Method for activating myeloid tissue regeneration in old laboratory animals

FIELD: medicine.

SUBSTANCE: method involves intravenous allogeneic transplantation of multipotent mesenchymal stromal cells recovered from the placenta in an amount of 6 mln cells/kg. Additionally, haemopoietic stem cells recovered from umbilical blood in an amount of 300 thousand cells/kg are introduced.

EFFECT: method enables reducing the number of cytogenetically changed cells, promotes activating myeloid tissue regeneration in old laboratory animals.

4 tbl, 1 ex

 

The invention relates to the field of cell biology and may find application in medicine for recovery of hemopoiesis in elderly and senile age.

Now in modern Biomedicine is a new section - cell therapy, which allows for the transplantation of cells to compensate for the lack of functional activity of the tissues and regenerate damaged organs. The update function and tissue repair in vivo perform stem cells, which represent a pool of spare undifferentiated precursor cells of different types. In this regard, the use of stem cells is the most promising area of cellular therapy (Grossman So Latest advances in antiaging medicine. Keio J Med. 2005; 54(2):85-94).

During the process of aging stem cells undergo both quantitative and qualitative changes that affect both the rate of aging and the life of the organism. With age, due to inhibition of the production of growth factors, developing common G1/S block of the cell cycle that leads to progressive loss of stem cells and reduces the regeneration of different tissues and organs. Studies in humans and various animals have shown that hematopoietic stem cells (HSC) age, showing substantially the decrease in functional ability with increasing age. Maintaining normal function of the HSC is critical for coagulation of blood, oxygen transport, and to enhance specific and nonspecific resistance of the organism.

Overcoming generalized G1/S block of the cell cycle to activate the regeneration of myeloid tissue during aging is achieved by using hormone replacement therapy: stimulation axis STH-insulin-like growth factors (IPPR). Increased levels IPR leads to the overcoming of the unit processes of differentiation and proliferation of cells and subsequent self-renewing tissues (A.A. Kiskun County. "Biological age and aging: opportunities definition and path correction: a Guide for physicians. - M.: GEOTAR-Media, 2008, - 976).

At the same time, studies on the restoration of tissue regeneration in the age aspect with the use of growth factors often contradict each other. It was found that elderly people with high levels of the hormone IPFR-1 living longer and the level of tissue regeneration is higher than in older people with low levels of IGF-1 (Brugts et al. Low Circulating IGF-I Bioactivity in Elderly Men is Associated with Increased Mortality. Journal of Clinical Endocrinology & Metabolism, 2008; DOI: 10.1210/jc.2007-1633).

However, studies on laboratory mice found that hypophysectomy (Bartke, A., Brown-Borg, H., J. Mattison et al. Prolonged longevity of hypopitui-tary mice// Exp. Gerontol. 2001. Vol.36. P.21-28.),a genetic modification (Coschigano et al., Endocrinology. 2000, 141(7):2608-2613), aimed at reducing the sensitivity of the receptor to somatotropic hormone (STH) lead to an increase in life span of mice. Today proved the possibility of insulin and IPFR-1 significantly reduce the resistance of cells to stress through the inhibition of operation of the transcription factors FOXO and SKN-1 due to the reduction of education agents peripheral stress-limiting systems (Direct Inhibition of the Longevity-Promoting Factor SKN-1 by Insulin-like Signaling in C. elegans Tullet JMA, Hertweck MT, Ai. JH, Baker J, Hwang JY, Liu S, Oliveira RP, Baumeister R, and Blackwell TK Cell, Vol 132, 1025-1038, 21 March 2008).

The next direction in the activation of the regeneration of myeloid tissue during aging is correction of antioxidant status with antioxidants (vitamin E, vitamin C). However, all antioxidants have a very limited "capacity" to absorb the active forms of oxygen and inactivation of free radical oxidation products (A.A. Kiskun County. "Biological age and aging: opportunities definition and path correction: a Guide for physicians. - M.: GEOTAR-Media, 2008, - 976).

The closest technical solution to the claimed method is the recovery of myeloid tissue of old laboratory animals (laboratory rats aged 3 years, weight 300 g) under physiological conditions (no ionizing radiation), by GNC is reveneu allogenic multipotent mesenchymal stromal cells (MMSC), isolated from the placenta, in the amount of 2 million cells per 1 animal (or 6·106cells/kg) (Impact multipotent mesenchymal stromal cells isolated from placenta, regeneration myeloid tissues of old animals exposed to ionizing radiation / A.P. Hawks, YOU Maklakov, DUE Grebnev, S.E. Emelyanova // the annals of the Russian Academy of medical Sciences. - 2008. No. 4. - P.93-97.) the prototype.

This method provides the activation of the regenerative potential of tissues, inhibited during aging. However, the use of transplantation MSC has insufficient effect on the activation of the regeneration of myeloid tissue in aged laboratory animals.

The objective of the invention is the expansion of the means that may lead to activation of the regeneration of myeloid tissue during aging.

The technical result that will be obtained from the use of the invention is to reduce the number cytogeneticist modified cells.

The technical result is achieved by the fact that the activation method of regeneration myeloid tissue of old laboratory animals by intravenous allogeneic transplantation multipotent mesenchymal stromal cells (MMSC), isolated from the placenta in the amount of 6 million cells/kg, impose additional hematopoietic stem glue the key (GSK), isolated from umbilical cord blood in the amount of 300 thousand cells/kg

The invention consists in the combined transplantation laboratory animals MMSC and GSK.

Property MMSC to develop a chemoattractant for HSC (SDF-1) will provide an increase in the pool of HSCs in the bone marrow at the expense of the transplanted (allogeneic) GSK, which in turn will contribute to the recovery of haematopoiesis (Log Cell Transplantology and tissue engineering. Volume II, No. 3, 2007. Page 21-22. "Regulation of homing of progenitor cells to the area of myocardial infarction method prolonged secretion of factor SDF-1").

The dose of transplanted HSC (300 thousand cells/kg) were selected experimentally.

Pluripotency MMSC specific migration into the site of injury and adhesive properties - all this provides a restorative function MMSC. MSC able to migrate to the injury site, to fix, to differentiate and to form a microenvironment for HSCs. MMSC promote directional migration of HSC: generating SDF-1 (determines the migration of HSC via receptor CXCR4 on the surface of the SIC). MMSC promote the growth of hematopoietic precursors by secreting a number of cytokines, such as IL-6, IL-8, IL-11, IL-12, IL-14, IL-15, macrophage colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, f is a torus growth of stem cells. Constant product secretion MMSC is prostaglandin E2 (immunosuppressive agent)is able to reduce the expression of receptors for interleukin-2 on the surface of peripheral lymphocytes, which prevents their activation.

From the analysis of scientific-technical and patent literature combined intravenous transplantation MSC and GSK, leading to reduction in the number cytogeneticist modified cells, providing cytoprotective effect on myeloid tissue, and consequently, to increase the activation of the regeneration of the myeloid tissue of old laboratory animals, we have not identified that allows to make a conclusion on the conformity of the proposed technical solution the criteria of "novelty" and "inventive step".

The invention is carried out as follows.

The experiments were performed on 36 white laboratory mice-males age 3 years, weight 50, the Experiments on the culture MMSC and GSK performed on 18 laboratory animals mice-female-age 3-4 months, weighing 30 g, gestation 18 days. The animals were kept in standard laboratory animal facility under the Rules of work with the use of experimental animals"approved by Order of the USSR Ministry of health No. 755 from 12.08.1977, and the Order of the USSR Ministry of health No. 1179 from 10.10.1983 "On approval of regulations of the cost of feed for laboratory animal who in health care". Manipulation of experimental animals were performed in accordance with the provisions of the Helsinki Declaration about the humane treatment of animals, methodological recommendations for their elimination from the experience and euthanasia.

The number of experimental animals and their distribution on the series of experiments presented in table 1.

Animals of the experimental group intravenously once introduced suspension MMSC and GSK respectively at a dose of 6 million cells/kg and 300 thousand cells/kg, the animals of the control group intravenously once were injected with 0.9% NaCl solution and 0.2 ml intravenously (see Table 1). In addition, the animals of the prototype was introduced MMSC in the amount of 6 million cells/kg (see Table 2). The slaughter of animals was carried out at 1 and 7 days after transplantation of the cells.

Table 1
The distribution of animals on the series of experiments
AnimalsRoute of administrationMedicationThe autopsy of the bodies
24 hoursday 7
Oldin/atMM IS about 6 million cells/kg and HSC 300 thousand CL/kg in 0.2 ml of saline9 PCs9 PCs
in/at0,9% aq NaCl 0.2 ml9 PCs9 PCs

Table 2
The distribution of animals on the series of experiments
AnimalsRoute of administrationMedicationThe autopsy of the bodies
24 hoursday 7
Oldin/atMMSC 6 million cells/kg in 0.5 ml saline9 PCs9 PCs
in/at0,9% aq NaCl 0.5 ml9 PCs9 PCs

Cooking, painting, microscopy and counting of microkernels in polychromatophilic normoblast bone marrow of rats was carried out as follows.

On fat-free optical glass inflicted serum AB0(IV) blood group man. Next, a glass rod, circular motion was preparing a suspension of bone marrow cells (it must be of a certain density to have a whitish opalescense color). Then a drop of this suspension was applied to the edge of the skim slides. The distribution of the material on the glass was carried out by moving behind polished glass at a 45°angle. The optimal length of the stroke - 2-3 see

The smear was dried on air for days.

Staining of smears on Pappenheim made on the next day, followed by fixation in methanol for 1 minute. (Dye - May-Grunwald (alcohol solution) was mixed with phosphate buffer 1:1. Painting the time is 1.5 minutes)

Then pour out the paint and without washing pour the dye solution Romanovsky-Gimza. Painting the time is 10 minutes.

The solution Romanovsky-Gimza was prepared in tap water 1:6 (10 ml Romanovsky + 60 ml water). A paint was prepared immediately before staining.

Then washed in histologicaly glasses under running water (stream, not on the glass).

Cytological preparations of bone marrow were analyzed using microscope Micros MS-50(Austria) at magnification 100*15.

Micronuclear test (MINTS) was calculated as the ratio of the number polychromatophilic erythrocytes with micronuclei in 1000 estimated polychromatophilic erythrocytes, Frank is in ppm (guidelines for the assessment of the mutagenic activity of chemical substances microkernel test prepared all-Union scientific research Institute of disinfection and sterilization of the Ministry of health of the USSR, Moscow 1984).

MIT=Handwith alaboutpaboutlandxpaboutmandtaboutfandlbnsxepandtpaboutCandtaboutinwith amandKpaboutIdpandmand1000paboutlandxpaboutmandtaboutfandlbnsxepandtpaboutCandtaboutin*1000%

Culture MMSC

Produced highlighting the placenta (gestation 18 days), a tissue sample weight of 1 g three times washed with physiological saline, phosphate buffered (PBS) at pH 7.2, without ions of Ca2+and Mg2+supplemented with antibiotics (penicillin 50 units/ml, streptomycin 50 μg/ml), then followed by mechanical grinding tissue and enzymatic treatment (0.25% trypsin - EDTA for 15 min at 37°C). The floor is built, the cell suspension was filtered twice through a 100 μm nylon membrane to remove large non-cut pieces of fabric. The suspension was diluted with medium α-MEM containing antibiotics, the cells are then besieged by centrifugation for 15 minutes at 1000 g.

The obtained cell sediment suspended in the medium α-MEM (ICN, USA) with 10% serum of cow embryos (Hyclone, New Zealand), a single solution of essential amino acids (Sigma, USA) and a single antibiotic solution (Chemicon). Suspension cells were sown at a concentration of 150000-160000 CL/cm2on Petri dishes 60 mm (Nunc, Denmark).

1.1. The cultivation conditions MMSC

The cultivation was performed at 37°C in humidified atmosphere with 5% CO2.

1.2. Counting cells

Counting cells produced in hemocytometer. Calculate the number of cells in 1 ml of the suspension was made according to the formula: X=a*10000, where X is the number of cells in 1 ml of suspension; and - the amount of cells in small squares.

1.3. Subcultivation MMSC

Subcultivation cells was carried out based on the achievement of 80% of the monolayer. Cells were washed with a mixture of 0.25% trypsin - EDTA at a ratio of 1:1, in which the cells are incubated for about 5 min at 37°C. Trypsin iactiveaware the addition of growth medium with CEQ (10%), and the suspension was centrifuged at 200 g for 5 minutes, Removing the supernatant, the cells are suspended, made calculations and were sown in the desired concentration (10000 cells/ cm2).

1.4. The characteristics of the culture was performed using a set of primary Mesenchymal Stem Cel Characterization Kit) and secondary antibody (secondary antibody Cy3 conjugated).

Selection GSK

To highlight GSK has used a set of Mouse Hematopoietic Progenitor (Stem) Cell Enrichment Set-DM. (StemCell Technologies, Canada).

Methods of statistical processing of the obtained results

Each row of the metric value was calculated arithmetic mean, standard error of the mean. The reliability of differences between subgroups were assessed using t - student criterion. Differences were considered significant at p<0,05.

Analyzing the data micronuclear test old laboratory animals, the mutagenic action MMSC not identified, as the number of cores corresponds to the spontaneous level of mutagenesis (table 3).

Table 3
Content cytogeneticist modified bone marrow cells in aged laboratory animals at 1 day after injection, M±m (n=9)
OptionsValue
The inventive methodThe placeholder
Micronuclear test, %3,37±0,308,83±1,83

As can be seen from the table, by the present method microkernel test 2.3-2.9 times lower compared to the prototype.

Nigerianization modified bone marrow cells in aged laboratory animals by day 7, the present method and the method according to the prototype shown in table 4.

Table 4
Content cytogeneticist modified bone marrow cells in aged laboratory animals on day 7 after injection, M±m (n=9)
OptionsValue
OldThe placeholder
Micronuclear test, %1,50±0,30the ceiling of 5.60±1,27

As can be seen from the table, on day 7, the present method microkernel test 3.6-3.8 times lower in comparison with the prototype, which leads to a decrease in the spontaneous level of mutagenesis in aged laboratory animals. Thus, the data obtained indicate that under physiological conditions in aged laboratory animals combined transplantation MSC and GSK for 7 days reduces the content cytogeneticist modified cells. Comparing the data on activation of regeneration in aged laboratory animals after transplantation MSC and combined transplantation MSC and GSK, it should be noted a considerably higher efficiency of the combined transplantation. So, after combined transplantation MSC and GSK on day 7 in physiologically what these conditions are established, the content cytogeneticist modified cells was decreased after the introduction of MSC and co-transplantation, respectively, by 41.0% and 57.1%.

Conclusions

The old laboratory animals under physiological conditions MMSC and GSK has a cytoprotective effect on myeloid tissue by reducing cytogeneticist modified cells.

The activation method of regeneration myeloid tissue of old laboratory animals, including intravenous allogeneic transplantation multipotent mesenchymal stromal cells isolated from the placenta in the amount of 6 million cells/kg, characterized in that it further injected hematopoietic stem cells isolated from umbilical cord blood in the amount of 300 thousand cells/kg



 

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1 dwg, 6 tbl, 1 ex

FIELD: biotechnology.

SUBSTANCE: composition is proposed which comprises stem cells of human amniotic fluid with the phenotype CD73+/CD90+/CD105+/CK19+, nutrient medium, erythropoietin, epidermal growth factor, and collagen taken in an effective amount.

EFFECT: invention enables to increase the proliferative potential and viability of the cells, while simultaneously providing cytoprotective effect on the cells of the transplant and stimulation of migration and proliferation of patient's own cells, and also to reduce significantly the concentration of injectable cells and to activate vascularisation and regeneration at the defect site and can be used in therapy for elimination of congenital and acquired defects of soft tissue arising as the result of injuries, after removal of tumors, congenital diseases, age-related changes or other damages.

2 tbl, 4 ex

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