CN109868259A - A kind of recombination mescenchymal stem cell and application thereof - Google Patents
A kind of recombination mescenchymal stem cell and application thereof Download PDFInfo
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- CN109868259A CN109868259A CN201910147227.1A CN201910147227A CN109868259A CN 109868259 A CN109868259 A CN 109868259A CN 201910147227 A CN201910147227 A CN 201910147227A CN 109868259 A CN109868259 A CN 109868259A
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Abstract
The invention belongs to stem cells technology fields, and in particular to a kind of recombination mescenchymal stem cell and application thereof.Recombination mescenchymal stem cell provided by the invention is that the mRNA genetic fragment for obtaining IFN-β in 293T cell is integrated into mescenchymal stem cell, recombination mescenchymal stem cell obtained has low immune response risk, active high, the low advantage of residual, to tumor disease, especially oophoroma has significant therapeutic effect, it is a kind of ideal treatment tumor disease, the especially preparation of ovarian cancer disease.
Description
Technical field
The invention belongs to stem cells technology fields, and in particular to a kind of recombination mescenchymal stem cell and application thereof.
Background technique
More and more theories show that the occurrence and development of tumour are related with tumor microenvironment.Oophoroma is in Cancerous disease
The primary killers of women's health are endangered, how to treat female ovarian cancer simultaneously and are avoided that pair brought by conventional chemotherapeutic drugs is made
With being problem to be solved in treatment of ovarian cancer.It is common to have chemotactic factor (CF), cell factor, at fiber in oophoroma lesion
These tumours such as cell, tumour associated fibroblast cell, mescenchymal stem cell, Mononuclear Infiltrate cell, T cell and B cell are micro-
Environment composition provides raw material and energy for vital movements such as the proliferation of tumour cell and growths, such as tumor vascular growth.
Mescenchymal stem cell comes from the sub-fraction cell colony in bone marrow microenvironment, has certain self-renewing
With the ability of differentiation.Marrow is the main source of mescenchymal stem cell, in addition to this, in placenta, umbilical cord, amniotic fluid, kidney, skin
There is also mescenchymal stem cells.The mescenchymal stem cell of these separate sources generally has common feature, such as surface marker
Expression, CD10+, CD13+, CD73+, CD90+, CD105+, CD34-, CD45+, adherent growth ability, have be divided into rouge,
Skeletonization, the versatility potential at cartilage.Meanwhile mescenchymal stem cell also has the energy of secretion cytokine profiles, chemotactic factor (CF)
Power, such as IL-6, IL-8, CCL2, IGFBPs, PDGF- α, VEGF, IGF1, TGFs.In tumor microenvironment, these factors may
Facilitate the growth of tumour cell by Cellular signalling network.
Patent document CN103384824A discloses a kind of Method for cancer diagnostics and application thereof, the Method for cancer diagnostics be by
Adult stem cell is contacted with the blood derivative sample of individual to be analyzed, and passes through immunofluorescence, immunohistochemistry, ELISA
Or RT-PCR means verify expression of at least one epithelium marker in the stem cell.This method can be used for diagnosing cancer
Or relative remaining illness, perhaps for prognosis cancer or for monitor for cancer antineoplaston it is effective
Property, or for cancer individual carry out follow-up visit monitoring, the cancer especially colorectal cancer, gastric cancer, breast cancer,
Lung cancer or prostate cancer, liver cancer, oophoroma, kidney, thyroid cancer, bladder cancer or cancer of pancreas.
The high paper for having delivered one entitled " interaction of mescenchymal stem cell and oophoroma " such as red, the paper table
Bright, mescenchymal stem cell (mesenchymal stem cell, MSCs) can pass through secrete cytokines, promotion tumor stem cell
Change etc. inhibits or promotes human epithelial ovarian carcinoma cells proliferation；Reciprocation occurs with ovarian cancer cell, promotes or inhibit the invasion of oophoroma
And transfer；MSCs can also pass through phosphatidylinositol3 3 kinase/protein kinase B (PI3K/AKT), Bone Morphogenetic Protein 4/Hedgehog
(BMP4/HH) signal path enhances chemotherapy in ovarian cancer drug resistance；Using MSCs to the taxis of tumor tissues as load
Body constructs targeting drug delivery system and carries out targeted therapy to oophoroma.
Therefore, MSCs plays an important role in the occurrence and development of oophoroma, provides new research think of for the treatment of the disease
Road, but specific effect and mechanism need further to be studied there are still more dispute.
Summary of the invention
In order to preferably treat tumor disease, the purpose of the present invention is to provide a kind of recombination mescenchymal stem cell and its use
On the way, which has significant therapeutic effect to tumor disease, especially oophoroma.
The present invention provides a kind of recombination mescenchymal stem cells, and the mRNA genetic fragment of IFN-β will be obtained in 293T cell
It is integrated into mescenchymal stem cell.
Further, the mescenchymal stem cell is to fill between placenta mesenchyma stem cell, Amniotic Fluid-derived Mesenchymal Stem Cells, bleeding of the umbilicus
Matter stem cell, mesenchymal stem cell or fat mesenchymal stem cell.
Further, the Integration Mode is that lentivirus mediated mode or electricity turn mode.
Further, the recombination mescenchymal stem cell is the mescenchymal stem cell for being overexpressed IFN-β.
In addition, the use the present invention also provides the recombination mescenchymal stem cell in preparation treatment tumor disease preparation
On the way.
Further, the tumor disease is oophoroma.
The present invention also provides the mescenchymal stem cells of the overexpression IFN-β in preparation treatment tumor disease preparation
Purposes.
Further, the tumor disease is oophoroma.
The administration mode of recombination mescenchymal stem cell provided by the invention passes through intravenously administrable, recombination by intravenously administrable
Mescenchymal stem cell can be distributed in the ovary position of lesion, and hetero-organization and organ are substantially not detectable, and recombination mesenchyma is dry
Cell constantly synthesizes IFN-β before life termination, has the cell behaviors of targeting ovarian cancer cell.
Further, by rat ovary cancer cell model, it is good that inventor has found that recombination mescenchymal stem cell has
The effect of ovarian cellular apoptosis is induced, and recombination mescenchymal stem cell provided by the invention has low immune response risk,
Active high, the low advantage of residual, and preparation cost is cheap, provides a kind of new therapeutic agent for ovarian cancer patients.
In short, compared with prior art, recombination mescenchymal stem cell provided by the invention has low immune response risk, living
Property high, the low advantage of residual, there is significant therapeutic effect to tumor disease, especially oophoroma, be a kind of ideal
The preparation for treating tumor disease, especially ovarian cancer disease.
Detailed description of the invention:
Fig. 1 is the proliferation activity figure for recombinating mescenchymal stem cell；
Fig. 2 is that qPCR analysis recombination mescenchymal stem cell expresses IFN-β mRNA ability to express figure；
Fig. 3 is that western blot analysis recombination mescenchymal stem cell expression IFN-β albumen can try hard to；
Fig. 4 is elisa assay rat blood serum IFN-β protein expression spirogram；
Fig. 5 is rat ovary cancer model in situ structure figures.
Specific embodiment
The present invention is further described below by way of specific embodiment, the present invention is not limited only to following embodiment.In this hair
In bright range or the contents of the present invention are not being departed from, in spirit and scope, the change that carries out to the present invention is combined or replaced
It changes, will be apparent to the person skilled in the art, and be included within the scope of the present invention.It is of the present invention to grind
Study carefully method can inquire to obtain from conventional study method, and reagent according to the present invention is commercially available.
Embodiment 1, the preparation method of mesenchymal stem cell
A takes the male SD rat of 4 week old, is injected intraperitoneally with yellow Jackets and puts to death rat；
B takes rat femur, and the epiphysis at femur both ends is cut off with sterile scissors, contains 10% fetal calf serum, 100u/ with 5ml
The low sugar DMEM culture medium of the penicillin streptomycin of ml rinses femur, rinses 3 times；
The DMEM culture medium of penicillin streptomycin of the C containing 10% fetal calf serum, 100u/ml is blown and beaten cell repeatedly and is allowed to
As single suspension cell；
D adjusts cell density 1.0 × 106It is inoculated in Tissue Culture Flask, more renews culture medium after 3 days, cell reaches 80%
When degrees of fusion, pancreatin had digestive transfer culture to get.
Embodiment 2, the preparation for recombinating mescenchymal stem cell
The mRNA genetic fragment for obtaining IFN-β in 293T cell is integrated into medulla mesenchyma by lentivirus mediated mode
Stem cell to get.
Embodiment 3, the proliferation activity for recombinating mescenchymal stem cell
Recombination mescenchymal stem cell made from embodiment 2 is incubated at low sugar DMEM culture medium, collects logarithmic growth respectively
The recombination mescenchymal stem cell of phase is diluted to 3 × 10 with low sugar DMEM culture solution4The cell suspension of/ml is inoculated in 96 orifice plates.
After mescenchymal stem cell to be reorganized is sufficiently adherent, if 3 multiple holes, while blank control group and DMSO (dimethyl sulfoxide) solvent are set
Control group.Be put in incubator be incubated for for 24 hours, after 48h, 72h, 96h, be added MTT solution, continue 1~4h of culture, surveyed using microplate reader
OD value (OD value) at fixed each hole 450nm, measures absorbance A value.Wherein: the calculation formula of growth inhibition ratio are as follows: proliferation
Rate (%)=(OD test group/OD control group) × 100%.It can be mapped to obtain dose-effect curve according to the inhibiting rate of each concentration,
Mapping software is Origin 8, such as Fig. 1.
Embodiment 4, qPCR analysis recombination mescenchymal stem cell express IFN-β mRNA ability to express
(1) its mRNA, the cracking of 1.0ml Trizol reagent are extracted using the mescenchymal stem cell for stablizing expression IFN-β mRNA
1.0×106Recombinate mescenchymal stem cell, obtained total serum IgE again reverse transcription at mRNA.Reverse transcription system such as table 1:
1 reverse transcription reaction system of table
| Reagent | Usage amount |
| 2 times of Reverse Transcription mixtures | 5 |
| Total serum IgE | 300 nanograms |
| Mend distilled water | Total volume is 10 microlitres |
After mini compact centrifuge mixes, reverse transcription reaction is carried out, condition is as follows:
37 DEG C, 15 minutes；85 DEG C, 5 seconds；4 DEG C of preservations.
Obtained cDNA carries out quantitative PCR reaction, PCR reaction system and reaction condition such as table 2 again:
2 quantitative PCR reaction system of table
| Reagent | Dosage |
| Enzymatic reagent | 10.0 microlitres |
| Upstream primer | 1.0 microlitre |
| Downstream primer | 1.0 microlitre |
| CDNA reaction solution | 2.0 microlitre |
| Distilled water | 6.0 microlitre |
| Total volume | 20.0 microlitres |
After centrifuge mixes, upper machine testing, reaction condition is as follows:
First stage: initial denaturation recurring number: 1, reaction condition: 95 DEG C, 30 seconds；Second stage: PCR reaction cycle number: 40；
95 DEG C, 5 seconds；60 DEG C, 30 seconds.
(2) observation recombination mescenchymal stem cell 1 day in the reassembled, 10 days, 20 days, 30 days, 40 days, 50 days and 60 days weights
The ability of group mescenchymal stem cell synthesis IFN-β mRNA, test result are as shown in Figure 2.
Embodiment 5, western blot analysis recombination mescenchymal stem cell express IFN-β albumen ability
(1) mescenchymal stem cell will be recombinated with 2 × 105The cell density of a/mL is inoculated in 6 orifice plates, is collected after 2 days thin
Each sample concentration is tuned into one and shown and guaranteed that albumen applied sample amount is identical using BCA method test sample protein concentration by born of the same parents.Using
SDS-PAGE electrophoresis separates protein sample, goes to pvdf membrane, and 5% skimmed milk power closes 1h, and TBST washes film and washes film 1 time,
Be incubated for the first antibody of anti-IFN-β, using GAPDH as reference, 4 DEG C of refrigerators are incubated overnight, and next day TBST is washed film 3 times, rear chamber
Temperature is incubated for the secondary antibody 1h of fluorescent marker, and TBST is washed film 3 times, developed to obtain purpose band using ECL chemoluminescence method, uses
Bandscan software carries out gray scale scanning to band, is corrected with GAPDH internal reference.
(2) variation for the mescenchymal stem cell pSTAT1 expression quantity being engineered by western blot means analysis, grinds
Study carefully 10 days, 20 days, 30 days, 40 days, 50 days, pSTAT1 expressing quantity changed within 60 days, and test result is as shown in Figure 3.
Embodiment 6, elisa assay rat blood serum IFN-β expressing quantity
1, serum: room temperature blood natural coagulation 10~20 minutes is centrifuged 20 minutes or so (2000-3000 revs/min).Carefully
Collecting supernatant should be centrifuged again as precipitated during preservation.
2, according to following procedure detection and IFN-β expression quantity in analyzing rat body
(1) it is loaded: setting blank well, gauge orifice, sample to be tested hole respectively, blank well adds 100 microlitres of sample diluting liquid, Yu Kong
Respectively plus standard items or 100 microlitres of sample to be tested, bubble has been careful not to it；Sample is added on ELISA Plate bottom when sample-adding, as far as possible
Hole wall is not touched, mixing is shaked gently.ELISA Plate overlay film is given, 37 DEG C of incubation 90min are guarantee test result validity, every time
Test please use new standard solution.
(2) preceding 15min is used, biotinylated antibody working solution: is calculated before test when time test institute's expense is (micro- with 100
Liter/hole meter reality answers 100~200 microlitres of polygamy system when preparing.It is anti-with biotinylated antibody diluted concentrated biological elementization
Body (1:100) is at working concentration.The same day uses.
(3) liquid is discarded, is dried, washing is not had to.Every hole is added 100 microlitres of biotinylated antibody working solution, and ELISA Plate adds
Upper overlay film, 37 DEG C incubate 1 hour.
(4) concentrated cleaning solution distilled water is diluted into (1:25), the same day uses.
(5) preceding 15min is used, enzyme combination working solution is matched: is calculated before test when time test institute's expense is (with 100 microlitres/hole
Meter), reality answers 100~200 microlitres of polygamy system when preparing.Concentration HRP enzyme conjugates (1:100) is diluted with enzyme combination diluent
At working concentration.The same day uses.
(6) liquid in hole is discarded, dries, board-washing 3 times, gets rid of liquid in most hole, is patted dry on clean blotting paper, every hole adds
350 microlitres of cleaning solution, 1~2min is impregnated, (untouchable wooden partition) is sucked or gets rid of the liquid in ELISA Plate, in thick blotting paper
On pat dry.
(7) 100 microlitres of the enzyme conjugate working solution in every hole, in addition overlay film, 37 DEG C of incubation 30min.
(8) liquid in hole is discarded, is dried, board-washing 5 times, the same step of method (6).
(9) every hole adds 90 microlitres of substrate solution (TMB), ELISA Plate be protected from light plus 37 DEG C of overlay film be incubated for 15min or so (according to
Practical colour developing situation is taken the circumstances into consideration to shorten or be extended, but may not exceed 30min.It when obvious gradient occurs in gauge orifice, can terminate).
(10) every hole adds 50 microlitres of terminate liquid, terminates reaction, and blue is vertical at this time turns yellow.The addition sequence of terminate liquid should use up
It measures identical as the addition sequence of substrate solution.
(11) use microplate reader in the optical density (OD value) in each hole of 450nm wavelength measurement immediately.Microplate reader electricity should be opened in advance
Source, preheater apparatus set detection program.
3, rat ovary cancer model in situ is established, intravenous injection rat is administered mescenchymal stem cell, gives cell quantity every time
It is 2 × 106, gives cell 3 times a week, gives cell 3 weeks, at 20 days, 40 days, 60 days 500 microlitres of blood of extraction rat veins passed through
It is horizontal that ELISA detects IFN-β in rat body.Test result is as shown in Figure 4.
The building of embodiment 7, rat ovary cancer model in situ
(1) 6~8 week old Female nude mice 6 is taken, intraperitoneal injection fiber crops are carried out to rat with 1% yellow Jackets 20mg/kg
It is liquor-saturated, fixed after anaesthetizing successfully, routine disinfection drape, take right side upper abdomen longitudinal incision 1cm (wound temperature should not be too near to a side,
Because easily leading to Great Vascular Injury, cause nude mice shock death), abdominal cavity is opened, intestinal tube is gently pushed open, sees that one is greyish white below kidney
Color is irregularly organized as muroid ovary.A small notch, the cancerous tissue block that sutures will be got ready are cut in ovary body portion with microscissors
Threading method (sutures are passed through from cancerous tissue block edge) embedding is fixed in ovary, and absorbable gutstring successively closes abdomen.Alcohol disappears
Malicious skin suture is raised under SPF grades of environment, the general growing state of close observation nude mice.
(2) rat ovary cancer model in situ is established, intravenous injection rat is administered mescenchymal stem cell, gives cell quantity every time
It is 2 × 106A/mL gives cell 3 times a week, gives cell 3 weeks.It is euthanized and rat and dissects after 2 months, find test group tumour
Weight is significantly less than model group.Test result is as shown in figure 5, test data is as shown in table 3.
The knurl weight data of 3 experimental group of table and control group
| Experimental group/g | Control group/g |
| 0.08 | 0.31 |
| 0.09 | 0.33 |
| 0.09 | 0.29 |
| 0.09 | 0.34 |
| 0.13 | 0.34 |
| 0.14 | 0.35 |
| 0.13 | 0.36 |
Claims (8)
1. a kind of recombination mescenchymal stem cell, which is characterized in that integrate the mRNA genetic fragment for obtaining IFN-β in 293T cell
To mescenchymal stem cell.
2. recombination mescenchymal stem cell as described in claim 1, which is characterized in that the mescenchymal stem cell fills between placenta
Matter stem cell, Amniotic Fluid-derived Mesenchymal Stem Cells, umbilical cord blood mesenchymal stem cells, mesenchymal stem cell or fat mesenchymal are dry thin
Born of the same parents.
3. recombination mescenchymal stem cell as described in claim 1, which is characterized in that the Integration Mode is lentivirus mediated side
Formula or electricity turn mode.
4. recombination mescenchymal stem cell as described in claim 1, which is characterized in that the recombination mescenchymal stem cell was table
Up to the mescenchymal stem cell of IFN-β.
5. purposes of the recombination mescenchymal stem cell in preparation treatment tumor disease preparation as described in claims 1 to 3 is any.
6. purposes as claimed in claim 5, which is characterized in that the tumor disease is oophoroma.
7. being overexpressed use of the mescenchymal stem cell of IFN-β in preparation treatment tumor disease preparation as claimed in claim 4
On the way.
8. purposes as claimed in claim 7, which is characterized in that the tumor disease is oophoroma.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110819594A (en) * | 2019-11-04 | 2020-02-21 | 四川大学 | Mesenchymal stem cell for continuously over-expressing IFN-gamma and application thereof |
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| WO2003073998A2 (en) * | 2002-03-02 | 2003-09-12 | Board Of Regents, The University Of Texas System | Local production and/or delivery of anti-cancer agents by stromal cell precursors |
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| CN110819594A (en) * | 2019-11-04 | 2020-02-21 | 四川大学 | Mesenchymal stem cell for continuously over-expressing IFN-gamma and application thereof |
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Application publication date: 20190611 |