Hypoxic pretreatment of feline fat mesenchymal stem cell-derived exosomes for the treatment of feline kidney failure diseases
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ABSTRACT:
ORGANISM(S): Felis Catus
SUBMITTER: 
Shiqiang Zhang
PROVIDER: PXD061626 | iProX | Fri Mar 07 00:00:00 GMT 2025
REPOSITORIES: iProX
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Project description:Background: Neonatal hypoxic-ischemic (HI) brain injury, is one of the leading causes of mortality and long-term neurological morbidity in newborns. Current treatment options for HI brain injury are very limited, but mesenchymal stem cell (MSC) therapy is a promising strategy to boost neuroregeneration after injury. Optimization strategies to further enhance the potential of MSCs are in development. In the current study we aimed to test the potency of hypoxic preconditioning (HP) to enhance the therapeutic efficacy of MSCs in a mouse model for neonatal HI injury. Methods: HI was induced on postnatal day 9 in C57Bl/6 mouse pups. MSCs were cultured at 1% oxygen levels for 24 hours prior to use (HP-MSCs) or under normoxic (21% O2) control conditions (NP-MSCs). At 10 days after induction of HI brain injury, HP-MSCs or NP-MSCs were intranasally administered. Lesion size, sensorimotor outcome, MSC migration and neuroinflammation were assessed by HE staining, cylinder rearing task, gold nanoparticle-labeled MSC tracing and IBA1 staining, respectively. In vitro, the effect of hypoxic preconditioning on MSC migration, potency and proteome profile was studied using assays for transwell-migration, neural stem cell differentiation and neuroinflammation, and LC-MS/MS, respectively. Results: HP-MSCs were superior to NP-MSCs in reducing lesion size and improving sensorimotor outcome after HI. Moreover, hypoxic preconditioning enhanced MSC migration specifically to the HI lesion after intranasal application and in vitro. Additionally, HP-MSCs enhanced neural stem cell (NSC) differentiation into more complex neurons in vitro but did not enhance anti-inflammatory effects compared to NP-MSCs. Lastly, hypoxic preconditioning enriched the expression of pathways mainly related to glucose metabolism and extracellular matrix remodeling in MSCs. Conclusions: Overall, this study showed for the first time that intranasal HP-MSC therapy is a promising optimization strategy to superiorly reduce lesion size and improve neurodevelopmental outcome in a mouse model of neonatal HI brain injury.
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Project description:Hypoxic-ischemic (HI) injury in the developing brain is a common cause of disability in children, and there are no effective treatments at this time. Erythropoietin (EPO) has recently gained interest as a neuroprotective drug, and EPO and its receptor are expressed within the central nervous system. We have recently shown that pretreatment with EPO markedly reduced brain injury caused by unilateral hypoxic-ischemic insult in 7 day old mice. EPO did not reduce early signs of neuronal injury at 6 hours, but significantly protected the neonatal brain when assessed 24 hours and 7 days after HI. The mechanism of this delayed protection is unclear, but is thought to involve transcription of neuroprotective genes, possibly subsequent to activation of NFkB. By comparing gene expression in EPO- and vehicle- (VEH) treated mice after HI, we should gain insight into the mechanisms underlying the neuroprotective effects of EPO and may identify additional targets for therapeutic interventions. We will compare gene expression patterns in 7-day old mouse forebrain after 1) VEH pretreatment plus sham surgery, 2) VEH pretreatment plus HI, and 3) EPO pretreatment plus HI. We will thus identify genes induced by HI in the developing brain and characterize changes in gene expression caused by EPO pretreatment. We will use the model of neonatal hypoxic-ischemic injury and EPO treatment parameters that were used in our prior studies demonstrating neuroprotection. Based on the time-course of neuroprotection defined in our prior study and the pharmacokinetic profile of EPO, we will examine gene expression 18 hours after HI. We hypothesize that changes in gene expression after EPO pretreatment underlie the neuroprotective effects of this cytokine after neonatal hypoxic ischemic injury. We will examine gene expression in 3 groups: 1) 1) VEH pretreatment + sham surgery, 2) VEH pretreatment + HI, and 3) EPO pretreatment + HI. EPO (5U/g, i.p.) or VEH was injected in 7 day old mice, drawn from 4 litters, with 3 to 4 pups per treatment group in each litter. One hour later, the right common carotid artery was ligated under isoflurane anesthesia, animals were allowed to recover for 90 min and were then placed in hypoxic chambers (10% oxygen, balance nitrogen) for 50 min. The animals subjected to sham surgery received isoflurane anesthesia for a comparable period, incision and dissection to visualize the common carotid artery, but no ligation and no hypoxia. Eighteen hrs later, animals were anesthetized with isoflurane and the right hemisphere was rapidly dissected and placed in RNA Later (Qiagen) at 4C. Total RNA was isolated using an RNeasy lipid tissue mini kit (QIAzol lysis and RNeasy purification, Qiagen). RNA concentrations were determined spectrophotometrically and an aliquot of each sample was examined by gel electrophoresis to screen for degradation. Samples were stored at -80C. After quality control screening, we selected 5 male and 5 female samples per treatment group (extra samples were reserved). We plan to pool 1 male and 1 female for each microarray sample and we plan to run 5 microarrays from each treatment group, for a total of 15 microarrays. We would like to have Agilent Bioanalyzer quality control assays on the individual samples carried out by the consortium before pooling. We will send 10 micrograms of each sample for Agilent QC and subsequent pooling of equimolar amounts. We would like to use Affymetrix mouse gene chips (please advise which specific chips are available; are you using the GeneChip Mouse Expression array 430A or the GeneChip Mouse Genome 430 2.0 Array?).
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Project description:GLB1, a class 1 haemoglobin gene from Arabidopsis thaliana (GLB1) is essential for plant survival following hypoxic stress. Keywords = haemoglobin, hypoxic stress, stress
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Project description:Tibetan chickens, a unique plateau breed, have good performances to adapt to high-altitude hypoxic environments. A number of positively selected genes have been reported in Tibetan chickens; however, the mechanisms of gene expression for hypoxia adaptation are not fully understood. In the present study, eggs from Tibetan (TC) and Chahua (CH) chickens were incubated under hypoxic and normoxic conditions, and vascularization in the chorioallantoic membrane (CAM) of embryos was observed. We found that the vessel density index (VDI) in CAM of TCs was lower than in CHs under hypoxia incubation.Proteomic analyses of CAM tissues were performed in TC and CH embryos under hypoxic incubation using iTRAQ. We obtained 387 differentially expressed proteins (DEPs) that were mainly enriched in angiogenesis, vasculature development, blood vessel morphogenesis, blood circulation, renin-angiotensin system, and HIF-1 and VEGF signaling pathways. Twenty-six genes involved in angiogenesis and blood circulation, two genes involved in ion transport, and six genes that regulated energy metabolism were identified as candidate functional genes in regulating hypoxic adaption of chicken embryos. Therefore, this research provided insights into the molecular mechanism of hypoxia adaptation in Tibetan chickens.
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