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1.
Sci Rep ; 14(1): 12251, 2024 05 28.
Article in English | MEDLINE | ID: mdl-38806615

ABSTRACT

Mesenchymal stem cells (MSCs) have demonstrated promising advantages in the therapies of many diseases, while its multi-directional differentiation potential and immunotoxicity are the major concerns hindered their clinical translation. In this study, human umbilical Mesenchymal stem cell (hUC-MSCs) were labeled with a near-infrared fluorescent dye DiR before infused into cynomolgus monkeys, and the amount of hUC-MSCs in the peripheral blood were dynamically estimated from 5 min to 28 days post a single administration at 3 × 106 cells/kg and 2 × 107 cells/kg intravenously. As results, some hUC-MSCs distributed to the whole body within 5 min, while most of the cells accumulate in the lungs along with the systemic blood circulation, and subsequently released into the blood. The toxicity potentials of hUC-MSCs were investigated in another 30 cynomolgus monkeys, and the cells were repeatedly administrated at doses of 3 × 106 cells/kg and 2 × 107 cells/kg for 5 times on a weekly basis, with a recovery period of 1 months. hUC-MSCs showed no obvious toxic effects in cynomolgus monkeys, except xenogeneic immune rejection to human stem cells. Low levels of the hUC-MSC gene were detected in the peripheral blood of a few animals administered 2 × 107 cells/kg at 30 min subsequent to the first and last administration, and there was no significant difference in the copy number of the hUC-MSC gene in the blood samples compared with the first and last administration, indicating that the hUC-MSC was not significantly amplified in vivo, and it its safe in non-human primates. Our study for the first time verified the safety of long-term use of hUC-MSCs in primates. We have pioneered a technology for the real-time detection of hUC-MSCs in peripheral blood and provide dynamicand rapid monitoring of the distribution characteristics of hUC-MSCs in vivo. Here, we provide data supporting the application of such products for clinical treatment and the application of stem cells in major refractory diseases and regenerative medicine.


Subject(s)
Macaca fascicularis , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells , Umbilical Cord , Animals , Mesenchymal Stem Cells/cytology , Mesenchymal Stem Cells/metabolism , Humans , Umbilical Cord/cytology , Mesenchymal Stem Cell Transplantation/methods , Male , Cell Differentiation , Female
2.
Transpl Immunol ; 84: 102051, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38744348

ABSTRACT

BACKGROUND: Premature ovarian failure (POF), also known as primary ovarian insufficiency, is a common endocrine disease in young women. The emergence of regenerative medicine using stem cells may improve ovarian function and structure, and represents a promising prospect for POF treatment. In his study, we explored the therapeutic effects of human umbilical cord mesenchymal stem cell (HUCMSC) transplantation in a Tibetan miniature pig model of cyclophosphamide (CTX)-induced POF. METHODS: We cultured and identified HUCMSCs, labeled them with DiR iodide red dye, and implanted them into a CTX-induced model of POF in Tibetan miniature pigs. The daily weight changes were recorded, and the levels of estradiol (E2) and follicle-stimulating hormone (FSH) were measured on days 0, 7, and 14. At the end of the 21-day observation period, in vivo imaging of the bilateral ovaries was performed, and the ovarian index was measured. Ovarian tissue morphology and follicles were examined by hematoxylin-eosin staining. The terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay was employed to assess cell apoptosis, and immunohistochemistry was used to determine the levels of p-AKT, p-ERK1/2, BAX, and BCL2 expression. RESULTS: Our analysis indicated successful delivery of HUCMSCs to the ovaries of the POF pig model. Significant increases were observed in body weight, E2 levels, ovarian index, and number of normal follicles (all p < 0.05). Moreover, FSH levels reduced and ovarian tissue morphology improved following HUCMSCs transplantation (all p < 0.05). Importantly, upregulated p-AKT, p-ERK1/2, and BCL2 expression were observed, whereas the expression of BAX was suppressed (all p < 0.05), suggesting the inhibition of ovarian cell apoptosis. CONCLUSION: Our study highlights the significant therapeutic effects of HUCMSC transplantation on CTX-induced POF in a Tibetan miniature pig model.


Subject(s)
Apoptosis , Cyclophosphamide , Disease Models, Animal , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells , Primary Ovarian Insufficiency , Swine, Miniature , Animals , Female , Primary Ovarian Insufficiency/therapy , Primary Ovarian Insufficiency/chemically induced , Swine , Mesenchymal Stem Cell Transplantation/methods , Humans , Apoptosis/drug effects , Umbilical Cord/cytology , Cells, Cultured , Estradiol/blood , Ovary/pathology
3.
BMJ Case Rep ; 17(5)2024 May 08.
Article in English | MEDLINE | ID: mdl-38719262

ABSTRACT

We present the case of a term newborn with trisomy 21 who presented to the paediatric emergency department with periumbilical flare and green-brown discharge from a clamped umbilical cord, initially suspected to be omphalitis. However, it was noticed later, that when the infant strained or cried, a thick, bubbling and offensive green-brown discharge came out of the clamped umbilical cord with umbilical flatus. An ultrasound abdomen and umbilical cord confirmed the presence of a persistent omphalomesenteric duct (POMD). He was then transferred to the paediatric surgical unit. There, he underwent a laparotomy and surgical resection of the POMD and was discharged home 2 days later.


Subject(s)
Down Syndrome , Vitelline Duct , Humans , Down Syndrome/complications , Infant, Newborn , Vitelline Duct/abnormalities , Vitelline Duct/diagnostic imaging , Male , Umbilical Cord/abnormalities , Umbilical Cord/diagnostic imaging , Umbilical Cord/pathology , Laparotomy/methods
4.
Front Immunol ; 15: 1384718, 2024.
Article in English | MEDLINE | ID: mdl-38745668

ABSTRACT

Background: Researchers are focusing on cellular therapy for chronic obstructive pulmonary disease (COPD) using mesenchymal stem cells (MSCs), with human bone marrow-derived MSCs (hBM-MSCs) leading the way. However, BM-MSCs may not be as optimal as therapeutic cells owing to their low growth potential, invasive harvesting, and high expression of aging-related genes with poor differentiation potential. Consequently, umbilical cord-derived MSCs (hUC-MSCs), which have many excellent features as allogeneic heterologous stem cells, have received considerable attention. Allogeneic and heterologous hUC-MSCs appear to be promising owing to their excellent therapeutic properties. However, MSCs cannot remain in the lungs for long periods after intravenous infusion. Objective: To develop designer hUC-MSCs (dUC-MSCs), which are novel therapeutic cells with modified cell-adhesion properties, to aid COPD treatment. Methods: dUC-MSCs were cultured on type-I collagen gels and laminin 411, which are extracellular matrices. Mouse models of elastase-induced COPD were treated with hUC-MSCs. Biochemical analysis of the lungs of treated and control animals was performed. Results: Increased efficiency of vascular induction was found with dUC-MSCs transplanted into COPD mouse models compared with that observed with transplanted hUC-MSCs cultured on plates. The transplanted dUC-MSCs inhibited apoptosis by downregulating pro-inflammatory cytokine production, enhancing adhesion of the extracellular matrix to alveolar tissue via integrin ß1, promoting the polarity of M2 macrophages, and contributing to the repair of collapsed alveolar walls by forming smooth muscle fibers. dUC-MSCs inhibited osteoclastogenesis in COPD-induced osteoporosis. hUC-MSCs are a promising cell source and have many advantages over BM-MSCs and adipose tissue-derived MSCs. Conclusion: We developed novel designer cells that may be involved in anti-inflammatory, homeostatic, injury repair, and disease resistance processes. dUC-MSCs repair and regenerate the alveolar wall by enhancing adhesion to the damaged site. Therefore, they can contribute to the treatment of COPD and systemic diseases such as osteoporosis.


Subject(s)
Disease Models, Animal , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells , Pulmonary Disease, Chronic Obstructive , Regeneration , Animals , Mice , Mesenchymal Stem Cells/metabolism , Humans , Pulmonary Disease, Chronic Obstructive/therapy , Pulmonary Alveoli , Umbilical Cord/cytology , Cells, Cultured , Cell Differentiation , Cord Blood Stem Cell Transplantation/methods , Mice, Inbred C57BL , Male
5.
Eur J Med Res ; 29(1): 270, 2024 May 04.
Article in English | MEDLINE | ID: mdl-38704575

ABSTRACT

BACKGROUND: This study aims to investigate the effects of a conditioned medium (CM) from human umbilical cord mesenchymal stem cells (HuMSCs) cultivated in gelatin sponge (GS-HuMSCs-CM) on hair growth in a mouse model. METHODS: CM was collected from the HuMSCs cultivated in a monolayer or in a gelatin sponge. Vascular endothelial growth factor (VEGF), insulin-like growth factor-1 (IGF-1), keratinocyte growth factor (KGF), and hepatocyte growth factor (HGF) levels in CMs were measured by enzyme-linked immunosorbent assays (ELISAs). A hair loss model by a C57 BL/6J mouse was prepared. The effects of GS-HuMSCs-CM and HuMSCs on hair regrowth in mice were investigated by intradermal injection in the depilated back skin with normal saline (NS) as the control. The time for hair regrowth and full covering in depilated areas was observed, and the hair growth was evaluated histologically and by grossly measuring hair length and diameter. RESULTS: Compared with monolayer cultured cells, the three-dimensional (3D) culture of HuMSCs in gelatin sponge drastically increased VEGF, IGF-1, KGF, and HGF production. GS-HuMSCs-CM and HuMSCs injection both promoted hair regeneration in mice, while GS-HuMSCs-CM presented more enhanced effects in hair length, hair diameter, and growth rate. GS-HuMSCs-CM significantly promoted angiogenesis in injected skin areas, which might also contribute to faster hair regrowth. CONCLUSION: GS-HuMSCs-CM exerted significant effects on inducing hair growth and promoted skin angiogenesis in C57BL/6J mice.


Subject(s)
Hair , Insulin-Like Growth Factor I , Mesenchymal Stem Cells , Umbilical Cord , Animals , Mesenchymal Stem Cells/cytology , Mesenchymal Stem Cells/drug effects , Mesenchymal Stem Cells/metabolism , Humans , Culture Media, Conditioned/pharmacology , Mice , Umbilical Cord/cytology , Hair/growth & development , Hair/drug effects , Insulin-Like Growth Factor I/metabolism , Vascular Endothelial Growth Factor A/metabolism , Hepatocyte Growth Factor/metabolism , Gelatin/chemistry , Tissue Scaffolds/chemistry , Mice, Inbred C57BL , Cells, Cultured , Fibroblast Growth Factor 7/metabolism
6.
Int J Mol Sci ; 25(10)2024 May 14.
Article in English | MEDLINE | ID: mdl-38791378

ABSTRACT

Numerous challenges remain within conventional cell-based therapy despite the growing trend of stem cells used to treat various life-debilitating diseases. These limitations include batch-to-batch heterogeneity, induced alloreactivity, cell survival and integration, poor scalability, and high cost of treatment, thus hindering successful translation from lab to bedside. However, recent pioneering technology has enabled the isolation and enrichment of small extracellular vesicles (EVs), canonically known as exosomes. EVs are described as a membrane-enclosed cargo of functional biomolecules not limited to lipids, nucleic acid, and proteins. Interestingly, studies have correlated the biological role of MSC-EVs to the paracrine activity of MSCs. This key evidence has led to rigorous studies on MSC-EVs as an acellular alternative. Using EVs as a therapy was proposed as a model leading to improvements through increased safety; enhanced bioavailability due to size and permeability; reduced heterogeneity by selective and quantifiable properties; and prolonged shelf-life via long-term freezing or lyophilization. Yet, the identity and potency of EVs are still relatively unknown due to various methods of preparation and to qualify the final product. This is reflected by the absence of regulatory strategies overseeing manufacturing, quality control, clinical implementation, and product registration. In this review, the authors review the various production processes and the proteomic profile of MSC-EVs.


Subject(s)
Extracellular Vesicles , Mesenchymal Stem Cells , Proteomics , Humans , Mesenchymal Stem Cells/metabolism , Mesenchymal Stem Cells/cytology , Extracellular Vesicles/metabolism , Proteomics/methods , Umbilical Cord/cytology , Umbilical Cord/metabolism , Exosomes/metabolism , Proteome/metabolism
7.
ACS Nano ; 18(21): 13696-13713, 2024 May 28.
Article in English | MEDLINE | ID: mdl-38751164

ABSTRACT

The potential of human umbilical cord mesenchymal stromal cell-derived extracellular vesicles (hucMSC-EVs) in wound healing is promising, yet a comprehensive understanding of how fibroblasts and keratinocytes respond to this treatment remains limited. This study utilizes single-cell RNA sequencing (scRNA-seq) to investigate the impact of hucMSC-EVs on the cutaneous wound microenvironment in mice. Through rigorous single-cell analyses, we unveil the emergence of hucMSC-EV-induced hematopoietic fibroblasts and MMP13+ fibroblasts. Notably, MMP13+ fibroblasts exhibit fetal-like expressions of MMP13, MMP9, and HAS1, accompanied by heightened migrasome activity. Activation of MMP13+ fibroblasts is orchestrated by a distinctive PIEZO1-calcium-HIF1α-VEGF-MMP13 pathway, validated through murine models and dermal fibroblast assays. Organotypic culture assays further affirm that these activated fibroblasts induce keratinocyte migration via MMP13-LRP1 interactions. This study significantly contributes to our understanding of fibroblast heterogeneities as well as intercellular interactions in wound healing and identifies hucMSC-EV-induced hematopoietic fibroblasts as potential targets for reprogramming. The therapeutic targets presented by these fibroblasts offer exciting prospects for advancing wound healing strategies.


Subject(s)
Extracellular Vesicles , Fibroblasts , Mesenchymal Stem Cells , Single-Cell Analysis , Umbilical Cord , Wound Healing , Humans , Mesenchymal Stem Cells/metabolism , Mesenchymal Stem Cells/cytology , Extracellular Vesicles/metabolism , Extracellular Vesicles/chemistry , Umbilical Cord/cytology , Umbilical Cord/metabolism , Animals , Mice , Fibroblasts/metabolism , Sequence Analysis, RNA , Cells, Cultured , Cell Movement , Matrix Metalloproteinase 13/metabolism , Fetus
8.
Stem Cell Res Ther ; 15(1): 147, 2024 May 22.
Article in English | MEDLINE | ID: mdl-38773627

ABSTRACT

BACKGROUND: Bleomycin (BLM)-induced lung injury is characterized by mixed histopathologic changes with inflammation and fibrosis, such as observed in human patients with bronchopulmonary dysplasia, idiopathic pulmonary fibrosis, and chronic obstructive pulmonary disease. Although no curative therapies for these lung diseases exist, stem cell therapy has emerged as a potential therapeutic option. Multilineage-differentiating stress-enduring (Muse) cells are endogenous pluripotent- and macrophage-like stem cells distributed in various adult and fetal tissues as stage-specific embryonic antigen-3-positive cells. They selectively home to damaged tissue by sensing sphingosine-1-phosphate and replace the damaged/apoptotic cells by in vivo differentiation. Clinical trials for some human diseases suggest the safety and therapeutic efficacy of intravenously injected human leukocyte antigen-mismatched allogenic Muse cells from adult bone marrow (BM) without immunosuppressant. Here, we evaluated the therapeutic effects of human Muse cells from preterm and term umbilical cord (UC), and adult BM in a rat BLM-induced lung injury model. METHODS: Rats were endotracheally administered BLM to induce lung injury on day 0. On day 3, human preterm UC-Muse, term UC-Muse, or adult BM-Muse cells were administered intravenously without immunosuppressants, and rats were subjected to histopathologic analysis on day 21. Body weight, serum surfactant protein D (SP-D) levels, and oxygen saturation (SpO2) were monitored. Histopathologic lung injury scoring by the Ashcroft and modified American Thoracic Society document scales, quantitative characterization of engrafted Muse cells, RNA sequencing analysis, and in vitro migration assay of infused Muse cells were performed. RESULTS: Rats administered preterm- and term-UC-Muse cells exhibited a significantly better recovery based on weight loss, serum SP-D levels, SpO2, and histopathologic lung injury scores, and a significantly higher rate of both Muse cell homing to the lung and alveolar marker expression (podoplanin and prosurfactant protein-C) than rats administered BM-Muse cells. Rats receiving preterm-UC-Muse cells showed statistically superior results to those receiving term-UC-Muse cells in many of the measures. These findings are thought to be due to higher expression of genes related to cell migration, lung differentiation, and cell adhesion. CONCLUSION: Preterm UC-Muse cells deliver more efficient therapeutic effects than term UC- and BM-Muse cells for treating BLM-induced lung injury in a rat model.


Subject(s)
Bleomycin , Disease Models, Animal , Lung Injury , Umbilical Cord , Animals , Humans , Rats , Lung Injury/therapy , Lung Injury/chemically induced , Lung Injury/pathology , Umbilical Cord/cytology , Rats, Sprague-Dawley , Male , Cell Differentiation , Female
9.
JAMA Netw Open ; 7(5): e2411140, 2024 May 01.
Article in English | MEDLINE | ID: mdl-38758557

ABSTRACT

Importance: Providing assisted ventilation during delayed umbilical cord clamping may improve outcomes for extremely preterm infants. Objective: To determine whether assisted ventilation in extremely preterm infants (23 0/7 to 28 6/7 weeks' gestational age [GA]) followed by cord clamping reduces intraventricular hemorrhage (IVH) or early death. Design, Setting, and Participants: This phase 3, 1:1, parallel-stratified randomized clinical trial conducted at 12 perinatal centers across the US and Canada from September 2, 2016, through February 21, 2023, assessed IVH and early death outcomes of extremely preterm infants randomized to receive 120 seconds of assisted ventilation followed by cord clamping vs delayed cord clamping for 30 to 60 seconds with ventilatory assistance afterward. Two analysis cohorts, not breathing well and breathing well, were specified a priori based on assessment of breathing 30 seconds after birth. Intervention: After birth, all infants received stimulation and suctioning if needed. From 30 to 120 seconds, infants randomized to the intervention received continuous positive airway pressure if breathing well or positive-pressure ventilation if not, with cord clamping at 120 seconds. Control infants received 30 to 60 seconds of delayed cord clamping followed by standard resuscitation. Main Outcomes and Measures: The primary outcome was any grade IVH on head ultrasonography or death before day 7. Interpretation by site radiologists was confirmed by independent radiologists, all masked to study group. To estimate the association between study group and outcome, data were analyzed using the stratified Cochran-Mantel-Haenszel test for relative risk (RR), with associations summarized by point estimates and 95% CIs. Results: Of 1110 women who consented to participate, 548 were randomized and delivered infants at GA less than 29 weeks. A total of 570 eligible infants were enrolled (median [IQR] GA, 26.6 [24.9-27.7] weeks; 297 male [52.1%]). Intraventricular hemorrhage or death occurred in 34.9% (97 of 278) of infants in the intervention group and 32.5% (95 of 292) in the control group (adjusted RR, 1.02; 95% CI, 0.81-1.27). In the prespecified not-breathing-well cohort (47.5% [271 of 570]; median [IQR] GA, 26.0 [24.7-27.4] weeks; 152 male [56.1%]), IVH or death occurred in 38.7% (58 of 150) of infants in the intervention group and 43.0% (52 of 121) in the control group (RR, 0.91; 95% CI, 0.68-1.21). There was no evidence of differences in death, severe brain injury, or major morbidities between the intervention and control groups in either breathing cohort. Conclusions and Relevance: This study did not show that providing assisted ventilation before cord clamping in extremely preterm infants reduces IVH or early death. Additional study around the feasibility, safety, and efficacy of assisted ventilation before cord clamping may provide additional insight. Trial Registration: ClinicalTrials.gov Identifier: NCT02742454.


Subject(s)
Infant, Extremely Premature , Umbilical Cord Clamping , Humans , Infant, Newborn , Female , Male , Umbilical Cord Clamping/methods , Canada , Respiration, Artificial/methods , Cerebral Intraventricular Hemorrhage/prevention & control , Umbilical Cord , Continuous Positive Airway Pressure/methods , Gestational Age , Time Factors , United States
10.
BMC Pregnancy Childbirth ; 24(1): 362, 2024 May 15.
Article in English | MEDLINE | ID: mdl-38750520

ABSTRACT

BACKGROUND: Intact cord resuscitation in the first three minutes of life improves oxygenation and Apgar scores. The practise of intact cord resuscitation implies the umbilical cord still being connected to the placenta for at least one minute while providing temperature control and equipment for resuscitation. Healthcare professionals described practical challenges in providing intact cord resuscitation. This study aimed to explore neonatal healthcare professionals' experiences of providing intact cord resuscitation in the mother's bed. METHOD: An interview study with an inductive, interpretative approach was chosen and analysed according to reflexive thematic analysis by Braun & Clarke. An open interview guide was used and 20 individual interviews with neonatal healthcare professionals were performed. The study was conducted at five level I-III neonatal care units. In Sweden, resuscitation is performed either in or outside the labour room. RESULTS: The results contributed insight into the participants' experiences of prerequisites for providing neonatal care in intact cord resuscitation. The sense of the mother's vulnerability was noticeable, as the participants reported reducing the risk of exposure to protect and preserve the mother's integrity. The practical challenges in the environment involved working in a limited space. The desire for multi-professional team training comprised education and training as well as debriefing to manage intact cord resuscitation. CONCLUSION: The result of the present study highlights the fact that neonatal healthcare professionals' experiences of providing ICR in the mother's bed were positive and had significant benefits for the neonate, namely zero separation between the neonate and parents and better physical recovery for the neonate. However, the fact that ICR in the mother's bed can be challenging in several ways, such as emotionally, managing environmental circumstances and ensuring effective team collaboration. Therefore, it is of the utmost importance that healthcare professionals are given the opportunity to reflect and train together as a team. Future recommendations are to summarize evidence-based knowledge to design guidelines for ICR situation.


Subject(s)
Attitude of Health Personnel , Qualitative Research , Resuscitation , Umbilical Cord , Humans , Resuscitation/methods , Female , Sweden , Infant, Newborn , Adult , Mothers/psychology , Male , Interviews as Topic , Health Personnel/psychology , Pregnancy , Intensive Care Units, Neonatal
11.
Int J Mol Sci ; 25(9)2024 Apr 29.
Article in English | MEDLINE | ID: mdl-38732088

ABSTRACT

Pregnancy at advanced maternal age (AMA) is a condition of potential risk for the development of maternal-fetal complications with possible repercussions even in the long term. Here, we analyzed the changes in plasma redox balance and the effects of plasma on human umbilical cord mesenchymal cells (hUMSCs) in AMA pregnant women (patients) at various timings of pregnancy. One hundred patients and twenty pregnant women younger than 40 years (controls) were recruited and evaluated at various timings during pregnancy until after delivery. Plasma samples were used to measure the thiobarbituric acid reactive substances (TBARS), glutathione and nitric oxide (NO). In addition, plasma was used to stimulate the hUMSCs, which were tested for cell viability, reactive oxygen species (ROS) and NO release. The obtained results showed that, throughout pregnancy until after delivery in patients, the levels of plasma glutathione and NO were lower than those of controls, while those of TBARS were higher. Moreover, plasma of patients reduced cell viability and NO release, and increased ROS release in hUMSCs. Our results highlighted alterations in the redox balance and the presence of potentially harmful circulating factors in plasma of patients. They could have clinical relevance for the prevention of complications related to AMA pregnancy.


Subject(s)
Maternal Age , Mesenchymal Stem Cells , Nitric Oxide , Oxidation-Reduction , Reactive Oxygen Species , Thiobarbituric Acid Reactive Substances , Umbilical Cord , Humans , Female , Pregnancy , Adult , Mesenchymal Stem Cells/metabolism , Reactive Oxygen Species/metabolism , Nitric Oxide/metabolism , Nitric Oxide/blood , Thiobarbituric Acid Reactive Substances/metabolism , Umbilical Cord/cytology , Umbilical Cord/metabolism , Glutathione/metabolism , Glutathione/blood , Cell Survival , Oxidative Stress , Plasma/metabolism
12.
J Matern Fetal Neonatal Med ; 37(1): 2352088, 2024 Dec.
Article in English | MEDLINE | ID: mdl-38735870

ABSTRACT

OBJECTIVE: In the present study, we sought to identify risk factors for umbilical cord prolapse (UCP) and adapt the multidisciplinary team (MDT) first-aid simulation training for UCP patients. We evaluated the usefulness of the MDT first-aid simulation by comparing delivery outcomes for UCP patients before and after its implementation. MATERIAL AND METHODS: A retrospective review was conducted on 149 UCP cases (48 overt and 101 occult) and 298 control deliveries that occurred at the Third Affiliated Hospital of Sun Yat-sen University from January 1998 to December 2022. Patient data were compared between the groups. One-way analysis of variance (ANOVA) was used for means comparison, and the chi-square test was used for categorical data. Univariate and multivariate logistic regression analyses were performed to identify factors significantly associated with UCP. RESULTS: Overt UCP was strongly associated with all adverse delivery outcomes. Both univariate and multivariate analyses identified multiparity, breech presentation, polyhydramnios, and low birth weight as independent risk factors for overt UCP (all odds ratios [OR] > 1; all p < 0.05). Preterm labor and abnormal placental cord insertion were identified as independent risk factors for occult UCP (all OR > 1; all p < 0.05). After 2014, when obstetrical staff received MDT first-aid simulation training, patients with overt UCP experienced shorter decision-to-delivery intervals due to more timely cesarean sections. They also had higher Apgar scores at 1, 5, and 10 min, and lower admission rates to the neonatal intensive care unit compared to patients before 2014 (all p < 0.05). CONCLUSION: MDT first-aid simulation training for overt UCP can improve neonatal outcomes. However, medical simulation training efforts should initially focus on the early identification of risk factors for both overt and occult UCP.


Overt umbilical cord prolapse (UCP) is an obstetric emergency that can lead to adverse delivery outcomes. Early identification of risk factors for both overt and occult UCP is beneficial for facilitating early interventions. Multidisciplinary team first-aid simulation training specifically for overt UCP has been shown to effectively improve neonatal outcomes.


Subject(s)
Patient Care Team , Simulation Training , Umbilical Cord , Humans , Female , Prolapse , Retrospective Studies , Pregnancy , Risk Factors , Simulation Training/methods , Infant, Newborn , Adult , Case-Control Studies , Pregnancy Outcome/epidemiology , Obstetric Labor Complications/therapy , Obstetric Labor Complications/epidemiology
13.
J Zhejiang Univ Sci B ; 25(5): 422-437, 2024 May 15.
Article in English, Chinese | MEDLINE | ID: mdl-38725341

ABSTRACT

Viral myocarditis (VMC) is one of the most common acquired heart diseases in children and teenagers. However, its pathogenesis is still unclear, and effective treatments are lacking. This study aimed to investigate the regulatory pathway by which exosomes alleviate ferroptosis in cardiomyocytes (CMCs) induced by coxsackievirus B3 (CVB3). CVB3 was utilized for inducing the VMC mouse model and cellular model. Cardiac echocardiography, left ventricular ejection fraction (LVEF), and left ventricular fractional shortening (LVFS) were implemented to assess the cardiac function. In CVB3-induced VMC mice, cardiac insufficiency was observed, as well as the altered levels of ferroptosis-related indicators (glutathione peroxidase 4 (GPX4), glutathione (GSH), and malondialdehyde (MDA)). However, exosomes derived from human umbilical cord mesenchymal stem cells (hucMSCs-exo) could restore the changes caused by CVB3 stimulation. Let-7a-5p was enriched in hucMSCs-exo, and the inhibitory effect of hucMSCs-exolet-7a-5p mimic on CVB3-induced ferroptosis was higher than that of hucMSCs-exomimic NC (NC: negative control). Mothers against decapentaplegic homolog 2 (SMAD2) increased in the VMC group, while the expression of zinc-finger protein 36 (ZFP36) decreased. Let-7a-5p was confirmed to interact with SMAD2 messenger RNA (mRNA), and the SMAD2 protein interacted directly with the ZFP36 protein. Silencing SMAD2 and overexpressing ZFP36 inhibited the expression of ferroptosis-related indicators. Meanwhile, the levels of GPX4, solute carrier family 7, member 11 (SLC7A11), and GSH were lower in the SMAD2 overexpression plasmid (oe-SMAD2)+let-7a-5p mimic group than in the oe-NC+let-7a-5p mimic group, while those of MDA, reactive oxygen species (ROS), and Fe2+ increased. In conclusion, these data showed that ferroptosis could be regulated by mediating SMAD2 expression. Exo-let-7a-5p derived from hucMSCs could mediate SMAD2 to promote the expression of ZFP36, which further inhibited the ferroptosis of CMCs to alleviate CVB3-induced VMC.


Subject(s)
Enterovirus B, Human , Exosomes , Ferroptosis , Mesenchymal Stem Cells , MicroRNAs , Myocytes, Cardiac , Signal Transduction , Smad2 Protein , Umbilical Cord , Mesenchymal Stem Cells/metabolism , Exosomes/metabolism , Animals , Humans , Mice , Smad2 Protein/metabolism , MicroRNAs/metabolism , MicroRNAs/genetics , Enterovirus B, Human/physiology , Myocytes, Cardiac/metabolism , Umbilical Cord/cytology , Coxsackievirus Infections/metabolism , Male , Myocarditis/metabolism , Myocarditis/virology , Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism
14.
Aging (Albany NY) ; 16(9): 7928-7945, 2024 Apr 29.
Article in English | MEDLINE | ID: mdl-38696318

ABSTRACT

Recently, there has been growing interest in using cell therapy through core decompression (CD) to treat osteonecrosis of the femoral head (ONFH). Our study aimed to investigate the effectiveness and mechanism of human umbilical cord mesenchymal stem cells (hUCMSCs) in treating steroid-induced ONFH. We constructed a steroid-induced ONFH rabbit model as well as dexamethasone (Dex)-treated bone microvascular endothelial cells (BMECs) model of human femoral head. We injected hUCMSCs into the rabbit femoral head via CD. The effects of hUCMSCs on steroid-induced ONFH rabbit model and Dex-treated BMECs were evaluated via micro-CT, microangiography, histology, immunohistochemistry, wound healing, tube formation, and western blotting assay. Furthermore, we conducted single-cell RNA sequencing (scRNA-seq) to examine the characteristics of endothelial cells, the activation of signaling pathways, and inter-cellular communication in ONFH. Our data reveal that hUCMSCs improved the femoral head microstructure and bone repair and promoted angiogenesis in the steroid-induced ONFH rabbit model. Importantly, hUCMSCs improved the migration ability and angioplasty of Dex-treated BMECs by secreting COL6A2 to activate FAK/PI3K/AKT signaling pathway via integrin α1ß1.


Subject(s)
Dexamethasone , Endothelial Cells , Femur Head Necrosis , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells , Animals , Rabbits , Femur Head Necrosis/chemically induced , Femur Head Necrosis/therapy , Femur Head Necrosis/pathology , Humans , Mesenchymal Stem Cells/metabolism , Endothelial Cells/metabolism , Mesenchymal Stem Cell Transplantation/methods , Dexamethasone/pharmacology , Umbilical Cord/cytology , Femur Head/pathology , Disease Models, Animal , Neovascularization, Physiologic , Signal Transduction
15.
Mol Biol Rep ; 51(1): 675, 2024 May 24.
Article in English | MEDLINE | ID: mdl-38787484

ABSTRACT

BACKGROUND: Bioscaffolds and cells are two main components in the regeneration of damaged tissues via cell therapy. Umbilical cord stem cells are among the most well-known cell types for this purpose. The main objective of the present study was to evaluate the effect of the pretreatment of the foreskin acellular matrix (FAM) by monophosphoryl lipid A (MPLA) and Lactobacillus casei supernatant (LCS) on the attraction of human umbilical cord mesenchymal stem cells (hucMSC). METHODS AND RESULTS: The expression of certain cell migration genes was studied using qRT-PCR. In addition to cell migration, transdifferentiation of these cells to the epidermal-like cells was evaluated via immunohistochemistry (IHC) and immunocytochemistry (ICC) of cytokeratin 19 (CK19). The hucMSC showed more tissue tropism in the presence of MPLA and LCS pretreated FAM compared to the untreated control group. We confirmed this result by scanning electron microscopy (SEM) analysis, glycosaminoglycan (GAG), collagen, and DNA content. Furthermore, IHC and ICC data demonstrated that both treatments increase the protein expression level of CK19. CONCLUSION: Pretreatment of acellular bioscaffolds by MPLA or LCS can increase the migration rate of cells and also transdifferentiation of hucMSC to epidermal-like cells without growth factors. This strategy suggests a new approach in regenerative medicine.


Subject(s)
Lacticaseibacillus casei , Lipid A , Mesenchymal Stem Cells , Humans , Mesenchymal Stem Cells/metabolism , Lacticaseibacillus casei/metabolism , Lipid A/metabolism , Lipid A/analogs & derivatives , Cell Movement/drug effects , Skin/metabolism , Tissue Scaffolds/chemistry , Male , Umbilical Cord/cytology , Umbilical Cord/metabolism , Foreskin/cytology , Cell Transdifferentiation/drug effects , Tissue Engineering/methods , Extracellular Matrix/metabolism , Keratin-19/metabolism , Keratin-19/genetics
16.
Stem Cell Res Ther ; 15(1): 143, 2024 May 20.
Article in English | MEDLINE | ID: mdl-38764049

ABSTRACT

BACKGROUND: Spinal cord injury (SCI) is a debilitating illness in humans that causes permanent loss of movement or sensation. To treat SCI, exosomes, with their unique benefits, can circumvent limitations through direct stem cell transplantation. Therefore, we utilized Gelfoam encapsulated with exosomes derived from human umbilical cord mesenchymal stem cells (HucMSC-EX) in a rat SCI model. METHODS: SCI model was established through hemisection surgery in T9 spinal cord of female Sprague-Dawley rats. Exosome-loaded Gelfoam was implanted into the lesion site. An in vivo uptake assay using labeled exosomes was conducted on day 3 post-implantation. Locomotor functions and gait analyses were assessed using Basso-Beattie-Bresnahan (BBB) locomotor rating scale and DigiGait Imaging System from weeks 1 to 8. Nociceptive responses were evaluated through von Frey filament and noxious radiant heat tests. The therapeutic effects and potential mechanisms were analyzed using Western blotting and immunofluorescence staining at week 8 post-SCI. RESULTS: For the in vivo exosome uptake assay, we observed the uptake of labeled exosomes by NeuN+, Iba1+, GFAP+, and OLIG2+ cells around the injured area. Exosome treatment consistently increased the BBB score from 1 to 8 weeks compared with the Gelfoam-saline and SCI control groups. Additionally, exosome treatment significantly improved gait abnormalities including right-to-left hind paw contact area ratio, stance/stride, stride length, stride frequency, and swing duration, validating motor function recovery. Immunostaining and Western blotting revealed high expression of NF200, MBP, GAP43, synaptophysin, and PSD95 in exosome treatment group, indicating the promotion of nerve regeneration, remyelination, and synapse formation. Interestingly, exosome treatment reduced SCI-induced upregulation of GFAP and CSPG. Furthermore, levels of Bax, p75NTR, Iba1, and iNOS were reduced around the injured area, suggesting anti-inflammatory and anti-apoptotic effects. Moreover, exosome treatment alleviated SCI-induced pain behaviors and reduced pain-associated proteins (BDNF, TRPV1, and Cav3.2). Exosomal miRNA analysis revealed several promising therapeutic miRNAs. The cell culture study also confirmed the neurotrophic effect of HucMSCs-EX. CONCLUSION: Implantation of HucMSCs-EX-encapsulated Gelfoam improves SCI-induced motor dysfunction and neuropathic pain, possibly through its capabilities in nerve regeneration, remyelination, anti-inflammation, and anti-apoptosis. Overall, exosomes could serve as a promising therapeutic alternative for SCI treatment.


Subject(s)
Disease Models, Animal , Exosomes , Mesenchymal Stem Cells , Neuralgia , Rats, Sprague-Dawley , Spinal Cord Injuries , Animals , Spinal Cord Injuries/therapy , Exosomes/metabolism , Neuralgia/therapy , Neuralgia/metabolism , Rats , Female , Humans , Mesenchymal Stem Cells/metabolism , Mesenchymal Stem Cells/cytology , Locomotion , Gelatin Sponge, Absorbable , Umbilical Cord/cytology
17.
Stem Cell Res Ther ; 15(1): 144, 2024 May 20.
Article in English | MEDLINE | ID: mdl-38764077

ABSTRACT

BACKGROUND: The aim of this study was to evaluate potential synergistic effects of a single, local application of human umbilical cord MSC-derived sEVs in combination with a low dose of recombinant human rhBMP-2 to promote the regeneration of a metaphyseal femoral defect in an osteoporotic rat model. METHODS: 6 weeks after induction of osteoporosis by bilateral ventral ovariectomy and administration of a special diet, a total of 64 rats underwent a distal femoral metaphyseal osteotomy using a manual Gigli wire saw. Defects were stabilized with an adapted Y-shaped mini-locking plate and were subsequently treated with alginate only, or alginate loaded with hUC-MSC-sEVs (2 × 109), rhBMP-2 (1.5 µg), or a combination of sEVs and rhBMP-2 (n = 16 for each group). 6 weeks post-surgery, femora were evaluated by µCT, descriptive histology, and biomechanical testing. RESULTS: Native radiographs and µCT analysis confirmed superior bony union with callus formation after treatment with hUC-MSC-sEVs in combination with a low dose of rhBMP-2. This finding was further substantiated by histology, showing robust defect consolidation 6 weeks after treatment. Torsion testing of the explanted femora revealed increased stiffness after application of both, rhBMP-2 alone, or in combination with sEVs, whereas torque was only significantly increased after treatment with rhBMP-2 together with sEVs. CONCLUSION: The present study demonstrates that the co-application of hUC-MSC-sEVs can improve the efficacy of rhBMP-2 to promote the regeneration of osteoporotic bone defects.


Subject(s)
Bone Morphogenetic Protein 2 , Extracellular Vesicles , Femur , Osteoporosis , Recombinant Proteins , Umbilical Cord , Animals , Bone Morphogenetic Protein 2/pharmacology , Bone Morphogenetic Protein 2/genetics , Recombinant Proteins/pharmacology , Recombinant Proteins/genetics , Osteoporosis/pathology , Rats , Female , Humans , Femur/pathology , Femur/drug effects , Femur/diagnostic imaging , Umbilical Cord/cytology , Extracellular Vesicles/metabolism , Bone Regeneration/drug effects , Rats, Sprague-Dawley , Transforming Growth Factor beta/pharmacology , Disease Models, Animal , X-Ray Microtomography , Mesenchymal Stem Cells/metabolism
18.
Int J Nanomedicine ; 19: 3475-3495, 2024.
Article in English | MEDLINE | ID: mdl-38623080

ABSTRACT

Purpose: Human umbilical cord mesenchymal stem cell (hucMSC)-derived small extracellular vesicles (sEVs) are natural nanocarriers with promising potential in treating liver fibrosis and have widespread applications in the fields of nanomedicine and regenerative medicine. However, the therapeutic efficacy of natural hucMSC-sEVs is currently limited owing to their non-specific distribution in vivo and partial removal by mononuclear macrophages following systemic delivery. Thus, the therapeutic efficacy can be improved through the development of engineered hucMSC-sEVs capable to overcome these limitations. Patients and Methods: To improve the anti-liver fibrosis efficacy of hucMSC-sEVs, we genetically engineered hucMSC-sEVs to overexpress the anti-fibrotic gene bone morphogenic protein 7 (BMP7) in parental cells. This was achieved using lentiviral transfection, following which BMP7-loaded hucMSC-sEVs were isolated through ultracentrifugation. First, the liver fibrosis was induced in C57BL/6J mice by intraperitoneal injection of 50% carbon tetrachloride (CCL4) twice a week for 8 weeks. These mice were subsequently treated with BMP7+sEVs via tail vein injection, and the anti-liver fibrosis effect of BMP7+sEVs was validated using small animal in vivo imaging, immunohistochemistry (IHC), tissue immunofluorescence, and enzyme-linked immunosorbent assay (ELISA). Finally, cell function studies were performed to confirm the in vivo results. Results: Liver imaging and liver histopathology confirmed that the engineered hucMSC-sEVs could reach the liver of mice and aggregate around activated hepatic stellate cells (aHSCs) with a significantly stronger anti-liver fibrosis effect of BMP7-loaded hucMSC-sEVs compared to those of blank or negative control-transfected hucMSC-sEVs. In vitro, BMP7-loaded hucMSC-sEVs promoted the phenotypic reversal of aHSCs and inhibited their proliferation to enhance the anti-fibrotic effects. Conclusion: These engineered BMP7-loaded hucMSC-sEVs offer a novel and promising strategy for the clinical treatment of liver fibrosis.


Subject(s)
Extracellular Vesicles , Mesenchymal Stem Cells , Animals , Mice , Humans , Hepatic Stellate Cells/pathology , Mice, Inbred C57BL , Liver Cirrhosis/chemically induced , Liver Cirrhosis/therapy , Liver Cirrhosis/metabolism , Fibrosis , Extracellular Vesicles/pathology , Mesenchymal Stem Cells/metabolism , Umbilical Cord , Bone Morphogenetic Protein 7/genetics , Bone Morphogenetic Protein 7/metabolism
19.
Int J Nanomedicine ; 19: 3555-3575, 2024.
Article in English | MEDLINE | ID: mdl-38638364

ABSTRACT

Background: Neutrophils rapidly accumulate in large numbers at sites of tissue damage, exhibiting not only their well-known bactericidal capabilities but also playing crucial roles in angiogenesis and tissue repair. While exosomes derived from human umbilical cord mesenchymal stem cells (HucMSC-Exo) have emerged as a promising therapeutic tool, their exact mechanisms of action remain partly elusive. We hypothesize that HucMSC-Exo treatment may modulate neutrophil phenotypes, thereby significantly influencing wound healing outcomes. Methods: HucMSC-Exo were isolated via ultracentrifugation and subsequently administered through subcutaneous injection into full-thickness cutaneous wounds in mice. To determine the impact of host neutrophils on the healing effects of HucMSC-Exo in skin injuries, strategies including neutrophil depletion and adoptive transfer were employed. Flow cytometry was used to evaluate the proportion of N2 subtype neutrophils in both normal and diabetic wounds, and the effect of HucMSC-Exo on this proportion was assessed. Furthermore, the mitochondrial metabolic reprogramming driven by HucMSC-Exo during N2 polarization was investigated through JC1 staining, ATP quantification, fatty acid uptake assays, and assessment of FAO-related genes (Cpt1b, Acadm, and Acadl). Results: Depleting host neutrophils strikingly dampened prohealing effect of HucMSC-Exo on skin injury, while adoptive transfer of bone marrow neutrophils rescued this process. During normal healing process, some neutrophils expressed N2 markers, in contrast, diabetic wounds exhibited a reduced expression of N2 markers. After treatment with HucMSC-Exo, most neutrophils increased the phosphorylation of STAT6, leading to mitochondrial metabolic reprogramming and thus acquired an N2 phenotype. These N2 neutrophils, polarized by HucMSC-Exo, boosted the release of proangiogenic factors, particularly BV8, a myeloid cell-derived proangiogenic factor, and induced angiogenesis thereby favoring tissue restoration. Conclusion: This research uniquely demonstrates the identification of N2 neutrophils in skin injury and shows that HucMSC-Exo could skew neutrophils toward N2 phenotype, enhancing our insight into how cells react to HucMSC-Exo.


Subject(s)
Diabetes Mellitus , Exosomes , Mesenchymal Stem Cells , Mice , Humans , Animals , Neutrophils , Angiogenesis , Wound Healing , Mesenchymal Stem Cells/metabolism , Diabetes Mellitus/metabolism , Exosomes/metabolism , Umbilical Cord
20.
Aging (Albany NY) ; 16(8): 7009-7021, 2024 Apr 17.
Article in English | MEDLINE | ID: mdl-38637117

ABSTRACT

BACKGROUND: Reduced numbers and dysfunction of thymic epithelial cells (TECs) are important factors of thymic degeneration. Previous studies have found that umbilical cord mesenchymal stem cells (UCMSCs) reverse the structure and function of the senescent thymus in vivo. However, the transcriptomic regulation mechanism is unclear. METHODS: TECs were cultured with H2O2 for 72 hours to induce senescence. UCMSCs were cocultured with senescent TECs for 48 hours to detect SA-ß-gal, P16 and Ki67. The cocultured TECs were collected for lncRNA, mRNA and miRNA sequencing to establish a competitive endogenous regulatory network (ceRNA). And RT-qPCR, immunofluorescence staining, and western blot were used to identified key genes. RESULTS: Our results showed that H2O2 induced TEC aging and that UCMSCs reversed these changes. Compared with those in aged TECs, 2260 DE mRNAs, 1033 DE lncRNAs and 67 DE miRNAs were differentially expressed, and these changes were reversed by coculturing the cells with UCMSCs. Differential mRNA enrichment analysis of ceRNA regulation revealed that the PI3K-AKT pathway was a significant signaling pathway. UCMSC coculture upregulated VEGFA, which is the upstream factor of the PI3K-AKT signaling pathway, and the expression of the key proteins PI3K and AKT. Thus, the expression of the cell cycle suppressor P27, which is downstream of the PI3K-AKT signaling pathway, was downregulated, while the expression of the cell cycle regulators CDK2 and CCNE was upregulated. CONCLUSION: UCMSC coculture upregulated the expression of VEGFA, activated the PI3K-AKT signaling pathway, increased the expression of CDK2 and CCNE, decreased the expression of P27, and promoted the proliferation of TECs.


Subject(s)
Cellular Senescence , Coculture Techniques , Epithelial Cells , Gene Expression Profiling , Mesenchymal Stem Cells , MicroRNAs , Oncogene Proteins , Thymus Gland , Umbilical Cord , Mesenchymal Stem Cells/metabolism , Humans , Epithelial Cells/metabolism , Umbilical Cord/cytology , Thymus Gland/cytology , Thymus Gland/metabolism , MicroRNAs/metabolism , MicroRNAs/genetics , Cyclin-Dependent Kinase 2/metabolism , Cyclin-Dependent Kinase 2/genetics , Cyclin E/metabolism , Cyclin E/genetics , Biomarkers/metabolism , Hydrogen Peroxide/toxicity , Hydrogen Peroxide/pharmacology , Signal Transduction , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor A/genetics , Phosphatidylinositol 3-Kinases/metabolism , Cells, Cultured , Proto-Oncogene Proteins c-akt/metabolism , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Transcriptome , Cyclin-Dependent Kinase Inhibitor p27/metabolism , Cyclin-Dependent Kinase Inhibitor p27/genetics
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