CN109735485A - Humanization liver animal model and its construction method and application - Google Patents
Humanization liver animal model and its construction method and application Download PDFInfo
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Abstract
The present invention relates to a kind of humanization liver animal model and its construction method and applications.The construction method of the humanization liver animal model obtains humanization liver animal model the following steps are included: source of people hepatic progenitor cells are injected into immunodeficient animals of the liver through partially cutting off.Construction method through above-mentioned humanization liver animal model is simple and direct, avoids the problem that the application in building process using liver injury medicament, virus, bacterium etc. and to the modeling later period brings interference.
Description
Technical field
The present invention relates to a kind of humanization liver animal model and its construction method and applications.
Background technique
Hepatopathy refer to occur liver lesion, hepatopathy it is many kinds of include hepatitis A, hepatitis B, hepatitis, fatization, liver cancer,
Cirrhosis, Alcoholic or non-alcoholic hepatopathy etc., hepatopathy are that the common life to the mankind of one kind has high risks disease.In
State is one of maximum country of hepatopathy disease incidence, there is data statistics hepatitis, fatty liver, medicamentous liver lesion, liver cancer in recent years
The hepatopathys such as hardening have threatened the healthy living of the mankind, wherein with the disease incidence highest of virus hepatitis, disease incidence increases year by year.Root
Research according to the World Health Organization (WHO) to the hepatopathy death rate, in past 20 years, the whole world is because of cirrhosis and PLC mortality
Total number of persons increases by 50,000,000 every year.By years of researches, the liver diseases spectrum of our countries is haveed the characteristics that as follows: first is that
Hepatopathy type is abundant, and at least more than 100 kinds；Second is that infectious hepatopathy is still than great；Third is that the age of infection hepatopathy is young
Change；Fourth, the trend obviously risen is presented in the type of non-infection hepatopathy.
For above-mentioned hepatopathy, global medicine R&D institution of reaching actively puts into a large amount of man power and materials, makes every effort to develop and provide
There is the drug of good therapeutic effect.But current liver disease drug, which is developed, mainly uses conventional animal modeling to carry out drug progress just early period
The screening of step and evaluating drug effect, such as mouse model, but after all the liver of animal and the liver of the mankind there are sizable difference,
It is thus impossible to reaction of the simulation people's liver to drug well.
Summary of the invention
Based on this, it is necessary to provide a kind of construction method of humanization liver animal model.
In addition, also providing a kind of humanization liver animal model and application.
A kind of construction method of humanization liver animal model, comprising the following steps:
Source of people hepatic progenitor cells are injected into immunodeficient animals of the liver through partially cutting off, humanization liver animal is obtained
Model.
The construction method of above-mentioned humanization liver animal model uses immunodeficient animals of the liver through partially cutting off for structure
The object of established model carries out the injection of source of people hepatic progenitor cells and constructs humanization liver animal model, on the one hand avoids in source of people liver ancestral
Cell infusion carries out the immunosupress such as ciclosporin A, radioactive ray and band to animal due to the immunological rejection of xenogenesis after entering in animal body
Application after the model construction come is completed is limited to；On the other hand it also avoids causing hepatic injury using drug, virus, bacterium etc.
The application bring after modeling is interfered afterwards.And, it turned out that, according to the humanization liver animal of the construction method arrived
Model has people's gallbladder tube structure, shows that the humanization liver animal model of building has the function of liver, can be clinically liver
Disease research or new drug metabolic research provide a kind of feasible animal model support, all for liver regeneration and correlative study
There is important meaning.
Source of people hepatic progenitor cells are injected into immune deficiency of the liver through partially cutting off described in one of the embodiments,
In step in animal, the dosage of the source of people hepatic progenitor cells is 1 × 106A/animal~1 × 107A/animal.
In one of the embodiments, further include the obtaining step of the source of people hepatic progenitor cells:
Human stem cell is subjected to induction differentiation in hepatocyte differentiation culture medium, wherein the hepatocyte differentiation culture medium
In include hepatocyte growth factor, fibroblast growth factor and epidermal growth factor.
The mass-volume concentration of the hepatocyte growth factor is 10 μ of μ g/L~40 g/L in one of the embodiments,；
The mass-volume concentration of the fibroblast growth factor is 10 μ of μ g/L~20 g/L；The mass-volume concentration of the epidermal growth factor
For 10 μ of μ g/L~20 g/L.
The quality of the removed liver of the immunodeficient animals is the immune deficiency in one of the embodiments,
The 50%~70% of the quality of animal Original Liver.
The immunodeficient animals are immunodeficient mouse or immunodeficient rats in one of the embodiments,.
It is small to be selected from Nude mouse, SCID mice, NOD-SCID for the immunodeficient mouse in one of the embodiments,
One of mouse, NSI mouse, NCG mouse, Rag2 mouse and IL2RG mouse.
The immunodeficient animals are NCG mouse in one of the embodiments,.
A kind of humanization liver animal model is obtained by the construction method of above-mentioned humanization liver animal model.
Application of the above-mentioned humanization liver animal model in liver disease drug screening and evaluating drug effect.
Detailed description of the invention
Fig. 1 is the immunofluorescence of the source of people hepatic progenitor cells of embodiment 1；
Fig. 2 is the schematic diagram that the NCG mouse of embodiment 2 is fixed and abdomen is open；
Fig. 3 is the removed part of the liver of the NCG mouse of embodiment 2；
Fig. 4 is the schematic diagram in the spleen that source of people hepatic progenitor cells are injected into NCG mouse of embodiment 2；
Fig. 5 is the Liver immunity group testing result figure of the humanization liver animal model of embodiment 2.
Specific embodiment
To facilitate the understanding of the present invention, a more comprehensive description of the invention is given in the following sections with reference to the relevant attached drawings.In attached drawing
Give section Example of the invention.But the invention can be realized in many different forms, however it is not limited to this paper institute
The embodiment of description.On the contrary, purpose of providing these embodiments is keeps the disclosure of invention more thorough and comprehensive.
Unless otherwise defined, all technical and scientific terms used herein and belong to technical field of the invention
The normally understood meaning of technical staff is identical.Term as used herein in the specification of the present invention is intended merely to description tool
The purpose of the embodiment of body, it is not intended that in the limitation present invention.
The construction method of the humanization liver animal model of one embodiment, comprising the following steps:
S110, the liver underwent operative part of immunodeficient animals is cut off, obtains Liver damaged animal.
Immunodeficient animals refer to that method due to congenital hereditary mutation or manually causes one or more siberian crabapples
The animal for constituent defect of uniting.In the present embodiment, immunodeficient animals are non-human mammal.Preferably, described
Immunodeficient animals are rodent.Further, immunodeficient animals are immunodeficient rats or immunodeficient mouse.?
In one embodiment, it is small to be selected from Nude mouse, SCID mice, NOD-SCID mouse, NSI mouse, NCG for immunodeficient mouse
One of mouse, Rag2 mouse and IL2RG mouse.
Specifically, the step of liver underwent operative part of immunodeficient animals being cut off specifically includes:
The abdomen of immunodeficient animals is open, then squeezes out the liver of immune animal from opening, by the immune of extrusion
The liver of animal is ligatured and is cut off, wherein the quality of removed liver is the quality of immunodeficient animals Original Liver
50%~70%.Further, the quality of removed liver be immunodeficient animals liver quality 50%, 55%,
60%, 65% or 70%.
Immunodeficient animals of the above-mentioned liver through partially cutting off can be avoided use after being injected into source of people hepatic progenitor cells
Drug such as ciclosporin A carries out immunosupress processing to animal and weakens xenogeneic immunological rejection, do not influence subsequent animal structure
The application of such as drug screening and evaluating drug effect after the completion of building.In addition, the immune deficiency because of above-mentioned liver through partially cutting off is dynamic
Object avoids immunosupress processing and the survival rate of animal can be also improved.
In some embodiments, immunodeficient animals of the liver through partially cutting off are commercially available.
S130, source of people hepatic progenitor cells are injected into immunodeficient animals of the liver through partially cutting off, obtain humanization liver
Dirty animal model.
Specifically, source of people hepatic progenitor cells are injected into immunodeficient animals of the liver through partially cutting off, obtain humanization liver
The step of dirty animal model includes following operation:
S131, preparation source of people hepatic progenitor cells.
Hepatic progenitor cells are also known as small liver cell, epithelial duct like cell, are that one kind is distributed in adult hepatic, have two-way point
Change the heterogeneous cell of potential.Source of people hepatic progenitor cells that is to say the hepatic progenitor cells of people, be broken up by human stem cell.Wherein, people
Stem cell is the human stem cell being separately cultured or commercialized human stem cell.Further, human stem cell fills between being selected from people's umbilical cord
One of matter stem cell, IPS cell and embryonic stem cell.
Specifically, human stem cell is subjected to induction differentiation in hepatocyte differentiation culture medium, wherein hepatocyte differentiation culture
It include hepatocyte growth factor, fibroblast growth factor and epidermal growth factor in base.Stem cell has versatility, if not fixed
To differentiation, it is also difficult to form hepatic progenitor cells.Further, the quality volume of hepatocyte growth factor is dense in cell differential medium
Degree is 10 μ of μ g/L~40 g/L；The mass-volume concentration of fibroblast growth factor is 10 μ of μ g/L~20 g/L；Epidermal growth factor
Mass-volume concentration is 10 μ of μ g/L~20 g/L.Preferably, the mass-volume concentration of hepatocyte growth factor is 12 μ g/L, 16 μ
G/L, 20 μ g/L, 25 μ g/L, 30 μ g/L or 35 μ g/L；The mass-volume concentration of fibroblast growth factor is 12 μ g/L, 14 μ g/L, 16
μ g/L or 18 μ g/L；The mass-volume concentration of epidermal growth factor is 12 μ g/L, 14 μ g/L, 16 μ g/L or 18 μ g/L.Further
The mass-volume concentration ratio of ground, hepatocyte growth factor and fibroblast growth factor is 2:0.5~4.Hepatocyte growth factor and table
The mass-volume concentration ratio of skin growth factor is 1:0.5~2.
S133, source of people hepatic progenitor cells are injected into immunodeficient animals of the liver through partially cutting off, obtain humanization liver
Animal model.
Specifically, injection system is in subcutaneous injection, coating injection, intravenous injection, intraperitoneal injection and spleen injection
It is a kind of.Preferably, injection system is spleen injection.Source of people hepatic progenitor cells are injected into spleen, source of people hepatic progenitor cells pass through blood
Liquid circulation is transported in liver, and is repaired to the liver of damage.Using the superpower repair ability of liver, in hepatotomy
Source of people hepatic progenitor cells are supplemented afterwards, so that the liver of immunodeficient animals of the liver through partially cutting off utilizes rapidly the source of people liver of external source
Progenitor cells repair the damage, thus the humanization liver mouse model generated.
The dosage of source of people hepatic progenitor cells is 1 × 10 in one of the embodiments,6/ animal~1 × 107/ animal.Into
One step, the dosage of source of people hepatic progenitor cells is 1 × 106A/animal, 3 × 106A/animal, 5 × a 106/ animal, 7 ×
A 106/ animal or 1 × 107/ animal.It is injected according to this dosage, source of people hepatic progenitor cells are easier in mouse liver
Middle Growth and Differentiation forms bile duct.
Can the dosage of source of people hepatic progenitor cells be to influence source of people hepatic progenitor cells move in immune deficiency of the liver through partially cutting off
The key of object tumor growth survival.Cell concentration is excessively high, will cause animal blood vessels blocking, causes animal dead；Cell concentration is too low
Effect is not achieved.According to above-mentioned dosage, source of people hepatic progenitor cells Growth and Differentiation and can be repaired impaired in the liver of Liver damaged animal
Liver.
The construction method of above-mentioned humanization liver animal model, it is easy to operate, the period is short, convenient for large-scale production.Through upper
State the gallbladder in the above-mentioned humanization liver animal model that the construction method of humanization liver animal model constructs with source of people
The formation of pipe, the interference such as no other drugs, virus, bacterium, is conducive to screening and the evaluating drug effect of liver disease drug.
Application of the above-mentioned humanization liver animal model in liver disease drug screening and evaluating drug effect.
A kind of method of evaluating drug effect of liver disease drug, comprising the following steps:
Liver disease drug is injected into above-mentioned humanization liver animal model；And the drug effect of evaluation liver disease drug.
A kind of screening technique of liver disease drug, comprising the following steps:
Liver disease drug is injected into above-mentioned humanization liver animal model；And screening liver disease drug.
Specific embodiment
It is described in detail below in conjunction with specific embodiment.In embodiment if not otherwise indicated using drug and instrument,
For this field conventional selection.Test method without specific conditions in embodiment, according to normal conditions, such as document, books
In condition or manufacturer recommend method realize.
Embodiment 1 separates and induces into source of people hepatic progenitor cells
(1) in an aseptic environment, people's umbilical cord (coming from South Mountain hospital) is cut off, after separating blood vessel along center, by remaining set
It knits and is cut into about 2mm3Fritter, then inside is affixed in advance with (the source of people umbilical cord mesenchymal stem cells training of 1ml stem cell complete medium
Support base, friendly health biology) in the 10cm Tissue Culture Dish of wetting.It is subsequently placed in 37 DEG C, the CO that volume fraction is 5%2Carbon dioxide
2h is cultivated in incubator, and 8ml complete medium (source of people umbilical cord mesenchymal stem cells culture medium, friendly Kang Sheng are added after organizing to be adjacent to
Object).It changes the liquid once within every 3 days, during which observes attached cell around paste block and climb out of situation；The primary umbilical cord of source of people is obtained after cultivating 2 weeks
Mescenchymal stem cell.
(2) isolated primary umbilical cord mesenchymal stem cells of source of people are collected, with liver directed differentiation culture medium (match industry:
HUXMX-90101 it) carries out inducing differentiation into source of people hepatic progenitor cells, after induction differentiation 14 days, after immunofluorescence technique identification,
Obtain source of people hepatic progenitor cells.Wherein qualification result is as shown in Figure 1, brilliant white part is source of people hepatic progenitor cells in Fig. 1.
The foundation of 2 humanization liver animal model of embodiment
(1) shown in as shown in Figure 2~Fig. 3, dorsal position after NCG mouse (model animal research institute, Nanjing University) anesthesia is solid
It is fixed, and squeeze out liver from the both sides of opening to intermediate extruding in the notch of mouse web portion opening 1cm long, and by the liver of extrusion
It is dirty to be ligatured to proximal part, by 50% excision of entire liver volume after ligation, and remaining liver is put back into abdomen, small
Mouse puts back in cage and raises 2 days, obtains hepatic injury mouse.
(2) as shown in figure 4, by source of people hepatic progenitor cells with 1 × 107It is a/to be only injected into the hepatic injury mouse that step (1) obtains
Spleen in, respectively after injection 1 week, 2 weeks, 4 weeks by immunohistochemistry detection liver detection people's ALB marker protein, with group
It knits slice immunohistochemistry standard and determines the foundation for exempting from humanization liver animal model.Wherein, the liver testing result after injecting 4 weeks
As shown in Figure 5.In Fig. 5, Dark grey (being brown in practical photochrome) is ALB marker protein, and black is (practical colored
It is navy blue in photo) it is bile duct, the chimeric rate of source of people liver is 60% in mouse liver.As seen from Figure 5, humanization liver
The foundation of dirty animal model.
Each technical characteristic of embodiment described above can be combined arbitrarily, for simplicity of description, not to above-mentioned reality
It applies all possible combination of each technical characteristic in example to be all described, as long as however, the combination of these technical characteristics is not deposited
In contradiction, all should be considered as described in this specification.
The embodiments described above only express several embodiments of the present invention, and the description thereof is more specific and detailed, but simultaneously
It cannot therefore be construed as limiting the scope of the patent.It should be pointed out that coming for those of ordinary skill in the art
It says, without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to protection of the invention
Range.Therefore, the scope of protection of the patent of the invention shall be subject to the appended claims.
Claims (10)
1. a kind of construction method of humanization liver animal model, which comprises the following steps:
Source of people hepatic progenitor cells are injected into immunodeficient animals of the liver through partially cutting off, humanization liver animal mould is obtained
Type.
2. the construction method of humanization liver animal model according to claim 1, which is characterized in that described by source of people
Hepatic progenitor cells are injected into the step in immunodeficient animals of the liver through partially cutting off, and the dosage of the source of people hepatic progenitor cells is
1×106A/animal~1 × 107A/animal.
3. the construction method of humanization liver animal model according to claim 1, which is characterized in that further include the people
The obtaining step of source hepatic progenitor cells:
Human stem cell is subjected to induction differentiation in hepatocyte differentiation culture medium, wherein wrap in the hepatocyte differentiation culture medium
Include hepatocyte growth factor, fibroblast growth factor and epidermal growth factor.
4. the construction method of humanization liver animal model according to claim 3, which is characterized in that the liver cell is raw
The mass-volume concentration of the long factor is 10 μ of μ g/L~40 g/L；The mass-volume concentration of the fibroblast growth factor be 10 μ g/L~
20μg/L；The mass-volume concentration of the epidermal growth factor is 10 μ of μ g/L~20 g/L.
5. the construction method of humanization liver animal model according to claim 1, which is characterized in that the immune deficiency
The quality of the removed liver of animal is the 50%~70% of the quality of the immunodeficient animals Original Liver.
6. the construction method of humanization liver animal model according to claim 1, which is characterized in that the immune deficiency
Animal is immunodeficient mouse or immunodeficient rats.
7. the construction method of humanization liver animal model according to claim 6, which is characterized in that the immune deficiency
Mouse is in Nude mouse, SCID mice, NOD-SCID mouse, NSI mouse, NCG mouse, Rag2 mouse and IL2RG mouse
One kind.
8. the construction method of humanization liver animal model according to claim 7, which is characterized in that the immune deficiency
Animal is NCG mouse.
9. a kind of humanization liver animal model, which is characterized in that the humanization liver animal model is by claim 1~8
The construction method of described in any item humanization liver animal models obtains.
10. application of the humanization liver animal model as claimed in claim 9 in liver disease drug screening and evaluating drug effect.
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