CN112011512A - Neural stem cell exosome and application thereof in treating neurodegenerative diseases - Google Patents

Neural stem cell exosome and application thereof in treating neurodegenerative diseases Download PDF

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CN112011512A
CN112011512A CN202010948182.0A CN202010948182A CN112011512A CN 112011512 A CN112011512 A CN 112011512A CN 202010948182 A CN202010948182 A CN 202010948182A CN 112011512 A CN112011512 A CN 112011512A
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Abstract

The invention discloses a neural stem cell exosome and application thereof in treating neurodegenerative diseases. The invention discovers that the neural stem cell exosome can inhibit Abeta25～35Apoptosis of the nerve cell PC12 increases the activity of the nerve cell; compound C-loaded neural stem cell exosomes can also be activated by inhibiting A beta25～35The apoptosis caused by the PC12 on the nerve cells improves the activity of the nerve cells, and the anti-apoptosis activity is obviously superior to that of the unloaded nerve stem cells. Therefore, it is possible to secrete neural stem cell exosomes and Compound C-loaded neural stem cellsThe compound is prepared into a medicament for treating Alzheimer disease.

Description

Neural stem cell exosome and application thereof in treating neurodegenerative diseases
Technical Field
The invention belongs to the field of biology, relates to application of stem cells in treating diseases, and particularly relates to a neural stem cell exosome and application of the neural stem cell exosome in treating neurodegenerative diseases.
Background
Alzheimer's Disease (AD) is a neurodegenerative disease with progressive memory function decline, cognitive behavior disorder and other neuropsychiatric symptoms as clinical manifestations, and is characterized by extensive cerebral cortex atrophy, neuronal loss at the parts of temporal lobe, hippocampus and the like, senile plaque and neurofibrillary tangle.
Current research suggests that a β deposition is a common pathway for AD due to various factors. The β -amyloid precursor is hydrolyzed to form a β. Under normal conditions, the generation and hydrolysis of A beta are in dynamic balance, only a small amount of A beta is expressed in brain, when the conditions occur, such as mutation or over-expression of APP gene, degeneration, in-vivo reactivity reduction to nerve growth factor, participation of external toxin, infection and the like, the dynamic balance between the generation and decomposition of A beta is gradually broken, abnormal release and deposition of a large amount of A beta occur due to abnormal normal metabolism of human body to APP and A beta, a series of complex reactions are further initiated, including synapse/protrusion change, phosphorylation of Tau protein, central neurotransmitter loss, glial proliferation, inflammatory reaction and the like, and finally pathological phenomena such as neuron dysfunction, neuronal apoptosis, senile plaque formation, NFTs and the like are caused.
Neural Stem Cells (NSCs) are cells that are self-renewing and have the potential to differentiate into multiple cells such as neurons, astrocytes, oligodendrocytes, and the like. It is mainly used as a kind of reserve cell in the nervous system, i.e. when the nervous system is damaged, such as acute ischemic cerebral infarction, neurodegenerative disease, etc., the stem cells begin to proliferate, migrate and differentiate into corresponding tissue cells so as to realize structural and functional compensation. Exosomes (exosomes) refer to small membrane vesicles containing complex RNAs and proteins, which are secreted by all cultured cell types and possess a variety of physiological activities.
At present, no neural stem cell exosome is applied to the treatment of neurodegenerative diseases.
Disclosure of Invention
The invention aims to provide a neural stem cell exosome and application thereof in treating neurodegenerative diseases.
The technical scheme of the invention is as follows:
a neural stem cell exosome is extracted from culture solution of human neural stem cells.
The neural stem cell exosome is used for preparing a medicine for treating neurodegenerative diseases.
Preferably, the neurodegenerative disease is alzheimer's disease.
A Compound C-loaded neural stem cell exosome, which is obtained by loading Compound C into a neural stem cell exosome.
Preferably, the above neural stem cell exosomes are introduced into the neural stem cell exosomes from compound c by electroporation or other transfection methods.
The Compound C-loaded neural stem cell exosome is used for preparing a medicament for treating neurodegenerative diseases.
Preferably, the neurodegenerative disease is alzheimer's disease.
Has the advantages that:
the invention discovers that the neural stem cell exosome can inhibit Abeta25～35Apoptosis of the nerve cell PC12 increases the activity of the nerve cell; compound C-loaded neural stem cell exosomes can also be activated by inhibiting A beta25～35The apoptosis caused by the PC12 on the nerve cells improves the activity of the nerve cells, and the anti-apoptosis activity is obviously superior to that of the unloaded nerve stem cells.
Therefore, the neural stem cell exosome and the Compound C-loaded neural stem cell exosome can be prepared into a medicament for treating the Alzheimer disease.
Drawings
FIG. 1 shows the values of A and cell viability for each group;
FIG. 2 shows the expression levels of apoptosis-related proteins in each group.
Detailed Description
The following examples are given to illustrate the essence of the present invention, but not to limit the scope of the present invention.
First, experimental material
Human neural stem cells (hNSCs) are purchased from Shenzhen, luxury and luxury Tuo biotechnology, Limited, and are currently available in the third generation.
H-DMEM medium was purchased from Saimer Feishale science (China) Co.
RPMI 1640 medium, fetal bovine serum was purchased from Gibco.
ExoQuick kits were purchased from Biotech, Inc., Bomais, Beijing.
BCA kit was purchased from petunia.
The purity of Compound C is more than or equal to 98 percent, and the chemical structural formula is as follows:
Figure BDA0002676008930000021
second, Experimental methods
1. Recovery, culture and passage of hNSCs
And taking out the hNSCs cryopreservation tube, immersing the tube body in a water bath at 37 ℃, slightly oscillating, dissolving more than 90% of solids in the cryopreservation tube within 1 minute, and taking out the tube body from the water bath. Inoculating into cell culture flask under aseptic condition, and culturing with H-DMEM containing 10% FBS and double antibody at 37 deg.C and 5% CO2Culturing under the condition, changing the liquid every 2-3 d for half and carrying out passage every 4-6 d.
And (3) taking hNSCs passage cells, and identifying the Nestin protein by a cell immunofluorescence single-label chemical method. The Nestin protein is a specific marker of NSCs, and subsequent experiments are carried out after cellular immunofluorescence single-label identification shows that the Nestin protein is positive.
2. Extraction and concentration determination of hNSCs exosomes
And (3) taking the passaged hNSCs, culturing in vitro for 6 days, and extracting hNSCs exosomes by using an ExoQuick kit according to an exosome extraction operation protocol attached to the instruction. Firstly, transferring culture supernatant of hNSCs into a high-speed centrifuge tube, and centrifuging at 4 ℃ to remove cell debris; then transferring the supernatant to a new high-speed centrifuge tube, adding an extraction reagent according to the volume ratio of the cell supernatant to the reagent of 2:1, fully and uniformly mixing, and incubating overnight at 4 ℃; and finally, centrifuging the next day, removing the supernatant, re-suspending the suspension by using PBS (phosphate buffer solution) to obtain an exosome suspension, and uniformly subpackaging the exosome suspension into a plurality of freezing tubes for freezing at the temperature of-20 ℃ for later use.
Exosome concentrations were determined according to the routine method using the BCA kit. Taking out the exosome suspension cryopreservation tube, immersing the tube body in water bath at 37 ℃, slightly oscillating for thawing, then adding a proper amount of RIRP-PMSF lysate for cracking, and finally determining the protein concentration in the lysate by the BCA kit according to the determination method provided by the instruction, converting the protein concentration in the exosome suspension, and taking the protein concentration in the exosome suspension as the exosome concentration.
3. Loading and concentration determination of hNSCs exosomes
The compounds to be loaded were transferred into hNSCs exosomes using electroporation according to literature methods. Taking out the exosome suspension cryopreservation tube, immersing the tube body in water bath at 37 ℃, and slightly oscillating for thawing; then adding Compound C according to the proportion that 50 mug of protein (exosome suspension containing 50 mug of protein) corresponds to 100 mug of Compound to be loaded, oscillating and mixing uniformly, transferring into a 4mm electric rotating cup for electric shock transfection, wherein the voltage is 420V, and the capacitance is 150 mug F; and finally, removing untransfected Compound C by ultrafiltration, carrying out resuspension by using a PBS (phosphate buffer solution) to obtain a loaded exosome suspension, uniformly subpackaging the suspension into a plurality of cryopreservation tubes, and carrying out cryopreservation at the temperature of-20 ℃ for later use.
The loading exosome concentration was determined using the BCA kit according to the conventional method. Taking out the cryopreserved tube loaded with the exosome suspension, immersing the tube body in water bath at 37 ℃, slightly oscillating for thawing, then adding a proper amount of RIRP-PMSF lysate for cracking, finally determining the protein concentration in the lysate by the BCA kit according to the determination method provided by the instruction, converting the protein concentration in the loaded exosome suspension, and taking the protein concentration in the loaded exosome suspension as the loaded exosome concentration.
4. Culture of PC12 cells and A.beta.25～35Incubation aging of
PC12 cells were cultured in RPMI 1640 containing 10% FBS and 1% penicillin and streptomycin at 37 ℃ under 5% CO2Culturing under the condition, and changing the culture solution every 2 days. A beta is separated from the culture solution of RPMI 164025～35Preparing stock solution of 200 mu mol/L, filtering, subpackaging, and storing at-20 ℃; when in use, 1 of the cells is taken out and diluted to the required concentration by serum-free RPMI 1640, and incubated for 7 days for aging at 37 ℃.
5. Establishment, grouping, administration and cell viability assay of AD cell models
PC12 cells were plated at 5X 10 per well4The cells were plated in 96-well plates at 200. mu.L/well and cultured in RPMI 1640 medium containing 10% FBS and 1% penicillin and streptomycin at 37 ℃ in 5% CO2After culturing for 24h under the condition, the culture is continued by replacing the culture medium with complete culture medium containing different components according to the following groups, and each group comprises 5 multiple wells:
blank group (Blank): a complete culture medium;
model group (Model): contains 20 mu mol/LA beta25～35The complete medium of (4);
exosome group (Exo): contains 20 mu mol/LA beta25～35+250ng/mL complete medium of exosomes;
compound C load exosome group (Exo-C): contains 20 mu mol/LA beta25～35+250ng/mL Compound C-loaded complete medium of exosomes;
after further incubation for 24h, 20. mu.L of MTT solution (5mg/mL) was added to each well at 37 ℃ with 5% CO2After further incubation for 4h, the culture was terminated, the culture supernatant in the wells was carefully aspirated off, 150. mu.L of DMSO was added to each well, and the mixture was shaken for 10min to dissolve the crystals sufficiently. The enzyme linked immunosorbent assay detector measures the absorbance (A) value of each hole at 490nm, the blank group A value is recorded as the cell survival rate of 100%, and the cell survival rates of the model group and the administration group are calculated according to the ratio of the model group A value to the blank group A value.
6. Western blot method for determining apoptosis-related protein expression
Taking PC12 cells with good growth state, preparing the cells with the density of 5 × 10 with complete culture medium5Cell suspension/mL, inoculated into 6-well plates, 2mL per well, at 37 ℃ with 5% CO2After culturing for 24h under the condition, replacing complete culture media with different components according to the above groups, continuously culturing for 24h, collecting cells, washing, extracting total protein, and measuring the protein concentration of the sample by using a BCA protein concentration measuring kit according to the reagent instruction. Performing SDS-PAGE electrophoresis on 30 mu g of total protein, separating protein, electrically transferring the protein to a PVDF membrane, sealing the PVDF membrane with 5% of skimmed milk powder by mass fraction for 2h, and washing the membrane with 1 × TBST for 10min × 3 times; adding Bcl-2, Bax and beta-actin primary antibody, and incubating overnight at 4 ℃; washing the membrane with 1 × TBST for 10min × 3 times; adding HRP coupled secondary antibody for incubation for 2h, washing the membrane with 1 × TBST for 10min × 3 times; protein bands were visualized by ECL dark-room exposure and imaged with BIO-RAP and protein intensity was analyzed using Image J software.
7. Statistical method
SPSS 20.0 statistical software is used for data analysis, the measured data are expressed by mean plus or minus standard deviation, the comparison among groups adopts one-way analysis of variance (ANOVA), and the difference is statistically significant when P is less than 0.05.
Third, experimental results
1. Survival rate of cells of each group
Cell survival rates of the groups are shown in table 1 and fig. 1, and compared with the blank group, the cell survival rate of the model group is significantly reduced; compared with the model group, the cell survival rates of the exosome group and the Compound C-loaded exosome group are both remarkably improved, and the cell survival rate of the Compound C-loaded exosome group is remarkably higher than that of the exosome group.
TABLE 1 values of groups A and cell viability
Group of Value of A Cell survival rate
Blank 0.489±0.022 100％
Model 0.314±0.019 64.2％
Exo 0.366±0.025 74.8％
Exo-C 0.465±0.023 95.1％
2. Expression level of apoptosis-related proteins of each group
The Western blot results are shown in FIG. 2. The anti-apoptotic protein Bcl-2 and the pro-apoptotic protein Bax are the most important pair of apoptosis regulating proteins known at present, and the anti-apoptotic protein Bcl-2 and the pro-apoptotic protein Bax form a dimer to play a role in regulating apoptosis. Compared with the blank group, the expression of the pro-apoptotic protein Bax protein in the model group cells is up-regulated, and the expression of the anti-apoptotic protein Bcl-2 protein is down-regulated; compared with the model group, the expression of the pro-apoptotic protein Bax protein in the cells of the exosome group and the expression of the anti-apoptotic protein Bcl-2 protein in the cells of the exosome group and the Compound C load exosome group are down-regulated. It can be seen that the drugs in the drug group all exert the anti-apoptosis effect of PC 12.
In conclusion, neural stem cell exosomes can be induced by inhibition of a β25～35Apoptosis of the nerve cell PC12 increases the activity of the nerve cell; compound C-loaded neural stem cell exosomes may also be produced by inhibiting A β25～35The apoptosis caused by the PC12 on the nerve cells improves the activity of the nerve cells, and the anti-apoptosis activity is obviously superior to that of the unloaded nerve stem cells. Therefore, the neural stem cell exosome and the Compound C-loaded neural stem cell exosome can be prepared into a medicament for treating the Alzheimer disease.
The above examples are intended to illustrate the essence of the present invention, but it should be understood by those skilled in the art that the scope of the present invention should not be limited to the above specific examples.

Claims (7)

1. A neural stem cell exosome is extracted from culture solution of human neural stem cells.
2. Use of the neural stem cell exosome according to claim 1 for the preparation of a medicament for treating a neurodegenerative disease.
3. The use according to claim 2, wherein the neurodegenerative disease is alzheimer's disease.
4. A Compound C-loaded neural stem cell exosome, comprising: the exosome is obtained by loading Compound C on the neural stem cell exosome.
5. The neural stem cell exosome according to claim 4, Compound C is introduced into the neural stem cell exosome by electrotransformation or other transfection method.
6. Use of the neural stem cell exosome according to claim 4 or 5 for preparing a medicament for treating a neurodegenerative disease.
7. The use according to claim 6, wherein the neurodegenerative disease is Alzheimer's disease.
CN202010948182.0A 2020-09-10 2020-09-10 Neural stem cell exosome and application thereof in treating neurodegenerative diseases Withdrawn CN112011512A (en)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112891375A (en) * 2021-01-20 2021-06-04 张平 Preparation method and application of medicine absorbed by neural stem cell exosome through nose
CN113082058A (en) * 2021-03-19 2021-07-09 瑞太生物科技(沈阳)有限公司 Application of cell-derived exosome in preparation of biological preparation for treating Alzheimer disease
CN113577108A (en) * 2021-08-31 2021-11-02 中国科学院苏州纳米技术与纳米仿生研究所 Multifunctional collagen scaffold, preparation method and application thereof
CN114292807A (en) * 2021-12-28 2022-04-08 深圳市夏同生物医药科技有限公司 Method for extracting exosome and application thereof
WO2023155825A1 (en) * 2022-02-18 2023-08-24 谛邈生物科技(北京)有限公司 Human-induced pluripotent stem cell overexpressing tlx and use thereof
WO2023224431A1 (en) * 2022-05-20 2023-11-23 코아스템켐온 주식회사 Pharmaceutical composition for preventing and treating geriatric diseases comprising neural stem cells derived from three-dimensional hypothalamus organoid and use thereof

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112891375A (en) * 2021-01-20 2021-06-04 张平 Preparation method and application of medicine absorbed by neural stem cell exosome through nose
CN112891375B (en) * 2021-01-20 2023-03-14 张平 Preparation method and application of medicine absorbed by neural stem cell exosome through nose
CN113082058A (en) * 2021-03-19 2021-07-09 瑞太生物科技(沈阳)有限公司 Application of cell-derived exosome in preparation of biological preparation for treating Alzheimer disease
CN113577108A (en) * 2021-08-31 2021-11-02 中国科学院苏州纳米技术与纳米仿生研究所 Multifunctional collagen scaffold, preparation method and application thereof
CN114292807A (en) * 2021-12-28 2022-04-08 深圳市夏同生物医药科技有限公司 Method for extracting exosome and application thereof
WO2023155825A1 (en) * 2022-02-18 2023-08-24 谛邈生物科技(北京)有限公司 Human-induced pluripotent stem cell overexpressing tlx and use thereof
WO2023224431A1 (en) * 2022-05-20 2023-11-23 코아스템켐온 주식회사 Pharmaceutical composition for preventing and treating geriatric diseases comprising neural stem cells derived from three-dimensional hypothalamus organoid and use thereof

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Application publication date: 20201201