CN109266603A - It is a kind of improve heart infarction curative effect excretion body and application - Google Patents
It is a kind of improve heart infarction curative effect excretion body and application Download PDFInfo
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- 230000029142 excretion Effects 0.000 title abstract description 41
- 206010061216 Infarction Diseases 0.000 title abstract description 29
- 230000007574 infarction Effects 0.000 title abstract description 29
- 230000000694 effects Effects 0.000 title abstract description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000012228 culture supernatant Substances 0.000 claims abstract description 6
- 239000007789 gas Substances 0.000 claims abstract description 4
- 210000002901 mesenchymal stem cell Anatomy 0.000 claims abstract description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 4
- 239000012679 serum free medium Substances 0.000 claims abstract description 3
- 239000006228 supernatant Substances 0.000 claims description 17
- 208000010125 myocardial infarction Diseases 0.000 claims description 8
- 239000012141 concentrate Substances 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
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- 238000002360 preparation method Methods 0.000 claims description 4
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- 239000002244 precipitate Substances 0.000 claims 5
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- 230000004217 heart function Effects 0.000 abstract description 10
- 238000004393 prognosis Methods 0.000 abstract description 5
- 238000007634 remodeling Methods 0.000 abstract description 2
- 238000010255 intramuscular injection Methods 0.000 abstract 1
- 239000007927 intramuscular injection Substances 0.000 abstract 1
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- 239000007924 injection Substances 0.000 description 13
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- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
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- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
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- 230000002107 myocardial effect Effects 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 230000003076 paracrine Effects 0.000 description 1
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- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0652—Cells of skeletal and connective tissues; Mesenchyme
- C12N5/0662—Stem cells
- C12N5/0663—Bone marrow mesenchymal stem cells (BM-MSC)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/28—Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C12N2509/00—Methods for the dissociation of cells, e.g. specific use of enzymes
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Abstract
The present invention disclose it is a kind of improve heart infarction curative effect excretion body and application, the excretion body be prepared as follows: stable mesenchymal stem cell will be passed in serum free medium, in 37 DEG C, CO2It is cultivated 1~2 day in volumetric concentration 5%, the mixed gas of nitrogen volumetric concentration 95%, collects culture supernatant, excretion body is proposed by supercentrifugation.After carrying out intramuscular injection treatment in excretion body-centered after mouse heart infarction of the present invention, it can be obviously improved the unfavorable remodeling of heart function and heart, so as to improve the prognosis of heart infarction.
Description
(1) technical field
The present invention relates to application of the excretion body in preparation treatment myocardial infarction drug, in particular to a kind of raising heart infarction is treated
The excretion body of effect and application.
(2) background technique
The disease incidence of myocardial infarction increases year by year at present, because it will lead to the irreversible damage of cardiac muscle cell and missing, with
And cause cicatrization, serious remodeling ventricle is caused, a series of complication occurs, can finally be developed as heart failure, at
For the main cause of death in cardiovascular disease.Therefore promote cardiac muscle mitochondria, save cardiac muscle in imminent danger as after myocardial infarction
The key link of Regeneration and Repair.Although treatment efficiency is still not high enough there are many treatment method for alleviating heart injury, fail bright
The aobvious adverse consequences improved after patient's myocardial infarction, it is therefore desirable to seek new method to be given treatment to.Current cell transplantation
Therapy can promote that infarct local vascular is newborn and Myocardial Regeneration, and then improve the heart function after myocardial infarction, and it is in painstaking effort
Safety and validity in the treatment of pipe disease have been confirmed, and provide huge hope for impaired cardiac repair, but it is moved
Low survival rate, low field planting rate after plant and the problems such as be difficult to cardiovascular cell lineage as the key for restricting its curative effect
Factor, this promotes us to seek better pharmaceutical preparation just to promote therapeutic effect, and explores new replacement therapy method and come
Overcome the problems, such as all kinds of in cell therapy procedures.
Now with multiple studies have shown that, cell is usually to be played a role by paracrine effect, and wherein excretion body is other
One of the important member in molecule is secreted, is a kind of small film bubble that can be secreted by most cells, there is bilayer lipid membrane knot
Structure, diameter about 30-100nm can carry the various actives small-molecule substance such as lipid, protein, nucleic acid, mediate different in vivo
Cell-cell communication between cell type participates in the bio signal transmitting between cell, to adjust a variety of pathologic, physiologics in body
Process can play a significant role in cancer, infectious diseases and disease of cardiovascular system, and in addition to this, excretion body is also
The biomarker and prognostic factor that can be used as disease are also used as the carrier of drug delivery for clinic.Currently based on
The cell-free alternative medicine of excretion body is constantly risen, and excretion body also has its unique curative effect in cardiovascular field, they
Can during acute ischemic and re-perfusion model and chronic ischemia cardioprotection, the prognosis of disease process after heart infarction
In have and promote angiogenesis, mitigate fibrosis, reduce infarct size, inhibit the important biomolecules function such as apoptosis, can finally change
Mercy obstructs prognosis.It not only has stem cell transplantation curative effect, and reduces cell transplantation risk, such as immunological rejection,
Teratogenesis tumorigenesis etc., therefore excretion body in cardiovascular field has obtained extensive concern and research in recent years, in terms of heart infarction treatment
There is vast application prospect.
(3) summary of the invention
The purpose of the present invention is selecting a kind of preparation of alternative cell therapy for treating myocardial infarction, further to change
Mercy obstructs prognosis, improves heart function.
The technical solution adopted by the present invention is that:
The present invention provides a kind of excretion body for improving heart infarction curative effect, and the excretion body is prepared as follows: passage is steady
Fixed mesenchymal stem cell is in serum free medium, in 37 DEG C, CO2Volumetric concentration 5%, nitrogen volumetric concentration 95%
It is cultivated 1~2 day in mixed gas, collects culture supernatant；By culture supernatant under the conditions of 4 DEG C, respectively with 300g, 10min,
2000g, 20min, the revolving speed of 10000g, 30min and time carry out angle and turn centrifugation, to remove cell fragment and big vesica, obtain
Supernatant a and precipitating a；By the concentration tube of supernatant a 10kd, under the conditions of 4 DEG C, with the multiple horizontal centrifugal of the revolving speed of 4000g
10min obtains concentrate after being concentrated into 1/3-1/5 times of original volume, to reach after the upper machine body product of ultracentrifuge requires,
By concentrate under the conditions of 4 DEG C, 70min is centrifuged with 120000g rpm level, obtains supernatant b and precipitating b；Discard supernatant liquid
Precipitating b is centrifuged 70min with 120000g rpm level by b, obtains supernatant c and precipitating c, precipitating c is excretion body.The present invention
The supernatant a- supernatant c, precipitating a- precipitating c are the supernatant and precipitating that different step is collected, and letter does not contain itself
Justice.
The present invention also provides a kind of application of excretion body in preparation treatment heart infarction drug.
The beneficial effects are mainly reflected as follows:
After the excretion body in mesenchymal stem cell source carries out intramyocardial injection treatment to heart infarction mouse, with control group phase
Than the mouse heart function and morphological change for the treatment of group improve significantly, and have the effect of cell therapy, and side effect ratio
Cell therapy is few, therefore can be used as the alternative of cell therapy.
(4) Detailed description of the invention
For Fig. 1 to treat the improvement situation to heart function through excretion body after mouse heart infarction, the injection dosage of excretion body is 5 μ g/
Only, A is control group heart hypergraph, and B is excretion body treatment group heart hypergraph, and C is left ventricular ejection fraction (LVEF, %) analysis chart, and D is
Fractional shortening of the ventricular minor semi axis (LVFS, %) analysis chart, DMEM represent solvent control group, and EXO represents excretion body treatment group；NS is represented
Without significant difference.
For Fig. 2 to treat the improvement situation to heart function through excretion body after mouse heart infarction, the injection dosage of excretion body is 10 μ g/
Only.A is each group heart hypergraph, and B is fractional shortening of the ventricular minor semi axis (LVFS, %) analysis chart, and C is left ventricular ejection fraction
(LVEF, %) analysis chart；D is left indoor pressure descending branch maximum rate of change figure, and E is left indoor pressure ascent stage maximum rate of change
Figure；The representative of Sham group opens chest and does not perform the operation group, and PBS group represents solvent control group, and EXO group represents excretion body treatment group.
For Fig. 3 to treat the influence to infarct size through excretion body after mouse heart infarction, the injection dosage of excretion body is 5 μ g/.
A is using Masson colored graph, and B is infarct size assessment figure.DMEM group represents solvent control group, and EXO group represents excretion body and controls
Treatment group.
For Fig. 4 to treat the influence to infarct size through excretion body after mouse heart infarction, the injection dosage of excretion body is 10 μ g/
Only.A is using Masson colored graph, and B is infarct size assessment figure.PBS group represents solvent control group, and EXO group represents excretion body
Treatment group.
(5) specific embodiment
The present invention is described further combined with specific embodiments below, but protection scope of the present invention is not limited in
This:
Embodiment 1:
1.MSC cell line routine culture adds 100U/ml penicillin and 100U/ml strepto- in cell injuring model base
Element, once collect, using 0.25% pancreatin (w/v) -0.02% ethylenediamine tetra-acetic acid (EDTA) (w/v) (lucky promise biological medicine skill
Art Co., Ltd) had digestive transfer culture.The cell injuring model base composition is as follows: Sodium Pyruvate 110mg/L, glutamine 20mM,
Fetal calf serum 10% (volumetric concentration), solvent are low sugar DMEM culture medium (being purchased from U.S. BI company).
2. growing to 70%-80% convergence degree to MSC, cell injuring model base is removed, is washed 3 times using PBS, is changed into and add
The serum-free low sugar DMEM culture medium for adding 100U/ml penicillin and 100U/ml streptomysin, in 37 DEG C, CO2Volumetric concentration 5%, nitrogen
It is cultivated 1-2 days in the mixed gas of air volume concentration 95%.Serum-free low sugar DMEM culture medium composition is as follows: Sodium Pyruvate
110mg/L, glutamine 20mM, solvent are low sugar DMEM culture medium (being purchased from U.S. BI company).
3. 2 culture supernatant 300ml of take-up step is in 50ml centrifuge tube, under the conditions of 4 DEG C, respectively with 300g, 10min,
2000g, 20min, the revolving speed of 10000g, 30min and time carry out angle and turn centrifugation, to remove cell fragment and big vesica, obtain
Supernatant a and precipitating a, then supernatant a is transferred in new 50ml centrifuge tube.
4. supernatant a collected by the concentration tube concentration step 3 with 10kd, more with the revolving speed of 4000g under the conditions of 4 DEG C
Sub-level is centrifuged 10min, and supernatant a is concentrated into the 1/3-1/5 of original volume, concentrate is obtained, to reach ultracentrifuge
Upper machine body product require after, be transferred to and surpass from pipe, under the conditions of 4 DEG C, 70min is centrifuged with 120000g rpm level, in acquisition
Clear liquid b and precipitating b.Again by it is each surpass be pooled to one from the precipitating b in pipe and surpass from pipe, then with the centrifugation of 120000g rpm level
70min obtains supernatant c and precipitating c, and precipitating c is excretion body.It is resuspended and is precipitated according to the PBS of precipitation capacity proper volume, turned
It moves on in EP pipe and is saved in -80 DEG C.
5. evaluating the effect of excretion body treatment heart infarction: C57/B6 mouse using the internal transplanting of chmice acute heart infarction model
(southern mould animal center) after chloral hydrate anesthesia, trachea cannula, toy ventilator support opens chest, with 7-0 silk thread on a left side
Left anterior descending branch coronary artery is ligatured below auricle, point 5 points of injection excretion bodies in cardiac muscle, the injection volume of excretion body is respectively 5 μ g/
Only with 10 μ g/, chest is closed.Wherein 5 μ g/ excretion body treatment groups are to inject equivalent DMEM as control；10 μ g/ excretion body treatment groups
It is not performed the operation with injecting equivalent PBS and opening chest as control.
6. the improvement situation that cardiac ultrasonic evaluates mouse heart function after cell therapy:
Cardiac function was evaluated with through chest cardiac ultrasonic respectively at 3,7,14,28 days after the injection of mouse excretion body, is used
2100 system of VisualSonics Vevo, probe sampling frequency are 12.0.Two dimension M type ultrasound figure is acquired in mitral level
Picture.Left ventricular end diastolic dimension (LVEDD) and left ventricular end-systolic dimension (LVESD) at least analyze 3 it is independent aroused in interest
Period.Fractional shortening of the ventricular minor semi axis (LVFS, %) and left ventricular ejection fraction (LVEF, %) are matched by 2100 system of Vevo respectively
Cover software analysis.As a result as shown in Fig. 1 (injection dosage is 5 μ g/) and Fig. 2 (injection dosage is 10 μ g/).
The results show that being substantially better than solvent control to the improvement result of heart infarction mouse heart function after intramyocardial injection excretion body
Group.
7.Massen dyeing assessment infarct size
Coring is dirty after 28 days cervical dislocations are put to death after mouse heart infarction, after the heavy sugar of about 12h, prepares frozen section with OCT embedding, cuts
Piece thickness about 7um, each heart choose many levels and cut section, carry out data system using Image-Pro Plus6.0 software
Meter.As a result as shown in Fig. 3 (injection dosage is 5ug/) and Fig. 4 (injection dosage is 10ug/).
As the result is shown: after mouse heart infarction, compared with solvent control group, the infarct size of excretion body treatment group is smaller.
Conclusion: the excretion body of MSC source can obviously improve the heart function of heart infarction mouse, mitigate fibrosis, hence it is evident that improve the heart
The prognosis of stalk.
Claims (2)
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Cited By (5)
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|---|---|---|---|---|
| CN110433175A (en) * | 2019-09-09 | 2019-11-12 | 陕西佰傲干细胞再生医学有限公司 | Application of the serum excretion body in preparation treatment myocardial infarction drug under the conditions of heart infarction |
| CN112402458A (en) * | 2020-11-30 | 2021-02-26 | 陕西佰傲干细胞再生医学有限公司 | Application of mesenchymal stem cell and exosome combined preparation in preparation of myocardial infarction medicament |
| CN113846058A (en) * | 2021-12-02 | 2021-12-28 | 诺希(天津)生物科技有限公司 | Bone marrow mesenchymal stem cell exosome and preparation and application thereof |
| CN114099534A (en) * | 2021-11-29 | 2022-03-01 | 苏州大学附属第一医院 | Exosome of high-expression miR-214, preparation method and application thereof |
| CN115227875A (en) * | 2022-08-08 | 2022-10-25 | 山西医科大学第一医院 | Cell-free conductive composite material with biological properties, preparation method and application thereof |
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| CN110433175A (en) * | 2019-09-09 | 2019-11-12 | 陕西佰傲干细胞再生医学有限公司 | Application of the serum excretion body in preparation treatment myocardial infarction drug under the conditions of heart infarction |
| CN112402458A (en) * | 2020-11-30 | 2021-02-26 | 陕西佰傲干细胞再生医学有限公司 | Application of mesenchymal stem cell and exosome combined preparation in preparation of myocardial infarction medicament |
| CN114099534A (en) * | 2021-11-29 | 2022-03-01 | 苏州大学附属第一医院 | Exosome of high-expression miR-214, preparation method and application thereof |
| CN113846058A (en) * | 2021-12-02 | 2021-12-28 | 诺希(天津)生物科技有限公司 | Bone marrow mesenchymal stem cell exosome and preparation and application thereof |
| CN113846058B (en) * | 2021-12-02 | 2022-02-18 | 诺希(天津)生物科技有限公司 | Bone marrow mesenchymal stem cell exosome and preparation and application thereof |
| CN115227875A (en) * | 2022-08-08 | 2022-10-25 | 山西医科大学第一医院 | Cell-free conductive composite material with biological properties, preparation method and application thereof |
| CN115227875B (en) * | 2022-08-08 | 2023-09-15 | 山西医科大学第一医院 | Cell-free conductive composite material with biological performance and preparation method and application thereof |
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