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PRODUCT CHARACTERIZATION AND PRECLINICAL SAFETY OF UMBILICAL CORD MESENCHYMAL STROMAL CELL-DERIVED SMALL EXTRACELLULAR VESICLES

ABSTRACT: Mesenchymal stromal cells (MSCs) are multipotent progenitors that can be isolated from different sources, such as the bone marrow, adipose tissue and umbilical cord. The therapeutic potential of MSCs is related to a plethora of immunomodulatory, anti-inflammatory and pro-repair actions, which are at least partially dependent on their secretome. Among the components of MSCs' secretome, EVs have received considerable attention because MSC-EVs exert similar therapeutic properties as their parent cells. Among the different MSC sources for EV production, human umbilical cord MSCs (hUCMSCs) show advantages such as tissue availability, high proliferative profile of the cells and potential beneficial therapeutic effects in a variety of different diseases, such as stroke This study aimed to provide novel insights for future hUCMSC-EVs research and treatment selection. We investigated the influence of the culture and harvesting conditions on the EV proteomic profile, productivity, surface markers expression and evaluated their in vivo biodistribution and toxicity.

INSTRUMENT(S): LTQ Orbitrap XL ETD

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Mesenchymal Stromal Cell

SUBMITTER: Gisele Rocha

LAB HEAD: Bruno Solano de Freitas Souza

PROVIDER: PXD038850 | Pride | 2024-05-04

REPOSITORIES: Pride

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Project description:BACKGROUND: Ischemia/reperfusion injury (IRI) is the leading cause of acute kidney injury (AKI). The current standard of care focuses on supporting kidney function, stating the need for more efficient and targeted therapies to enhance repair. Mesenchymal Stromal Cells (MSCs) and their secretome, either as conditioned medium (CM) or extracellular vesicles (EVs), have emerged as promising options for regenerative therapy, however, their full potential in treating AKI remains unknown.METHODS: In this study, we employed an in vitro model of chemically-induced ischemia using antimycin A combined with 2-deoxy-D-glucose to induce ischemic injury in proximal tubule epithelial cells. Afterwards, we evaluated the effects of MSC secretome, CM or EVs obtained from adipose tissue, bone marrow and umbilical cord, on ameliorating the detrimental effects of ischemia. To assess the damage and treatment outcomes, we analyzed cell morphology, mitochondrial health parameters (mitochondrial activity, ATP production, mass and membrane potential) and overall cell metabolism by metabolomics.RESULTS: Our findings show that ischemic injury caused cytoskeletal changes confirmed by disruption of the F-actin network, energetic imbalance as revealed by a 50% decrease in the oxygen consumption rate, increased oxidative stress, mitochondrial dysfunction and reduced cell metabolism. Upon treatment with MSC secretome, the morphological derangements were partly restored and ATP production increased by 40-50%, with umbilical cord-derived EVs being most effective. Furthermore, MSC treatment led to phenotype restoration as indicated by an increase in cell bioenergetics, including increased levels of glycolysis intermediates, as well as an accumulation of antioxidant metabolites.CONCLUSION: Our in vitro model effectively replicated the in vivo-like morphological and molecular changes observed during ischemic injury. Additionally, treatment with MSC secretome ameliorated proximal tubule damage, highlighting its potential as a viable therapeutic option for targeting AKI.

Project description:BACKGROUND: 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.METHODS: 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.RESULTS: 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.CONCLUSIONS: 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.

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PRODUCT CHARACTERIZATION AND PRECLINICAL SAFETY OF UMBILICAL CORD MESENCHYMAL STROMAL CELL-DERIVED SMALL EXTRACELLULAR VESICLES

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