CN115212312A - Application of mesenchymal stem cells or cell extract thereof in combination with immunomodulator in preparation of medicine for preventing or treating premature ovarian failure - Google Patents
Application of mesenchymal stem cells or cell extract thereof in combination with immunomodulator in preparation of medicine for preventing or treating premature ovarian failure Download PDFInfo
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- CN115212312A CN115212312A CN202210702201.0A CN202210702201A CN115212312A CN 115212312 A CN115212312 A CN 115212312A CN 202210702201 A CN202210702201 A CN 202210702201A CN 115212312 A CN115212312 A CN 115212312A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/28—Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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Abstract
The invention relates to the technical field of biology, and particularly discloses application of a mesenchymal stem cell or a cell extract thereof in combination with an immunomodulator in preparation of a medicament for preventing or treating premature ovarian failure. The invention combines the mesenchymal stem cells or cell extracts thereof with the immunomodulator to prevent or treat premature ovarian failure, compared with the prior therapy, the mesenchymal stem cells have the advantages of easy acquisition of sources, easy realization of quantitative production, small ethical dispute and low immunogenicity, are ideal cell therapy preparations, are combined with the immunomodulator (small molecular drug hydroxychloroquine), and have basically no toxic or side effect compared with the traditional Chinese medicine preparation and the immunosuppressant. In addition, the proportion of the normal period of the mice can be improved through the drug combination treatment, so that the granular cells have better repairing degree, the follicular tissue morphology tends to be normal, the normal fertility capacity is obtained, and the drug combination treatment method has important significance for researching and developing the prevention and treatment drugs for premature ovarian failure caused by various reasons and improving the diagnosis and treatment level of premature ovarian failure.
Description
Technical Field
The invention relates to the technical field of biology, in particular to application of a mesenchymal stem cell or a cell extract thereof in combination with an immunomodulator in preparation of a medicament for preventing or treating premature ovarian failure.
Background
Premature Ovarian Failure (POF) refers to non-physiologic menopause that occurs after puberty, before the age of 40, with hot flashes, primary or secondary infertility, atrophy of the systemic and reproductive organs (ovaries, uterus, etc.). POF is a common disease in the field of gynecological endocrine, the incidence rate is about 1% -3%, the POF accounts for 10% -28% of primary amenorrhea patients, 4% -18% of secondary amenorrhea patients, and the average onset age is 23.3 years old. In recent years, the incidence of POF has increased year by year, and the proportion of POF in patients with female infertility tends to increase year by year. The low estrogen levels and loss of fertility caused by POF have become two major threats to reproductive health in women, and the earlier low estrogen levels have increased the risk of osteoporosis and coronary heart disease in women. Women in the childbearing period close their menstrual flow in advance, are psychologically burdened, and are prone to emotional and social psychosanitary problems such as depression, anxiety, interpersonal interaction difficulty, hostility and the like, so that marital life quality is reduced, and a series of psychological and social problems are caused. Therefore, POF not only threatens the reproduction and physical health of women, but also is a serious social problem.
The premature ovarian failure has complex etiology and mainly comprises genetic factors, immunological factors, iatrogenic factors (including immunosuppressants, chemotherapeutic drugs and radiotherapy) and other factors, such as galactose phosphate uridine transferase deficiency and the like. Because the mechanism of premature ovarian failure is unknown, effective means and medicines are lacked in clinical treatment.
The current treatment methods for premature ovarian failure are as follows: estrogen-progestogen substitution therapy, ovarian tissue transplantation, ovulation promotion therapy, life style regulation, traditional Chinese medicine therapy and the like. However, the current treatment method has poor treatment effect, and only 5-10% of patients are expected to recover the ovarian function after active treatment, but the treatment method has certain limitations, needs to take medicines for a long time, has large side effect or certain traumas, and cannot complete the recovery of the ovarian function to obtain normal fertility.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides the application of the mesenchymal stem cells or the cell extracts thereof in preparing the medicines for preventing or treating premature ovarian failure in combination with the immunomodulator.
In order to achieve the purpose, the invention adopts the technical scheme that:
the invention provides application of a mesenchymal stem cell or a cell extract thereof in combination with an immunomodulator in preparation of a medicament for preventing or treating premature ovarian failure.
Through a large number of researches and experiments, the inventor of the application finds that the mesenchymal stem cells or cell extracts thereof can be effectively used for preventing or treating premature ovarian failure by combining with an immunomodulator.
Experiments on the in vivo immune POF mice show that the proportion of the normal cycle of the mice can be increased by using mesenchymal stem cells or cell extracts thereof for intervention, or using an immunomodulator (such as hydroxychloroquine) for intervention, or using the mesenchymal stem cells or the cell extracts thereof for intervention in combination with the immunomodulator (such as hydroxychloroquine), wherein the effect of increasing the estrus cycle of the mice is optimal when the mesenchymal stem cells or the cell extracts thereof for intervention in combination with the immunomodulator. And according to the ovary histopathology, when the mesenchymal stem cells or the cell extract thereof are combined with the immunomodulator for treatment, the granular cells have better repairing degree, the follicular tissue morphology tends to be normal, the ovary function is recovered, and the mouse obtains normal fertility.
As a preferred embodiment of the application of the present invention, the mesenchymal stem cell is derived from human or other mammals, and preferably, the source of the mesenchymal stem cell includes one of umbilical cord Wharton's jelly, umbilical cord blood, bone marrow, gingiva, placenta, amnion, chorion, peripheral blood, fat and skin.
As a preferred embodiment of the application of the invention, the immunophenotype of the mesenchymal stem cell comprises high expression of CD73, CD90 and CD105 at the same time, and does not express CD45, CD34, CD11b, CD79 alpha/CD 19 and HLA-DR at the same time.
As a preferred embodiment of the application of the present invention, the preparation method of the mesenchymal stem cell comprises the following steps: and (3) performing primary culture and separation by using a tissue block adherence method to extract mesenchymal stem cells, and performing subculture by using a stem cell culture medium to obtain the mesenchymal stem cells.
As a preferred embodiment of the use of the present invention, the mesenchymal stem cells are passaged in stem cell culture medium for 3 to 5 passages.
The method comprises the following specific steps:
s1, organization treatment:
shearing the tissue into tissue homogenate blocks with sterile straight-head scissors, and cutting the obtained tissue into 1-4mm pieces 3 And (3) sizing, namely fixing the volume (40-45) ml of the sheared tissue homogenate block by using normal saline, and shaking the centrifugal tube to enable the colloidal tissue to be suspended in the centrifugal tube. Centrifuging at 300g for 5min at normal temperature. The remaining supernatant was discarded. According to the quantity of the colloidal tissues, inoculating the colloidal tissues in the centrifugal tube according to 0.5g per T75 culture bottle, uniformly inoculating a plurality of T75 culture bottles, adding a stem cell culture medium into each bottle, and shaking up, wherein the total volume is about 10 ml;
s2, primary cell collection and cell passage:
changing the liquid every 5 days, observing the cell state under the microscope on the cultured (14-17) th day, collecting primary cells when the cell fusion reaches (80-90)% and taking out a T75 bottle, transferring the culture supernatant to a 50ml centrifuge tube, centrifuging at 300g and normal temperature for 5min, and taking the supernatant as the pancreatin digestion termination liquid for later use. Washing the bottom surface of the culture bottle, adding pancreatin substitute which is rewarming at 37 ℃ into the culture bottle according to the amount of 3ml of the culture bottle per T75 bottle, and timing (3-5) min. Observing the cells under a mirror to completely float or after timing is finished, adding 5-10m of supernatant to stop enzymolysis, shaking up and blowing, and transferring the suspension into a 50ml centrifuge tube to obtain cell suspension. And (3) taking a proper amount of normal saline to blow and wash the bottom surface once, and centrifuging the cell suspension for 5min at normal temperature by a centrifugal force of 300 g. Resuspending the cell pellet with 10ml of culture medium, filtering the cell suspension with a 70-100 μm cell sieve, and taking 10-20 μ l cell suspension for counting and survival rate.
According to the counting result, the subsequent treatment of the primary cells is carried out, each bottle is inoculated with a T175 culture bottle according to 140 ten thousand cells, and each bottle is added with cell suspension and culture solution, and the total volume is 18ml. The mixture is gently shaken evenly, and the distribution condition is observed under a mirror.
Subculturing the cells to 72h +/-24 h, observing the cell state under a microscope, pouring out the culture solution when the cell fusion reaches (85-90)%, and using raw materialsCleaning with saline water, adding 5ml of digestive juice, stopping digestion, centrifuging (300g, 5 min), and discarding supernatant; the cell suspension was transferred to a centrifuge tube, resuspended and counted, and the concentration adjusted (6X 10) 5 In ml). Sequentially adding 2ml of cell suspension and 16ml of culture medium into a T175 culture flask; at 37 ℃ C, 5% CO 2 The incubator is used for culturing for 36-72h.
S3, freezing and storing target cells, and inspecting quality:
the steps of digesting and preparing the cell suspension are the same as the previous description, sampling, counting and flow detecting, washing and centrifuging for the second time, centrifuging by 300g, and centrifuging for 5min at normal temperature. The washing centrifugation supernatant was retained for bacterial culture, endotoxin, mycoplasma detection and sample retention. Adding a certain amount of precooled serum-free freezing medium into the cell sediment for constant volume, gently and uniformly mixing, and according to the freezing requirement of the cells, multiplying 10 times by 0.1-2.0 in each tube 7 cells were frozen at a density of cells/mL.
As a preferred embodiment of the use according to the invention, the cell extract comprises exosomes whose expression markers are TSG101, CD9, CD63 and CD81.
As a preferred embodiment of the application of the present invention, the mesenchymal stem cells or cell extracts thereof are in the form of gel, injection, liposome, lyophilized powder or emulsion.
As a preferred embodiment of the use of the present invention, the premature ovarian failure comprises premature ovarian failure caused by immune factors; the premature ovarian failure caused by immune factors comprises systemic lupus erythematosus, rheumatoid arthritis, vasculitis, ankylosing spondylitis, psoriasis, mixed connective tissue, scleroderma, behcet disease, inflammatory bowel disease, polymyositis or dermatomyositis and premature ovarian failure caused by related disease treatment drugs.
As a preferred embodiment of the use of the present invention, the immunomodulator comprises hydroxychloroquine, chiral hydroxychloroquine and analogs thereof, azathioprine, tacrolimus, biologics, glucocorticoids and other reproductive and pregnancy safe immunomodulatory drugs and pharmaceutical compositions.
The invention also provides application of the mesenchymal stem cells in preparing a medicament for preventing or treating premature ovarian failure caused by immune factors.
In vivo immunity POF mouse experiments show that when mesenchymal stem cells or cell extracts thereof are used for intervention, the proportion of a normal cycle can be increased, the number of follicles is increased compared with that of a positive control group, and premature ovarian failure caused by immune factors is effectively treated.
In addition, the invention provides a pharmaceutical composition comprising mesenchymal stem cells or a cell extract thereof and an immunomodulator, wherein the immunomodulator comprises hydroxychloroquine, chiral hydroxychloroquine and analogues thereof, azathioprine, tacrolimus, biologicals, glucocorticoids and other immune regulation medicines and pharmaceutical compositions which are safe in reproduction and pregnancy.
Compared with the prior art, the invention has the following beneficial effects:
based on the immune regulation effect of mesenchymal stem cells and the double effects of certain antithrombotic effect and immune regulation of a small molecular drug hydroxychloroquine, the invention provides the application of the mesenchymal stem cells or cell extracts thereof in combination with an immune regulator in preparing the drugs for preventing or treating premature ovarian failure. In addition, the proportion of the normal period of the mice can be improved through the drug combination treatment, so that the granular cells have better repairing degree, the follicular tissue morphology tends to be normal, the ovarian function can be recovered, and the normal fertility capability can be obtained.
Drawings
FIG. 1 is a graph of the pathological staining of ovarian tissue by each group of drugs in example 3.
Detailed Description
To better illustrate the objects, technical solutions and advantages of the present invention, the present invention will be further described with reference to the accompanying drawings and specific embodiments.
In the following examples, the experimental methods used were all conventional methods unless otherwise specified, and the materials, reagents and the like used were commercially available unless otherwise specified.
Example 1 extraction and isolation of mesenchymal Stem cells
Taking a newly delivered umbilical cord tissue, soaking and rinsing the umbilical cord tissue by using normal saline to remove blood stains on the surface of the umbilical cord, and then putting the umbilical cord tissue into filtered 75% alcohol for soaking for 1min for disinfection; then the residual alcohol is washed by normal saline.
Using sterile scissors to cut two ends of the umbilical cord, cutting the rest umbilical cord into small sections of 2-3 cm, and washing with normal saline; peeling umbilical vein and umbilical artery with aseptic forceps with teeth, tearing off Wharton's jelly, transferring into 50ml centrifuge tube, centrifuging at 800g for 5min, discarding supernatant, and weighing. Shearing the Wharton's jelly into 1-4mm with another pair of sterile scissors 3 Washing and centrifuging the tissue blocks by using normal saline, fixing the volume of the sheared tissue homogenate blocks to be 40-45 ml, and shaking the centrifugal tube to enable the colloid to be suspended in the centrifugal tube. Centrifuging at 300g centrifugal force at room temperature for 5min, and discarding the supernatant.
According to the amount of the colloidal tissues, 0.5g of the colloidal tissues in each bottle is inoculated into a T75 culture bottle uniformly, the total volume of the culture medium is 7ml, and CO is added 2 Culturing in an incubator, and keeping aseptic conditions in the whole process.
The culture medium was changed every 5 days, and the state of the cells was observed under a microscope on the (14 th to 17 th) th day of culture. After culturing for 5 days, carrying out total liquid change; after 10 days of culture, half-exchange of the culture broth was carried out. After 15 days of culture, a cell fusion rate of more than 85% was observed, and primary cells were collected. Taking out the T75 bottles needing to be operated in the batch, transferring the culture supernatant to a 50ml centrifuge tube, centrifuging the centrifuge tube at 300g for 5min at normal temperature, and taking the supernatant as a pancreatin digestion stop solution for later use. Washing the bottom surface of the culture bottle with normal saline, adding 3ml pancreatin into each T75 culture bottle for digestion for 5min, observing the cells to float completely under the mirror or after timing is finished, adding 5-10m of supernatant to stop enzymolysis, shaking up and blowing, and transferring the suspension into a 50ml centrifuge tube to obtain cell suspension. And (3) taking a proper amount of normal saline to blow and wash the bottom surface once, and centrifuging the cell suspension for 5min at normal temperature by a centrifugal force of 300 g. The cell pellet was resuspended in 10ml of medium, a 100 μm cell sieve was used to filter the cell suspension, 20 μ l of cell suspension was used for counting, and the remaining cell suspension was passed on.
According to the counting result, the subsequent treatment of the primary cells is carried out, each bottle is inoculated with a T175 culture bottle according to 140 ten thousand cells, and each bottle is added with cell suspension and culture solution with the total volume of 18ml. The mixture is gently shaken evenly, and the distribution condition is observed under a mirror.
Example 2 phenotypic identification of mesenchymal Stem cells (flow type)
Taking the cell suspension to be detected to a 1.5ml EP tube, centrifuging at 1000rpm for 5min, cleaning twice, discarding the supernatant, adding 750 mu l of physiological saline, mixing gently, taking 7 EP tubes, adding 100 mu l of cell suspension, adding CD90, CD105, CD34, CD45, CD73 and HLA-DR respectively, blowing, mixing uniformly, and incubating at room temperature for at least 30min. Respectively adding 1mL of physiological saline, slightly blowing and washing cells, putting the cells into a centrifuge at 1000rpm for 5min, and removing supernatant; adding 400 mu L of physiological saline into each centrifuge tube respectively, blowing, beating and mixing uniformly, and sequentially loading on a machine for detection. The positive rate of CD34, CD45, HLA-DR, CD19 and CD14 is less than 2%, the positive rate of CD73, CD90 and CD105 is more than 95%, and the cell suspension is determined to be the umbilical cord mesenchymal stem cell.
Example 3 in vivo immune POF mouse experiment
The purpose is as follows: evaluating the effectiveness of the mesenchymal stem cell in combination with the hydrochloroquine treatment on the immune POF mice.
Grouping: blank control group, positive control group, umbilical cord mesenchymal stem cell treatment group, hydroxychloroquine treatment group and combination treatment group, 10 cases each. The blank control group was injected with physiological saline.
Preparing an umbilical cord mesenchymal stem cell injection: shaking the umbilical cord mesenchymal stem cells with the preset dose in a water bath kettle at 37 ℃ until most of the cells are dissolved, washing, diluting with 100-200ml of 0.9% sodium chloride injection and 1-10% human albumin, and preparing the umbilical cord mesenchymal stem cell injection.
The method comprises the following steps:
POF mouse model construction and identification:
10mg of mouse zona pellucida polypeptide 3 (ZP 3) is added into 10ml of triple distilled water, and the mixture is respectively mixed with complete Freund's adjuvant and incomplete Freund's adjuvant according to the proportion of 1. Female BALB/c mice of SPF grade 8 weeks old with normal estrus cycle are selected, and are immunized for the first time by subcutaneous multi-point injection with 0.15ml, and then are inoculated with 0.15ml of immunopotentiating agent 2 times after 2 weeks and 4 weeks. After the first immunization, the cytology examination of vaginal abscission is carried out at fixed points every day to judge whether the estrus cycle of the mice is disordered. The ELISA method compares the mouse serum E2, FSH levels and anti-zona pellucida antibody (AZPAb) levels at each vaccination time point (2 consecutive estrus cycle disturbances, significant decrease in serum E2 and FSH compared to before modeling, and an increase in AZPAb titer is successful in modeling).
2. Administration:
umbilical cord mesenchymal stem cell treatment group and combined treatment group are injected with equivalent umbilical cord mesenchymal stem cell injection (0.5 ml, 10 in total) in single tail vein 6 Cells), positive control group and hydroxychloroquine-treated group were injected with normal saline at a single tail vein, the hydrochloroquine-treated group and combination-treated group were perfused with hydroxychloroquine at 10mg/kg per day, and the mice were sacrificed 4 weeks later to evaluate 6 inter-group estrus cycles, ovarian histopathology.
3. Observation indexes are as follows: estrus cycle and ovarian histopathology.
The estrus cycle of the mice is shown in table 1, and the ovarian histopathology is shown in fig. 1.
TABLE 1
As can be seen from table 1, the estrus cycle of mice in three treatment groups, i.e., the stem cell treatment group, the hydroxychloroquine treatment group, and the combination treatment group, is increased in proportion to the normal proportion of the mice in the positive control group, and the highest ratio of the mice in the combination treatment group indicates that the mesenchymal stem cells can effectively prevent or treat premature ovarian failure caused by immune factors, and the effect of preventing and treating premature ovarian failure by combining the mesenchymal stem cells with hydroxychloroquine is optimal.
As shown in fig. 1, HE staining suggests that the combined treatment group had the best effect, that granulosa cells were repaired to a better extent than the other groups, and that the follicular tissue morphology tended to be normal, as shown in fig. 1-J to fig. 1-L; the recovery of the ovarian secondary follicles in the hydroxychloroquine treatment group is obvious, but the granulosa cell damage is not recovered, as shown in figures 1-G to 1-I; the number of follicles in the umbilical cord mesenchymal stem cell treatment group is increased compared with that in the positive control group (shown in figures 1-D to 1-F), but the granulosa cell damage is not recovered, as shown in figures 1-M to 1-O; normal ovarian histopathology is shown in figures 1-a to 1-C.
In conclusion, the mesenchymal stem cells and the combination hydroxychloroquine thereof have the treatment effectiveness in premature ovarian failure. Compared with the traditional therapy, the mesenchymal stem cell source is easy to obtain, the quantitative production is easy to realize, the ethical dispute is small, the immunogenicity is low, the preparation is an ideal cell therapy preparation, and the application of the preparation in combination with the small molecular drug hydroxychloroquine basically has no toxic or side effect compared with a traditional Chinese medicine preparation and an immunosuppressant.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (10)
1. The application of the mesenchymal stem cells or the cell extracts thereof in the preparation of the medicine for preventing or treating premature ovarian failure.
2. Use according to claim 1, wherein the mesenchymal stem cells are derived from a human or other mammal, preferably wherein the source of mesenchymal stem cells comprises one of umbilical cord Wharton's jelly, umbilical cord blood, bone marrow, gingiva, placenta, amnion, chorion, peripheral blood, fat and skin.
3. The use of claim 1, wherein the immunophenotype of the mesenchymal stem cell comprises simultaneous high expression of CD73, CD90, CD105, while not expressing CD45, CD34, CD11b, CD79 a/CD 19 and HLA-DR.
4. The use of claim 1, wherein the method of preparing the mesenchymal stem cells comprises the steps of: and performing primary culture and separation by using a tissue block adherence method to extract mesenchymal stem cells, and performing subculture by using a stem cell culture medium to obtain the mesenchymal stem cells.
5. The use of claim 4, wherein the mesenchymal stem cells are passaged in stem cell culture medium for 3-5 passages.
6. The use according to claim 1, wherein the cell extract comprises exosomes whose expression markers are TSG101, CD9, CD63 and CD81.
7. The use of claim 1, wherein the mesenchymal stem cell or the cell extract thereof is in a dosage form comprising a gel, an injection, a liposome, a lyophilized powder or an emulsion.
8. The use of claim 1, wherein the premature ovarian failure comprises premature ovarian failure due to an immune factor; the premature ovarian failure caused by immune factors comprises systemic lupus erythematosus, rheumatoid arthritis, vasculitis, ankylosing spondylitis, psoriasis, mixed connective tissue, scleroderma, behcet disease, inflammatory bowel disease, polymyositis or dermatomyositis and premature ovarian failure caused by related disease treatment drugs.
9. The use of claim 1, wherein said immunomodulator comprises hydroxychloroquine, chiral hydroxychloroquine and analogs thereof, azathioprine, tacrolimus, biologics, glucocorticoids and other reproductive and pregnancy safe immunomodulatory drugs and pharmaceutical compositions.
10. A pharmaceutical composition comprising mesenchymal stem cells or cell extracts thereof and an immunomodulator, wherein the immunomodulator comprises hydroxychloroquine, chiral hydroxychloroquine and analogues thereof, azathioprine, tacrolimus, biologicals, glucocorticoids and other reproductive and pregnancy safe immunomodulatory drugs and pharmaceutical compositions.
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