Human Umbilical Cord Mesenchymal Stem Cells and exosomes Alleviate Perioperative Neurocognitive Dysfunction in Mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus Musculus
SUBMITTER: 
Kai Wang
PROVIDER: PXD066744 | iProX | Mon Oct 20 00:00:00 BST 2025
REPOSITORIES: iProX
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Project description:Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) are recognized as a promising strategy for cell-free therapy, however, their therapeutic role in pulmonary fibrosis remains unrevealed. Here, we report the safety and efficacy of MSC-EVs from human umbilical cord (hUCMSC-EVs) evaluated in mouse models and pulmonary fibrosis patients. We established a rigorous system to produce high-quality of hUCMSC-EVs, characterized by miRNA, protein, and metabolite profiles. When administered via nebulization, hUCMSC-EVs predominantly accumulated in murine lungs and ameliorated bleomycin-induced pulmonary fibrosis, with increased survival rate (from 20% to 80%), restored lung volume, and attenuated injury severity accompanied by elevated oxyhemoglobin saturation and improved pulmonary function evaluations. We performed a phase l clinical trial involving twenty-four patients in a randomized, single-blind, and placebo-controlled study to treat pulmonary fibrosis (MR-46-22-004531, ChiCTR2300075466). All participants tolerated the nebulized hUCMSC-EVs well, with no serious adverse events. Patients receiving the combined therapy of nebulized hUCMSC-EVs and routine treatment demonstrated significant improvements in both lung function indices (forced vital capacity and maximal voluntary ventilation) and respiratory health status (as measured by the Saint George's Respiratory Questionnaire and Leicester Cough Questionnaire. Overall, patients upon the additional therapy with nebulized hUCMSC-EVs gained significant benefits compared with those accepted only routine treatment. Remarkably, two patients with advanced post-inflammatory pulmonary fibrosis exhibited clinically significant regression on serial CT scans after hUCMSC-EV therapy. These findings suggest that nebulized hUCMSC-EVs could be used as a promising therapeutic strategy for treating pulmonary fibrosis diseases.
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Project description:Mesenchymal stem cells (MSC) are multipotent cells which can be obtained from several adult and fetal tissues including human umbilical cord units. We have recently shown that umbilical cord tissue (UC) is richer in MSC than umbilical cord blood (UCB) but their origin and characteristics in blood as compared to the cord remains unknown. Here we compared, for the first time, the exonic protein-coding and intronic noncoding RNA (ncRNA) expression profiles of MSC from match-paired UC and UCB samples, harvested from the same donors, processed simultaneously and under the same culture conditions. The patterns of intronic ncRNA expression in MSC from UC and UCB paired units were highly similar, indicative of their common donor origin. The respective exonic protein-coding transcript expression profiles, however, were significantly different. Hierarchical clustering based on protein-coding expression similarities grouped MSC according to their tissue location rather than original donor. Genes related to systems development, osteogenesis and immune system were expressed at higher levels in UCB, whereas genes related to cell adhesion, morphogenesis, secretion, angiogenesis and neurogenesis were more expressed in UC cells. These molecular differences verified in tissue-specific MSC gene expression may reflect functional activities influenced by distinct niches and should be considered when developing clinical protocols involving MSC from different sources. In addition, these findings reinforce our previous suggestion on the importance of banking the whole umbilical cord unit for research or future therapeutic use.
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Project description:<p><strong>BACKGROUND:</strong> Perioperative neurocognitive disorder (PND) is a key complication affecting older individuals after anesthesia and surgery. Failure to translate multiple pharmacological therapies for PND from preclinical studies to clinical settings has necessitated the exploration of novel therapeutic strategies. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) treatment has emerged as a promising therapeutic strategy for treating neurodegenerative diseases and has the potential to translate basic science into clinical practice. In this study, we investigated the effects and underlying mechanism of hUC-MSCs on PND in aged mice.</p><p><strong>METHODS:</strong> hUC-MSCs were isolated from an infant umbilical cord and identified using flow cytometry and differentiation assays. We established PND model by undergoing aseptic laparotomy under isoflurane anesthesia maintaining spontaneous ventilation in 18-month-old male C57BL/6 mice. hUC-MSCs were slowly injected into mice by coccygeal vein before anesthesia. Cognitive function, neuroinflammation, neuroplasticity, endogenous neurogenesis and brain-derived neurotrophic factor (BDNF) were assessed. To determine the mechanisms underlying by which hUC-MSCs mediate their neuroprotective effects in PND, K252a, an antagonist of BDNF receptor, was administered intraperitoneally before surgery. Hippocampal BDNF/TrkB/CREB signaling pathway and metabolomic signatures were evaluated.</p><p><strong>RESULTS:</strong> hUC-MSC treatment ameliorated the learning and memory impairment in aged mice with PND. The downstream effects were the suppression of neuroinflammatory responses and restoration of neurogenesis and neuroplasticity dysregulation. Interestingly, the level of mature BDNF, but not that of proBDNF, was increased in the hippocampus after hUC-MSC treatment. Further analysis revealed that the improved cognitive recovery and the restoration of neurogenesis and neuroplasticity dysregulation elicited by exposure to hUC-MSCs were, at least partially, mediated by the activation of the BDNF/TrkB/CREB signaling pathway. Untargeted metabolomic further identified lipid metabolism dysfunction as potential downstream of the BDNF/TrkB/CREB signaling pathway in hUC-MSC-mediated neuroprotection for PND.</p><p><strong>CONCLUSIONS:</strong> Our study highlights the beneficial effects of hUC-MSC treatment on PND and provides a justification to consider the potential use of hUC-MSCs in the perioperative period.</p>
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