CN106309492A - Stem cell preparation, and preparation method and application thereof - Google Patents
Stem cell preparation, and preparation method and application thereof Download PDFInfo
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- CN106309492A CN106309492A CN201610878605.XA CN201610878605A CN106309492A CN 106309492 A CN106309492 A CN 106309492A CN 201610878605 A CN201610878605 A CN 201610878605A CN 106309492 A CN106309492 A CN 106309492A
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- stem cell
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- stem cells
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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
Abstract
The invention relates to the field of biological therapy, and discloses a stem cell preparation, and a preparation method and application thereof. The stem cell preparation disclosed by the invention comprises the following ingredients through being metered by the cell quantity: exosomes secreted by 5*10<4> to 1*10<6>/10muL retinal pigment epithelial cells and 1*10<6>/10ml umbilical cord mesenchymal stem cells, wherein the retinal pigment epithelial cells are obtained through performing induced differentiation on the umbilical cord mesenchymal stem cells. The stem cells disclosed by the invention have good curative effect on the diabetic retinopathy.
Description
Technical field
The present invention relates to Biotherapeutics field, particularly to a kind of stem cell medicine and its preparation method and application.
Background technology
Diabetes are as a kind of endocrine metabolism disease, and its prevalence is just along with the growth of population, aging, urbanization
And the generalization of obesity and shortage motion is gradually increased.Diabetic retinopathy (Diabetic Retinopathy,
DR) being one of its most serious microvascular complication, in China, especially the prevalence in the more flourishing big and medium-sized cities of economy is just
Increasing year by year.Show through investigation, in ten thousand blind persons worldwide, DR blinding account for 4.5%.Therefore, to cause
The treatment of blind property oculopathy DR is extremely urgent.
DR is the multifactor a kind of retina PD caused, and pathogeny is extremely complex, relates to a large amount of difference
Cell, the factor and molecule.Traditional theory is thought, DR is a kind of retinal microvascular disease, but in the last few years, more and more
Research confirm diabetes have impact on retina whole neural blood vessel unit, just cause neural blood vessel coupling numbers at the disease initial stage
The minimizing of amount, gradual neural degeneration, gliosis and neuroinflamation sexually revise, and these pathological changes appear at and face
Before the visible retinal microvascular of bed changes.Amphiblestroid neurocyte, glial cell, microcirculqtory system and chronic inflammatory disease
Factors etc. interact the development causing the state of an illness lasting in DR pathogenic process, and then amphiblestroid microangiopathies occur.
At present, the primary treatment measure of DR includes Drug therapy, laser therapy and 3 kinds of sides of Vitrectomy treatment
Formula.It is strict glycemic control and blood pressure, blood viscosity management, for middle severe non-proliferative type DR and proliferous type in early days at all
The feasible laser therapy of DR to reduce blinding risk, and for the proliferous type DR of vitreous hemorrhage or detachment of retina be only capable of row
Vitrectomy.Operation can remove hematocele, anatomical reduction retina, but amphiblestroid function suffers damage already, depending on
Power recovers unsatisfactory, and also operating difficulty is big, and operation itself is in amphiblestroid strike and art and post-operative complication is many etc.
Unfavorable factor.
Ocular angiogenesis progress shows in recent years: VEGF (vascular endothelial
Growth factor, VEGF) it is to cause Diabetic Macular water (diabeticmacularedema, DME) and retina and arteries and veins
The critical stimulus factor of network film new vessels (choroidal neo vascularization, CNV).Targeting anti-vegf is biological
Although treatment can improve the blood retina barrier damage that DR causes, however anti vegf agents treatment still fall within destruction new vessels,
The field of angiogenesis inhibitor, can not fundamentally stop the development of DR, and this medicine of duplicate injection can cause retina god
Toxicity damage through cell.
Take various mode to reduce the incidence rate of diabetes or to stop disease before visible microangiopathies occurs
Sick progress is only the most effective.It is true that the most effective method for the treatment of diabetic retinopathy is to reduce
The progress that disease occurs or stoped before visible microangiopathies occurs of diabetes.The forward sight of retina generation pathological changes
Have there is apoptosis in nethike embrane neuronal cell and M ü ller cell, if there being a kind of Therapeutic Method can be in early days the most right at DR
These aspects are intervened, then the treatment that may make DR is the most more meaningful.Retinal epithelial cells (retinal
Pigmented epithelium, RPE), the maintenance and self renewal of retinal neuronal cell have important function, such as:
The photoreceptor cell outer segment membranous disc that phagocytosis digestion comes off；Promote the regeneration of 11 1 cis retinenes；The immunoreation of regulation ophthalmic；
Participate in forming retinal vessel barrier etc..There are some researches show, RPE cell is transplanted to pathological changes subretinal space patient can be delayed to regard
Feel that the process lost or part recover its visual performance.Subretinal space autologous RPE cell transplantation is more stable, and has long-term
Curative effect.But its source and quantity limit the extensive application hindering the method clinically.
At present, progressively understand and the appearance successively of its novelty therapeutic modality, stem cell injection along with DR pathogenesis
Therapy increasingly causes everybody concern.Stem cell is the pluripotent cell that a class has the of self-replication capacity.With stem cell it is
The therapeutic modality on basis be central and the damage of peripheral nervous system, especially neural gaps create for neuranagenesis good
Good environment.
Secreting outward body (exosome) is a kind of film vesicle extracting from cell culture medium supernatant, containing its derived cell
After birth and cytoplasmic protein composition, therefore it can carry out information transmission at different iuntercellulars.Numerous studies are reported, Exosome energy
The cellular physiological events that enough participation regulation and control are important, plays in immunne response, apoptosis, angiogenesis, inflammatory reaction, condensation process
Middle important function, can become the early diagnosis label of multiple disease, also can carry out disease as the carrier of targeted drug and control
Treat.Therefore, secrete outward body to have a very important role in cell micro-environment.At present, research shows umbilical cord mesenchymal stem cells
The outer body (exosome) of secreting in source has neurotrophy and immunosuppressive action, can alleviate a variety of causes by transmission and cause
Retina injury, reduce inflammation reaction, thus improves retinal function, opens up new way for clinical treatment ophthalmic diseases.
Treat the Drug therapy medicine of diabetic retinopathy at present, although as anti vegf agents can improve retina
Damage, but blood vessel is had toxicity damage；There is special due to its source of human stem cell of the stem cell medicine of efficient curative effect
Property and the finiteness of quantity, limit clinic application.
Therefore, researching and developing little and easy preparation the stem cell medicine of a kind of high curative effect, toxic and side effects is those skilled in the art
The technical issues that need to address.
Summary of the invention
The invention discloses a kind of stem cell medicine and its preparation method and application, described stem cell medicine treatment diabetes
Retinopathy is evident in efficacy, toxic and side effects is little for property.
The present invention is achieved by the following technical solutions:
The invention discloses a kind of stem cell medicine, including following component:
5×104～1 × 106The retinal pigment epithelium and 1 × 10 of individual/10 μ L6Individual/10 μ L umbilical cord mesenchymas are dry thin
The outer of intracrine secretes body.
As preferably, described stem cell medicine includes following component:
5×105The retinal pigment epithelium and 1 × 10 of individual/10 μ L6Individual/10 μ L umbilical cord mesenchymal stem cells secretions
Secrete outward body.
As preferably, described retinal pigment epithelium is formed by the induction differentiation of described umbilical cord mesenchymal stem cells.
The invention also discloses the preparation method of described stem cell medicine, comprise the following steps:
The outer body of secreting secreted by described umbilical cord mesenchymal stem cells mixes with described retinal pigment epithelium, prepares institute
State stem cell medicine.
The invention also discloses the stem cell medicine that described stem cell medicine or described preparation method prepare to control in preparation
Treat the application in the pharmaceutical preparation of diabetic retinopathy.
The separation and Culture of umbilical cord mesenchymal stem cells and authentication method list of references " mesenchymal stem cell transplantation glycosuria
Sick rat retinopathy experimentation in early days ".
The preparation of the retinal pigment epithelium of umbilical cord mesenchymal stem cells induction and qualification list of references " transcription factor
Induction human umbilical cord mesenchymal stem cells transdifferentiation is the research of retinal pigment epithelium like cell ", Tongji University's journal, 2015,
36(5)。
Secrete outward the isolated and purified of body and identify that list of references " secretes body immunoloregulation function outside human umbilical cord mesenchymal stem cells
Research ", Chinese Medical Journal, the 2015, the 32nd phase.
In clinical studies, the application of the mescenchymal stem cell (MSCs) of embryonic stem cell and derived from bone marrow is relatively broad.
But, from the point of view of Point of View of Clinical, the acquisition of bone marrow is a kind of invasive mode, increase patient suffering, limited source, and along with
Its propagation/inducibility of the increase at age progressively declines；The limited source of embryonic stem cell and its safety and moral check are asked
There is dispute in topic always.
The present invention uses the mescenchymal stem cell from somatic umbilicus source and the retinal pigment epithelium of induction differentiation thereof
Combination preparation carry out the treatment of DR.Umbilical cord mesenchymal stem cells has wide material sources, convenience of drawing materials, proliferative ability is strong, it is many to possess
To differentiation potential and the feature that possesses immunoregulation effect.Human umbilical cord mesenchymal stem cells can be induced to differentiate into islets of langerhans in vitro
Like cell, enters in liver by this noble cells cluster transplantation, and internal peptide, insulin secretion increase, and blood sugar level is controlled.And
And umbilical chord mesenchymal cells can substitute or repair the retina of damage by drug-induced differentiation chemical conversion retinal epithelial cells
Pigment epithelium cell.Under suitable microenvironment, nerve trunk in retina can be promoted by secretory nerve trophic factors after local injection
Cell and the proliferation and differentiation of precursor, carry out immunomodulating, the local inflammation reaction on suppression optical fundus, nutrition and protection optical fundus group
Knit.
The outer body of secreting secreted by the umbilical cord mesenchymal stem cells of same Species origin, and done by the umbilical cord mesenchyma of autologous
The retinal pigment epithelium that cell induction is divided into can reduce the described stem cell medicine immunogenicity to body, and this
The administering mode of bright stem cell medicine is to be injected into eye vitreous chamber, is injected into vitreous chamber and causes immunological rejection possible
Property is little.
The stem cell medicine preparing the embodiment of the present invention carries out animal experiment, experiment results proved embodiment of the present invention system
Standby stem cell medicine has good curative effect to diabetic retinopathy.
Compared with prior art, stem cell medicine disclosed by the invention has good treatment to diabetic retinopathy
Imitate, and the cellular component in described stem cell medicine is drawn materials easily, wide material sources, it is easy to popularization and application.
Detailed description of the invention
The invention discloses a kind of stem cell medicine and its preparation method and application, described stem cell medicine is to diabetic
Retinopathy has good curative effect.Those skilled in the art can use for reference present disclosure, is suitably modified technological parameter and realizes.Special
Not it is pointed out that all similar replacements and change apparent to those skilled in the art, they all by
It is considered as being included in the present invention.Method and the application of the present invention are described by preferred embodiment, and related personnel is obvious
In without departing from present invention, spirit and scope, method described herein and application can be modified or suitably change and group
Close, realize and apply the technology of the present invention.
Below in conjunction with embodiment, the present invention is expanded on further.
In embodiment, component used and reagent are commercially available or self-control source.
The present embodiment is using rat as subjects, and umbilical cord mesenchymal stem cells used is the umbilicus drawn materials in rat body
Band mescenchymal stem cell, retinal epithelial cells used is for forming from the induction of rat umbilical cord mesenchymal stem cells.Should be noted that
, method disclosed in the present embodiment has universality, however it is not limited to applies on rat, applies also for other species, also
Can be applicable to human body.
The separation and Culture of umbilical cord mesenchymal stem cells and authentication method list of references " mesenchymal stem cell transplantation glycosuria
Sick rat retinopathy experimentation in early days ".
The preparation of the retinal pigment epithelium of umbilical cord mesenchymal stem cells induction and qualification list of references " transcription factor
Induction human umbilical cord mesenchymal stem cells transdifferentiation is the research of retinal pigment epithelium like cell ", Tongji University's journal, 2015,
36(5)。
Secrete outward the isolated and purified of body and identify that list of references " secretes body immunoloregulation function outside human umbilical cord mesenchymal stem cells
Research ", Chinese Medical Journal, the 2015, the 32nd phase.
Embodiment 1 prepares stem cell medicine
By 1 × 106The outer of individual umbilical cord mesenchymal stem cells secretion secretes body and 1 × 105Individual retinal pigment epithelium mixes
Closing, make 10 μ L mixing stem cell medicines, the solvent of use is normal saline.
Embodiment 2 prepares stem cell medicine
By 1 × 106The outer of individual umbilical cord mesenchymal stem cells secretion secretes body and 5 × 104Individual retinal pigment epithelium mixes
Closing, make 10 μ L mixing stem cell medicines, the solvent of use is normal saline.
Embodiment 3 prepares stem cell medicine
By 1 × 106The outer of individual umbilical cord mesenchymal stem cells secretion secretes body and 1 × 106Individual retinal pigment epithelium mixes
Closing, make 10 μ L mixing stem cell medicines, the solvent of use is normal saline.
The foundation of embodiment 4 DR animal model and qualification
1, the foundation of diabetes model
Take healthy female male SD rat totally 38,8～10 week old, body weight 200～220g.It is randomly divided into Normal group (n
=5) and model group (n=33).All after row slit lamp, direct ophthalmoscopy, get rid of ocular disease.Rat adaptability word supports 3
After it, every rat carries out measured body weight, calculates streptozotocin (STZ) consumption with 45mg/kg.STZ is dissolved in fresh joining
System Chinese catalpa lemon acid-lemon acid sodium buffer in, after being made into 2%STZ solution, carry out tail vein injection at once.After injection when 1 week
Tail point blood surveys blood glucose, blood glucose > 16.7mmol/L is that diabetes model is successfully established.After Cheng Mo, Rat Standard is raised and diet, sees
Examine the ordinary circumstances such as diet drinking-water, defecation, hair color, mobility, the mental status, weekly timing detection blood glucose and body weight, periodically
Observe anterior ocular segment and optical fundus, monthly row fundus photography, fundus fluorescein angiography.Period finds that dead and blood sugar recovery rat is timely
Remove.
2. the qualification of diabetic retinopathy model
Raise 10 weeks after diabetes rats modeling success, from Normal group and model group, randomly choose 2 respectively
Carry out FITC-dextran fluoroscopic visualization inner nuclear layer retina, to confirm that DR model is the most successful.FITC-dextran burns light radiography
The method of inner nuclear layer retina is as follows:
(1) dosing: 50mgFITC-dextran fluorescein is dissolved in 1mL and steams feedback water, standby after extracting with syringe.
(2) anesthesia: use 10% hydration chloric acid to experimental rat row intraperitoneal injection of anesthesia.
(3) perfusion: fixing rat head, extremity, opens rapidly breast and exposes heart, apex inserting needle row left ventricle irrigate,
The positions such as the ear of rat, nose occur that yellow is perfusion sufficiently mark.
(4) collection of specimens: extract eyeball at once, is fixed on 4% paraformaldehyde 30 minutes.
(5) inner nuclear layer retina: under ophthalmic operating microscope, cuts eyeball along corneoscleral junction, removes prosthomere tissue and glass
Glass body, careful separation goes out the most complete retina, and radial centered by optic disc cuts off, and is laid on microscope slide, drips
2% neutral gum 1, covered.
(6) observe: use prominent light microscope observe retinal vascular morphologies and take pictures, take excitation wavelength 490nm, filter
Optical wavelength 520nm.
Result shows, 38 rat modeling successes.
The clinical trial of embodiment 5 stem cell medicine
Model successful diabetic retinopathy rat model as subjects using embodiment 4, choose 16 rats
Being divided into 4 groups, often group is 4 rats (8 eyes).
Following 5 groups are set.
Normal process group: take healthy SD rat 4 (8 eyes).
Blank group: local injection normal saline solution.
Test group A: the stem cell medicine of embodiment 1 preparation.
Experiment group B: the retinal pigment epithelium 1 × 10 of umbilical cord mesenchymal stem cells induction5Individual/10 μ L.
Test group C: the retinal pigment epithelium 1 × 10 of induced differentiation of embryonic stem cells5Individual/10 μ L.
In addition to normal group, injecting 10 μ L normal saline in blank group eyes vitreous chamber respectively, other respectively organizes rat
Eyes vitreous chamber injects 10 μ L cell suspension respectively (all containing 1 × 105Retinal pigment epithelium)；Normal rats two
Eye does not give any intervention.Test after rat diabetes Cheng Mo, inject the liquid of above-mentioned group, locate after having injected 4 months
Dead rat, collects Eyeball exemplar.Detect rat blood sugar before setting up model, after diabetes Cheng Mo and when making a collection of specimens and record body
Weight.EB Perfused vessel inner nuclear layer retina detection by quantitative is used to observe retinal blood vessels leak situation.
The method of intravitreal stem cell medicine is as follows:
(1) by operating theater instruments high pressure steam sterilizations such as microsyringe (volume 10 μ L) and the micro-tweezers of ophthalmology before injection,
Cool drying is standby.
(2) anaesthetize and fix: rat weight, anaesthetizing by dosage lumbar injection 10% chloral hydrate of 3mL/kg.Greatly
Instill the abundant mydriasis of compound tropicamide eye drops in Mus conjunctival sac, instill proxymetacaine hydrochloride eye drop topical anesthesia, treat four
Limb is weak and limp, absent corneal reflex, is fixed on homemade foam operating-table.
(3) sterilization: iodophor disinfection conjunctival sac, clean with normal saline flushing after 1 minute.
(4) extract each test group cell suspension or normal saline 20 μ L with microsyringe, get rid of air, at ophthalmologic operation
Under microscope, after limbus of corneae, about 2mm sentences 45 DEG C of angle inserting needles and is injected in rat vitreous chamber, and avoids damage to crystalline
Body.Through syringe needle point seen from crystalline lens, slowly inject, pull out pin after stopping 10 seconds, gently press at puncture 1 minute with cotton swab,
Prevent injecting fluid from backflowing.
(5) last some Levofloxacin Eye drop and erythromycin eye ointment prevention infection in conjunctival sac.
(6) rat is placed in warm environment, observes to reviving.
Retinal EB seepage quantitative analysis method is as follows:
Azovan blue (evans blue, EB) is a kind of four sodium diazo colours, and molecular weight is 980Da, energy after intravenous injection
Combining closely with the ratio of 10:1 with plasma albumin, when vascular permeability increases, EB protein complex passes through blood vessel wall
Leak into surrounding tissue, be a kind of comparatively ideal tracer.
(1) Normal group takes 4 rats with bilateral eyeballs (8 eyes), and DR model experiment group takes 4 rat right eyes (8 respectively
Eye), carry out EB seepage quantitative analysis.
(2) anesthesia: rat weight, is anaesthetized by dosage lumbar injection 10% chloral hydrate of 3mL/kg.
(3) perfusion EB: cut off left side pars inguinalis skin with shear and expose left femoral vein, press with 1mL syringe
45mg/kg
Extraction concentration is the EB solution of 30g/L, is injected into femoral vein in 1 minute, and rat body at once becomes indigo plant and shows to fill
Form merit.
(4) circulating 2 hours in warm environment, period rat revives to add and supplements anesthesia with chloral hydrate.
(5) perfusion PBS: fixing rat extremity and head, open thoracic cavity, expose heart, left ventricle insert perfusion syringe needle,
Cutting off right auricle, perfusion PBS (37 DEG C of preheatings), injection pressure is 120mm Hg (irrigation flow is equivalent to 66mL/ minute), the time
2 minutes.
(6) draw materials: perfusion extracts rapidly eyeball after terminating, and cuts off along corneoscleral junction under operating microscope, remove prosthomere
And the tissue such as crystalline lens, vitreous body, carefully separate retinal tissue.
(7) it is dried and weighs: retinal tissue lucifuge, be placed in Constant Temp. Oven and be dried 45 minutes, claim its dry weight.
(8) every retina and 120 μ L first phthalein amine 70 DEG C are hatched 18 hours, 4 DEG C of 15000rpm high speed centrifugations of extracting solution
30 minutes, take supernatant and survey the absorbance of 620nm and 740nm respectively, seek its clean absorbance.
(9) ultraviolet spectrophotometer record concentration from the standard EB solution of 75ng/ μ L～1000ng/ μ L 620nm,
Absorbance at 740nm, both differences are clean absorbance, set up EB standard curve.Inhale with clean according to EB solution concentration
The relation of shading value, obtains EB concentration in sample real solution, is multiplied by 120 μ L by this concentration and draws retinal EB leakage
(ng).Finally by retina dry weight (mg) markization EB leakage (ng), result is expressed as ng/mg.
Result of the test is as follows
| Group | Normal group | Matched group | Test group A | Experiment group B | Test group C |
| EB infiltration capacity | 0 | 24.67±2.26 | 10.25±2.56 | 17.25±2.56 | 16.58±3.26 |
SPSS 20.0 software (IBM SPSS Statistics) is used to carry out statistical procedures, through comparing, matched group
And between each test group, there were significant differences (P < 0.05), and the difference the most statistically significant (P < 0.05) between test group A, B and C,
Wherein the therapeutic effect of test group A is best.Stem cell medicine prepared by embodiment 1 is described, umbilical chord mesenchymal cells is secreted
Secrete outward body to be used in mixed way with the retinal pigment epithelium induced differentiation into by umbilical chord mesenchymal cells, to diabetic view
Film pathological changes has the curative effect that tool is good.
The stem cell medicine prepared by embodiment 2 and embodiment 3 repeats above-mentioned test, obtains same conclusion.
The above is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For Yuan, under the premise without departing from the principles of the invention, it is also possible to make some improvements and modifications, these improvements and modifications also should
It is considered as protection scope of the present invention.
Claims (5)
1. a stem cell medicine, it is characterised in that include following component:
5×104～1 × 106The retinal pigment epithelium and 1 × 10 of individual/10 μ L6Individual/10 μ L umbilical cord mesenchymal stem cells divide
That secretes outer secretes body.
Stem cell medicine the most according to claim 1, it is characterised in that include following component:
5×105The retinal pigment epithelium and 1 × 10 of individual/10 μ L6Outer the secreting of individual/10 μ L umbilical cord mesenchymal stem cells secretions
Body.
Stem cell medicine the most according to claim 1 and 2, it is characterised in that described retinal pigment epithelium is by institute
State umbilical cord mesenchymal stem cells induction differentiation to form.
4. the preparation method of the stem cell medicine described in claims 1 to 3 any one, it is characterised in that comprise the following steps:
The outer body of secreting secreted by described umbilical cord mesenchymal stem cells mixes with described retinal pigment epithelium, prepares described dry
Cell preparation.
5. what the stem cell medicine described in claims 1 to 3 any one or the preparation method described in claim 4 prepared is dry thin
The application in the pharmaceutical preparation of preparation treatment diabetic retinopathy of born of the same parents' preparation.
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| CN201610878605.XA CN106309492A (en) | 2016-09-30 | 2016-09-30 | Stem cell preparation, and preparation method and application thereof |
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| CN201610878605.XA CN106309492A (en) | 2016-09-30 | 2016-09-30 | Stem cell preparation, and preparation method and application thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108743620A (en) * | 2018-06-21 | 2018-11-06 | 南开大学 | Bioactive materials promote source of human stem cell excretion body to treat corneal injury |
-
2016
- 2016-09-30 CN CN201610878605.XA patent/CN106309492A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108743620A (en) * | 2018-06-21 | 2018-11-06 | 南开大学 | Bioactive materials promote source of human stem cell excretion body to treat corneal injury |
| CN108743620B (en) * | 2018-06-21 | 2021-10-29 | 南开大学 | Bioactive material for promoting stem cell-derived exosome to treat corneal injury |
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Application publication date: 20170111 |