Effect of cell therapy on recovery of cognitive functions in rats during the delayed period after brain injury.

We studied the effect of systemic transplantation of human stem cells from various tissues on cognitive functions of the brain in rats during the delayed period after experimental brain injury. Stem cells were shown to increase the efficacy of medical treatment with metabolic and symptomatic drugs for recovery of cognitive functions. They accelerated the formation of the conditioned defense response. Fetal neural stem cells had a stronger effect on some parameters of cognitive function 2 months after brain injury. The efficacy of bone marrow mesenchymal stem cells from adult humans or fetuses was higher 3 months after brain injury.

Possibilities for the use of autologous mesenchymal stem cells in the therapy of radiation-induced lung injuries.

Possible therapeutic effect of systemic (intravenous) transplantation of autologous mesenchymal stem cells was studied in experiments (C57Bl/6 mice) and pilot clinical trial. Clinical trial was performed on 11 patients with radiation-induced lung injuries developed after combined chemotherapy and radiation therapy for lymphogranulomatosis or breast cancer. The patients were subjected to single transplantation of mesenchymal stem cells and course of standard pharmacotherapy. The method for isolation of autologous mesenchymal stem cells was licensed. The transplantation of mesenchymal stem cells was followed by a decrease in the mortality rate of mice with radiation-induced lung injury. Clinical trial showed that cell therapy with autologous mesenchymal stem cells does not induce progression of the underlying oncological disease. Parameters of spirography, immune status, lung scintigraphy, and markers for inflammation and tissue hypoxia in the patients remained practically unchanged 1 year after the treatment. These clinical signs reflect stabilization of the radiation process.

Morphofunctional study of the therapeutic efficacy of human mesenchymal and neural stem cells in rats with diffuse brain injury.

We studied the effect of transplantation of human stem cells from various tissues on reparative processes in the brain of rats with closed craniocerebral injury. Combined treatment with standard drugs and systemic administration of xenogeneic stem cells had a neuroprotective effect. The morphology of neurons rapidly returned to normal after administration of fetal neural stem cells. Fetal mesenchymal stem cells produced a prolonged effect on proliferative activity of progenitor cells in the subventricular zone of neurogenesis. Adult mesenchymal stem cells had a strong effect on recovery of the vascular bed in ischemic regions.

Possible involvement of NO in the stimulating effect of pifithrins on survival of hemopoietic clonogenic cells.

Pifithrin alpha (PFTalpha), one of the first known low molecular weight modulators of activity of tumor suppressor p53, increases survival of hemopoietic clonogenic cells (evaluated by the criterion of formation of endogenous spleen CFU-C8 colonies in irradiated animals). This effect appeared when PFTalpha was administered either before or after irradiation. Increase in CFU-C8 was also observed after administration of two PFTalpha analogs, derivatives of 2-amino-4,5,6,7-tetrahydrobenzothiazole. These included a parent compound, 2-ATBT (2-amino-4,5,6,7-tetrahydrobenzothiazole), which is used for synthesis of PFTalpha, and a product of its intramolecular cyclization under physiological conditions, cyclo-PFT (2-(4-methylphenyl)imidazo[2,1-b]-5,6,7,8-tetrahydrobenzothiazole). Earlier we found that many low molecular weight compounds increasing number of CFU-C8 (e.g. isothiourea derivatives) demonstrate NO inhibitory activity. Such activity was also found in 2-ATBT and cyclo-PFT by means of EPR spectroscopy of NO. These compounds caused more than twofold inhibition of NO production in vivo. Thus, it has been demonstrated that PFTalpha and its structural analogs increase survival of hemopoietic clonogenic cells in vivo, and NO may play a role in the mechanism of this effect.

Effects of gram-positive microorganisms and their products on in vivo survival of hemopoietic clonogenic cells.

The effects of gram-positive bacterial strains (Lactobacillus acidophilus and Lactobacillus rhamnosus) and their subcellular components on the survival of hemopoietic clonogenic cells were evaluated by the formation of endogenous splenic colonies. The effects of these preparations on NO production were studied by the spin-trap paramagnetic resonance spectroscopy. Bacterial preparations from gram-positive bacteria stimulated survival of hemopoietic clonogenic cells, but did not induce NO production in contrast to E. coli LPS.

Effects of (60)co whole-body gamma-irradiation in different doses on the distribution of (188)Re-labeled autologous mesenchymal stem cells in wistar rats after intravenous (systemic) transplantation during different periods after exposure.

The effects of whole-body gamma-irradiation in different doses on the distribution of (188)Re-labeled mesenchymal stem cells obtained by culturing of the rat bone marrow cells were studied in different organs and tissues of animals after intravenous (systemic) injection. Irradiation stimulated homing of (188)Re-labeled mesenchymal stem cells in organs and tissues of animals in comparison with this process in intact non-irradiated rats. The intensity of homing increased with increasing the irradiation dose and decreased with prolongation of the period between irradiation and systemic transplantation. It was hypothesized that increased migration of transplanted mesenchymal stem cells into irradiated organs and tissues can be caused by developing cell death processes. It seems that systemic transplantation of mesenchymal stem cells shortly after irradiation can be used for stimulation of reparative processes in damaged tissues.

Role of cyclooxygenases in the stimulatory effect of carcinogen 1,2-dimethylhydrazine on stem cell survival in the intestinal epithelium and bone marrow.

In vivo experimental studies showed that 1,2-dimethylhydrazine and product of its metabolism in the body azoximethane improve postradiation survival of two types of stem cells in the adult organism: hemopoietic stem cells and intestinal epithelial stem cells. This effect similar to the well-known radioprotective effect of E. coli lipopolysaccharide was observed, when the carcinogen was administered 1 day before gamma-irradiation. Treatment with 1,2-dimethylhydrazine prolonged the mean life-span of mice irradiated in supralethal doses inducing death of the majority of intestinal epithelial stem cells. Nonspecific cyclooxygenase inhibitor indometacin weakened this radioprotective effect of 1,2-dimethylhydrazine. We also found that carcinogen 1,2-dimethylhydrazine improved survival of hemopoietic stem cells. However, in contrast to intestinal epithelial stem cells, indometacin did not inhibit the radioprotective effect of the carcinogen. The radioprotective effect of 1,2-dimethylhydrazine and lipopolysaccharide on stem cells in the presence of indometacin was a sum of individual effects of these preparations and indometacin.

Morphofunctional study of the therapeutic effect of autologous mesenchymal stem cells in experimental diffuse brain injury in rats.

Effects of systemic transplantation of mesenchymal stem cells obtained by culturing of autologous bone marrow on proliferative activity of cells and functional morphology of neurons after diffuse brain injury were studied in Wistar rats. Comparative analysis of the results indicated that systemic injection of mesenchymal stem cells in a syngeneic organism produced proliferotropic, angiogenic, and, presumably, neurotrophic effects. The therapeutic effect visually manifested on day 2 after intravenous injection of mesenchymal stem cells during the early period of reparative regeneration of ischemic cell and tissue structures of the brain. The neuroprotective effect of mesenchymal stem cells was more pronounced against the background of basic therapy.