Placenta-Expanded Stromal Cell Therapy in a Rodent Model of Simulated Weightlessness.
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ABSTRACT:
SUBMITTER: Rubinstein L
PROVIDER: S-EPMC8073415 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Recently, disorders of intestinal homeostasis in the space environment have been extensively demonstrated. Accumulating evidence have suggested microgravity and simulated weightlessness could induce dysbiosis of intestinal microbiota, which may contribute to the bowel symptoms during spaceflight. However, the specific responses of intestinal metabolome under simulated weightlessness and its relationship with the intestinal microbiome and immune characteristics remain largely unknown. In the current study, 20 adult Sprague-Dawley (SD) rats were randomly divided into the control group and the simulated weightlessness group using a hindlimb unloading model. The metabolomic profiling of cecal contents from eight rats of each group was investigated by gas chromatography-time of flight/mass spectrometry. The significantly different metabolites, biomarkers, and related pathways were identified. Multivariate analysis, such as principal component analysis and orthogonal projections to latent structures-discriminant analysis, demonstrated an obvious separation between the control group and the simulated weightlessness group. Significantly different metabolites, such as xylose, sinapinic acid, indolelactate, and digalacturonic acid, were identified, which participate in mainly pyrimidine metabolism, pentose and glucuronate interconversions, and valine, leucine and isoleucine metabolism. Cytidine-5'-monophosphate, 4-hydroxypyridine, and phloretic acid were determined as pivotal biomarkers under simulated weightlessness. Moreover, the significantly different metabolites were remarkably correlated with dysbiosis of the intestinal microbiota and disturbance of immunological characteristics induced by simulated weightlessness. These metabolic features provide crucial candidates for therapeutic targets for metabolic disorders under weightlessness.
| S-EPMC6803529 | biostudies-literature
Project description:The hindlimb unloading (HU) model has been used extensively to simulate the cephalad fluid shift and musculoskeletal disuse observed in spaceflight with its application expanding to study immune, cardiovascular and central nervous system responses, among others. Most HU studies are performed with singly housed animals, although social isolation also can substantially impact behavior and physiology, and therefore may confound HU experimental results. Other HU variants that allow for paired housing have been developed although no systematic assessment has been made to understand the effects of social isolation on HU outcomes. Hence, we aimed to determine the contribution of social isolation to tissue responses to HU. To accomplish this, we developed a refinement to the traditional NASA Ames single housing HU system to accommodate social housing in pairs, retaining desirable features of the original design. We conducted a 30-day HU experiment with adult, female mice that were either singly or socially housed. HU animals in both single and social housing displayed expected musculoskeletal deficits versus housing matched, normally loaded (NL) controls. However, select immune and hypothalamic-pituitary-adrenal (HPA) axis responses were differentially impacted by the HU social environment relative to matched NL controls. HU led to a reduction in % CD4+ T cells in singly housed, but not in socially housed mice. Unexpectedly, HU increased adrenal gland mass in socially housed but not singly housed mice, while social isolation increased adrenal gland mass in NL controls. HU also led to elevated plasma corticosterone levels at day 30 in both singly and socially housed mice. Thus, musculoskeletal responses to simulated weightlessness are similar regardless of social environment with a few differences in adrenal and immune responses. Our findings show that combined stressors can mask, not only exacerbate, select responses to HU. These findings further expand the utility of the HU model for studying possible combined effects of spaceflight stressors.
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Project description:Exposure to microgravity or weightlessness leads to various adaptive and pathophysiological alterations in digestive structures and physiology. The current study was carried out to investigate responses of intestinal mucosal barrier functions to simulated weightlessness, by using the hindlimb unloading rats model. Compared with normal controls, simulated weightlessness damaged the intestinal villi and structural integrity of tight junctions, up-regulated the expression of pro-apoptotic protein Bax while down-regulated the expression of anti-apoptotic protein Bcl-2, thus improved the intestinal permeability. It could also influence intestinal microbiota composition with the expansion of Bacteroidetes and decrease of Firmicutes. The predicted metagenomic analysis emphasized significant dysbiosis associated differences in genes involved in membrane transport, cofactors and vitamins metabolism, energy metabolism, and genetic information processing. Moreover, simulated weightlessness could modify the intestinal immune status characterized by the increase of proinflammatory cytokines, decrease of secretory immunoglobulin A, and activation of TLR4/MyD88/NF-κB signaling pathway in ileum. These results indicate the simulated weightlessness disrupts intestinal mucosal barrier functions in animal model. The data also emphasize the necessity of monitoring and regulating astronauts' intestinal health during real space flights to prevent breakdowns in intestinal homeostasis of crewmembers.
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Project description:The ephemeral placenta provides a noncontroversial source of young, healthy cells of both maternal and fetal origin from which cell therapy products can be manufactured. The 2 advantages of using live cells as therapeutic entities are: (a) in their environmental-responsive, multifactorial secretion profile and (b) in their activity as a "slow-release drug delivery system," releasing secretions over a long time frame. A major difficulty in translating cell therapy to the clinic involves challenges of large-scale, robust manufacturing while maintaining product characteristics, identity, and efficacy. To address these concerns early on, Pluristem developed the PLacental eXpanded (PLX) platform, the first good manufacturing practice-approved, 3-dimensional bioreactor-based cell growth platform, to enable culture of mesenchymal-like adherent stromal cells harvested from the postpartum placenta. One of the products produced by Pluristem on this platform is PLX-R18, a product mainly comprising placental fetal cells, which is proven in vivo to alleviate radiation-induced lethality and to enhance hematopoietic cell counts after bone marrow (BM) failure. The identified mechanism of action of PLX-R18 cells is one of the cell-derived systemic pro-hematopoietic secretions, which upregulate endogenous secretions and subsequently rescue BM and peripheral blood cellularity, thereby boosting survival. PLX-R18 is therefore currently under study to treat both the hematopoietic syndrome of acute radiation (under the US Food and Drug Administration [FDA]'s Animal Rule) and the incomplete engraftment after BM transplantation (in a phase I study). In the future, they could potentially address additional hematological indications, such as aplastic anemia, myelodysplastic syndrome, primary graft failure, and acute or chronic graft versus host disease.
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Project description:BackgroundThe most applicable human models of weightlessness are -6° head-down bed rest (HDBR) and head-out dry immersion (DI). A detailed experimental comparison of cardiovascular responses in both models has not yet been carried out, in spite of numerous studies having been performed in each of the models separately.ObjectivesWe compared changes in central hemodynamics, autonomic regulation, plasma volume, and water balance induced by -6° HDBR and DI.MethodsEleven subjects participated in a 21-day HDBR and 12 subjects in a 3-day DI. During exposure, measurements of the water balance, blood pressure, and heart rate were performed daily. Plasma volume evolution was assessed by the Dill-Costill method. In order to assess orthostatic tolerance time (OTT), central hemodynamic responses to orthostatic stimuli, and autonomous regulation, the 80° lower body negative pressure-tilt test was conducted before and right after both exposures.ResultsFor most of the studied parameters, the changes were co-directional, although they differed in their extent. The changes in systolic blood pressure and total peripheral resistance after HDBR were more pronounced than those after DI. The OTT was decreased in both groups: to 14.2 ± 3.1 min (vs. 27.9 ± 2.5 min before exposure) in the group of 21-day HDBR and to 8.7 ± 2.1 min (vs. 27.7 ± 1.2 min before exposure) in the group of 3-day DI.ConclusionsIn general, cardiovascular changes during the 21-day HDBR and 3-day DI were co-directional. In some cases, changes in the parameters after 3-day DI exceeded changes after the 21-day HDBR, while in other cases the opposite was true. Significantly stronger effects of DI on cardiovascular function may be due to hypovolemia and support unloading (supportlessness).
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Project description:Endometrial dysfunction affects approximately 1% of infertile women, and there is currently no standard therapy for improving fertility treatment outcomes in these patients. In our study, we utilized a rodent model of thin endometrium to test whether intrauterine application of adipose-derived stromal vascular fraction cells (SVF) could improve morphological and physiological markers of endometrial receptivity. Using anhydrous ethanol, endometrial area and gland density were significantly reduced in our model of thin endometrium. Application of SVF was associated with a 29% reduction in endometrial vascular endothelial growth factor (VEGF) expression and significant increases in uterine artery systolic/diastolic velocity ratios and resistance index values, suggesting reduced diastolic microvascular tone. However, no significant improvements in endometrial area or gland density were observed following SVF treatment. 3D confocal imaging demonstrated poor engraftment of SVF cells into recipient tissue, which likely contributed to the negative results of this study. We suspect modified treatment protocols utilizing adjuvant estrogen and/or tail vein cell delivery may improve SVF retention and therapeutic response in subsequent studies. SVF is an easily-obtainable cell product with regenerative capability that may have a future role in the treatment of infertile women with endometrial dysfunction.
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Project description:Background: Our studies demonstrated that the space environment has an impact on the brain function of astronauts. Numerous ground-based microgravity and social isolation showed that the space environment can induce brain function damages in humans and animals. Dammarane sapogenins (DS), an active fraction from oriental ginseng, possesses neuropsychic protective effects and has been shown to improve depression and memory. This study aimed to explore the effects and mechanisms of DS in attenuating depressive-like behaviors and cognitive deficiency induced by simulated weightlessness and isolation [hindlimb suspension and isolation (HLSI)] in rats. Methods: Male rats were orally administered with two different doses of DS (37.5, 75 mg/kg) for 14 days, and huperzine-A (1 mg/kg) served as positive control. Rats were subjected to HLSI for 14 days except the control group during drug administration. The depressive-like behaviors were then evaluated by the open-field test, the novel object recognition test, and the forced swimming test. The spatial memory and working memory were evaluated by the Morris water maze (MWM) test, and the related mechanism was further explored by analyzing the activity of choline acetyltransferase (ChAT), acetylcholinesterase (AChE), and superoxide dismutase (SOD) in the hippocampus of rats. Results: The results showed that DS treatment significantly reversed the HLSI-induced depressive-like behaviors in the open-field test, the novel object recognition test, and the forced swimming test and improved the HLSI-induced cognitive impairment in the MWM test. Furthermore, after DS treatment, the ChAT and SOD activities of HLSI rats were increased while AChE activity was significantly suppressed. Conclusions: These findings clearly demonstrated that DS might exert a significant neuropsychic protective effect induced by spaceflight environment, driven in part by the modulation of cholinergic system and anti-oxidation in the hippocampus.
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Project description:Osteoarthritis (OA) is a degenerative multifactorial disease with concomitant structural, inflammatory, and metabolic changes that fluctuate in a temporal and patient-specific manner. This complexity has contributed to refractory responses to various treatments. MSCs have shown promise as multimodal therapeutics in mitigating OA symptoms and disease progression. Here, we evaluated 15 randomized controlled clinical trials (RCTs) and 11 nonrandomized RCTs using culture-expanded MSCs in the treatment of knee OA, and we found net positive effects of MSCs on mitigating pain and symptoms (improving function in 12/15 RCTs relative to baseline and in 11/15 RCTs relative to control groups at study endpoints) and on cartilage protection and/or repair (18/21 clinical studies). We examined MSC dose, tissue of origin, and autologous vs. allogeneic origins as well as patient clinical phenotype, endotype, age, sex and level of OA severity as key parameters in parsing MSC clinical effectiveness. The relatively small sample size of 610 patients limited the drawing of definitive conclusions. Nonetheless, we noted trends toward moderate to higher doses of MSCs in select OA patient clinical phenotypes mitigating pain and leading to structural improvements or cartilage preservation. Evidence from preclinical studies is supportive of MSC anti-inflammatory and immunomodulatory effects, but additional investigations on immunomodulatory, chondroprotective and other clinical mechanisms of action are needed. We hypothesize that MSC basal immunomodulatory "fitness" correlates with OA treatment efficacy, but this hypothesis needs to be validated in future studies. We conclude with a roadmap articulating the need to match an OA patient subset defined by molecular endotype and clinical phenotype with basally immunomodulatory "fit" or engineered-to-be-fit-for-OA MSCs in well-designed, data-intensive clinical trials to advance the field.
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Project description:Trim5alpha from primates (including humans), cows, and rabbits has been shown to be an active antiviral host gene that acts against a range of retroviruses. Although this suggests that Trim5alpha may be a common antiviral restriction factor among mammals, the status of Trim5 genes in rodents has been unclear. Using genomic and phylogenetic analyses, we describe an expanded paralogous cluster of at least eight Trim5-like genes in mice (including the previously described Trim12 and Trim30 genes), and three Trim5-like genes in rats. Our characterization of the rodent Trim5 locus, and comparison to the Trim5 locus in humans, cows, and rabbits, indicates that Trim5 has undergone independent evolutionary expansions within species. Evolutionary analysis shows that rodent Trim5 genes have evolved under positive selection, suggesting evolutionary conflicts consistent with important antiviral function. Sampling six rodent Trim5 genes failed to reveal antiviral activities against a set of eight retroviral challenges, although we predict that such activities exist.
| S-EPMC2692226 | biostudies-literature
Project description:The microgravity environment in space can impact astronauts' cognitive and behavioral activities. However, due to the limitations of research conditions, studies of biological changes in the primate brain, such as neurogenesis, have been comparatively few. We take advantage of - 6° head-down bed rest (HDBR), one of the most implemented space analogue on the ground, to investigate the effects of weightlessness on neurogenesis of non-human primate brain. Rhesus Macaque monkeys were subjected to HDBR for 42 days to simulate weightlessness. BrdU (5-bromodeoxyuridin) and IdU (iododeoxyuridine) were intraperitoneally injected separately before or after HDBR to label the survival and proliferation of newborn neurons. Immunohistochemistry was performed to study the effect of simulated weightlessness on neurogenesis. BrdU staining showed that survival of newborn neurons was reduced, while there were fewer BrdU-positive neurons in the HDBR group compared with the control. Furthermore, IdU-positive neurons also decreased in the HDBR group suggesting a reduced proliferation capacity for these newborn neurons. Our results demonstrate the definite neurogenesis in the adult rhesus macaque hippocampus, and simulated weightlessness HDBR procedure impairs the adult neurogenesis.
| S-EPMC6509794 | biostudies-literature