight. Removing sweat gland in the next day, sucking old culture solution when fibroblast growth is obvious, washing with HBSS without Na+ and Mg2+ for 2 times, adding D-Hank digestion solution containing 0.25% pancreatin and 0.02% ethylenediamine tetraacetic acid (EDTA) by mass fraction at about 1ml 37deg.C, placing in 5% CO 2 Incubating for 2min with 95% air and saturated humidity, adding DMEM containing 10% fetal bovine serum about 2ml to stop digestion, centrifuging for 6min at 1000r/min and collecting cells, dispersing cells with DMEM containing fetal bovine serum (10%), penicillin (100 kU/L) and streptomycin (100 mg/L), and mixing cells at 1×10 4 Inoculating/ml with 4ml to 25cm medium at 37deg.C with 5% CO 2 Culturing under the conditions of 95% air and saturated humidity, and obtaining purified fibroblasts after continuous 5 times of subculture. HE staining is carried out on a small number of cells, the cells are long fusiform, the cell nucleus is light blue, the cell plasma is pink, 46 chromosomes are shown by chromosome karyotype analysis, and the relatively pure fibroblast is obtained by identification.
Regulating cell number of isolated and cultured skin fibroblast to 1×10 6 Mu.l of Epi5 was added to 100. Mu.l of electrotransport buffer TM The reprogramming factors in the Epicomal iPSC reprogramming kit are inoculated into a 6-well plate coated with matrigel by adopting conventional electrotransfected cells according to the ratio of 2 ml/well, and are placed in an incubator for culture. And use ReproTeSR TM The reprogramming culture medium is changed every other day, the liquid is changed after transfection, the cells are inoculated on a feeder layer made of 5-generation mouse fibroblasts after digestion, typical cloning is observed by observing iPSCs on the 18 th day, and positive expression of OCT4, SOX2, NANOG, KLF4 and LIN28 is found by detecting stem cell multipotency genes by using a kit, which indicates that ips cells are prepared. Re-inoculating the screened positive ips clone into a 6-well plate coated with matrigel, culturing in an incubator, and using mTESR TM The culture medium is continuously cultured, and is screened and purified for standby.
Furthermore, in order to test the activity of the ips cells, the prepared ips cells are subjected to in vitro suspension culture to form EBs, RNA is extracted from the lysed cells, and the RNA is used for detecting the gene expression quantity of the EB cells by RT-PCR, and the results show that the expression levels of the germ layer differentiation genes ectodermal Nestin, mesodermal Eomes and endodermal AFP of the EB cells are all obviously higher than that of the ips cells of a control group by more than 5 times (P < 0.01), and the experimental results show that the established human ips cells have in vitro differentiation capacity.
Example 2 differentiation of ips cells into cardiomyocytes
No antibody induction group: the preparation of the myocardial differentiation complete medium I, II and III liquid and the equilibration to room temperature were carried out according to the description of CardioEasy human myocardial cell differentiation kit (Beijing Seebeck Biotechnology Co., ltd., cat. No. CA 2004500). Sucking out stock solution when iPSCs prepared in example 4 grow to 80% fusion, cleaning with PBS, adding 2mL of myocardial differentiation I solution, sucking out old solution after 48h, and adding myocardial differentiation II solution after PBS cleaning; after 48h, the mixture was changed to myocardial differentiation III solution at 37℃with 5% CO 2 The incubator continues to culture, changing the culture medium every 48 hours until the cells are observed beating.
There were antibody-induced groups: the iPSCs prepared in example 1 were grown to 80% confluence, stock solution was aspirated, washed with PBS, 2mL of myocardial differentiation I solution (containing 200. Mu.g/mL of SKP2-3F2 monoclonal antibody) was added, old solution was aspirated after 48h, and myocardial differentiation II solution (containing 200. Mu.g/mL of SKP2-3F2 monoclonal antibody) was added after PBS washing; after 48h, the mixture was changed to myocardial differentiation III solution (wherein the final concentration of SKP2-3F2 monoclonal antibody was 200. Mu.g/mL), 37℃and 5% CO 2 The incubator was kept in culture, and the culture medium was changed every 48 hours, and each change of culture medium contained 200. Mu.g/mL of the purified SKP2-3F2 monoclonal antibody of example 2, until cell pulsation was observed.
Group 2 was induced to 15d and the beating cells were collected 1X10 7 The sample was kept at one/mL. Pulsating cells are fixed by adopting 4% paraformaldehyde, 0.2% TritonX-100 is treated for 1h,5% skimmed milk is incubated for 2h, TNNT-2 (1:200) and alpha-actinin primary antibody are incubated, alexaFluor488 secondary antibody is added for incubation at normal temperature, nuclear DAPI staining and fluorescent microscopy observation and photographing are carried out. The results showed that both the cardiac markers TNNT-2 and α -actinin were expressed in beating cells, indicating differentiation into viable cardiomyocytes.
Example 3 construction of mouse model for myocardial infarction and verification of therapeutic Effect
BALB/C male mice were divided into normal group (without intervention), acute myocardial infarction group (AMI molding), experimental group 1 (acute myocardial infarction molding+no antibody induction myocardial cell injection), experimental group 2 (acute myocardial infarction molding+no antibody induction myocardial cell injection+red sage root injection lavage), experimental group 3 (acute myocardial infarction molding+antibody induction myocardial cell injection), experimental group 4 (acute myocardial infarction molding+antibody induction myocardial cell injection+red sage root injection lavage), 5 groups each.
The modeling method of the myocardial infarction mouse model comprises the steps of making a neck middle incision after local anesthesia of the mouse, penetrating a 22G needle into a trachea, connecting an artificial respirator, entering a thoracic cavity between 4-5 ribs of a left chest, separating pericardium, ligating a left anterior descending branch of a coronary artery by passing through a 8-0 suture between a pulmonary artery and a left auricle at the root of an aorta, presenting a dark red prompt success at the far end, stitching the thoracic cavity layer by layer, carrying out electrocardiography immediate tracing by a multi-guide physiological recorder, carrying out ultrasonic electrocardiography examination, presenting typical left ventricular reconstruction characteristics, showing left ventricular chamber enlargement (LVDd and LVDs increase), and weakening left ventricular contractility (LVEF and LVFS decrease), and prompting success of preparation of an AMI animal model.
The induced cardiomyocytes prepared as described above were resuspended in PBS and the density was adjusted to 2X 10 7 20. Mu.L of the suspension was injected around the infarcted myocardial region 30min after surgery and the chest was closed and sutured layer by layer. Extracting the cannula after spontaneous breathing is recovered, tightly suturing, intramuscular injection of 20000U penicillin, and single-cage feeding; the dosage of the red sage root injection is [5 g/(kg.d) ] [ corresponding to 0.560 g/(kg.d) ] of the adult dosage, and the injection is administrated by stomach irrigation.
An ultrasonic cardiography examination was performed on day 15 after cardiac function assessment, and left ventricular end-diastole (LVDd), left ventricular end-Systole (LVDs), left ventricular end-diastole volume (LEDV), left ventricular end-systole volume (LESV) were recorded, and Left Ventricular Ejection Fraction (LVEF) and left ventricular short axis foreshortening rate (LVFS) were calculated. Lvef= (EDV-ESV)/EDV; lvfs= (LVDd-LVDs)/lvdd×100%. Statistical methods data analysis was performed using graphpadprism8.02 software. The measurement data conforming to the normal distribution is expressed by mean ± standard deviation (x±s), the mean comparison among the groups adopts single factor analysis of variance, and the multiple comparison among the groups adopts GamesHowell test. P < 0.05 is statistically significant for the differences. The results are shown in fig. 1 and 2.
As can be seen from fig. 1, the model group had significantly lower LVFS, P <0.01, compared to the normal group. After treatment of groups 1-4, LVFS was significantly improved, as can be seen from figure 1, the LVFS value for treatment with antibody-induced cardiomyocytes (group 3) was about 10% higher than that for treatment without antibody-induced cardiomyocytes (group 1), which demonstrates from the side that cardiomyocytes induced with monoclonal antibodies have better biological activity. After the synergistic treatment of the injection of the red sage root, the value of LVFS can be effectively improved, which also shows that the injection of the red sage root can inhibit myocardial cell apoptosis by activating the Akt pathway known in the art and promote cell proliferation to improve the treatment effect of myocardial infarction.
As can be seen from the results of fig. 2, the model group showed a significant decrease in LVEF and P <0.01 compared to the normal group, similar to the results of fig. 1. After treatment of groups 1-4, LVEF was significantly improved, as can be seen from figure 2, the LVEF values for treatment with antibody-induced cardiomyocytes (group 3) were about 3.4% higher than those without antibody-induced cardiomyocytes (group 1), which demonstrates from the side that cardiomyocytes induced with monoclonal antibodies have better biological activity. After the co-therapy of the injection of the red sage root is adopted, the LVEF value can be effectively improved.
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and not for limiting the same; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some or all of the technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit of the invention.
Claims (3)
1. A pharmaceutical composition for treating heart failure, characterized in that directed differentiation is induced by IPSThe prepared cardiomyocyte and red sage root injection; wherein the cardiomyocytes induced by IPS to directionally differentiate are prepared by the following method: regulating cell number of skin fibroblast to 1×10 6 Adding 3 mu l of reprogramming factors in an Epi5 (TM) Epicomal iPSC reprogramming kit into 100 mu l of electrotransfection buffer solution, inoculating conventional electrotransfected cells into a 6-well plate coated with matrigel according to 2 ml/well, and culturing in an incubator; the ReproTeSRTM reprogramming culture medium is used for changing liquid every other day, cells are digested and re-inoculated on a feeder layer made of 5 th generation mouse fibroblasts on 8 th day after transfection, the culture is carried out for 18 days, typical clones seen by iPSCs are observed, ips clones are re-inoculated in a 6-hole plate coated by matrigel, the 6-hole plate is placed in an incubator for culture, and mTESRTM culture medium is used for continuous culture; preparing a myocardial differentiation complete medium I, II and a myocardial differentiation complete medium III according to a CardioEasy kit instruction, sucking the stock solution when the prepared iPSCs grow to 80% fusion, cleaning by using PBS, adding 2mL of the myocardial differentiation complete medium I solution containing 200 mug/mL of SKP2-3F2 monoclonal antibody, sucking the old solution after 48 hours, and adding the myocardial differentiation complete medium II solution containing 200 mug/mL of SKP2-3F2 monoclonal antibody after PBS cleaning; changing the culture solution into a myocardial differentiation complete culture medium III solution after 48 hours, wherein the culture solution contains 200 mug/mL of SKP2-3F2 monoclonal antibody, continuously culturing in a culture box with 5% CO2 at 37 ℃, changing the culture solution every 48 hours, and changing the culture solution each time to contain 200 mug/mL of SKP2-3F2 monoclonal antibody until the cell pulsation is observed, thus obtaining differentiated myocardial cells, wherein the variable region sequence of the light chain of the SKP2-3F2 monoclonal antibody is shown as SEQ ID NO:1, the heavy chain variable region sequence is shown as SEQ ID NO: 2.
Use of IPS-induced committed differentiated cardiomyocytes and a red sage root injection for the preparation of a pharmaceutical composition for the treatment of heart failure, wherein said IPS-induced committed differentiated cardiomyocytes are obtained by the method of claim 1.
3. The use according to claim 2, wherein said IPS induces directed differentiation intoThe transplantation amount of cardiomyocytes was 1×10 6 ～5×10 6 And each.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2012227337A1 (en) * | 2006-01-31 | 2012-10-18 | Daiichi Sankyo Company, Limited | A method for purifying cardiomyocytes or programmed cardiomyocytes derived from stem cells or fetuses |
| CN106399232A (en) * | 2016-09-08 | 2017-02-15 | 青海七彩花生物科技有限公司 | Method for inducing cardiac stem cell to be directionally differentiated into myocardial cell |
| JP2017176004A (en) * | 2016-03-29 | 2017-10-05 | テルモ株式会社 | Cell cultures and production methods thereof |
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| US9068167B2 (en) * | 2009-11-13 | 2015-06-30 | Wisconsin Alumni Research Foundation | Cardiac differentiation of human pluripotent stem cells under defined conditions using matrix overlay methods |
| WO2013006364A1 (en) * | 2011-07-05 | 2013-01-10 | Baylor Research Institute | Establishment of patient - or person - specific cardiac myocyte cell lines from human induced pluripotent stem cells (ipscs) |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2012227337A1 (en) * | 2006-01-31 | 2012-10-18 | Daiichi Sankyo Company, Limited | A method for purifying cardiomyocytes or programmed cardiomyocytes derived from stem cells or fetuses |
| JP2017176004A (en) * | 2016-03-29 | 2017-10-05 | テルモ株式会社 | Cell cultures and production methods thereof |
| CN106399232A (en) * | 2016-09-08 | 2017-02-15 | 青海七彩花生物科技有限公司 | Method for inducing cardiac stem cell to be directionally differentiated into myocardial cell |
Non-Patent Citations (5)
| Title |
|---|
| Wang, Yongfang等.N-myc downstream regulated gene 1(NDRG1) promotes the stem-like properties of lung cancer cells through stabilized c-Myc.《Cancer Letters》.2017,第401卷53-62. * |
| 中药注射液防治慢性心力衰竭的研究进展;李幕云等;《世界最新医学信息文摘》;20191119;第19卷(第93期);95-96 * |
| 人牙源性iPSCs分化心肌细胞促进急性心肌梗死小鼠心肌修复的研究;谭小兵等;《天津医药》;20220815;第50卷(第08期);822-826 * |
| 蔡昊等.冠心丹参滴丸联合诱导多能干细胞来源的心肌细胞移植对大鼠心肌梗死的影响.《中国中医药信息杂志》.第29卷(第11期),60-66. * |
| 诱导多能干细胞来源心肌细胞移植改善心肌梗死小鼠心功能;倪晓彬等;《血栓与止血学》;20190820;第25卷(第04期);541-544 * |
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