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The Efficacy of Transplanting Human Umbilical Cord Mesenchymal Stem Cell Sheets in the Treatment of Myocardial Infarction in Mice.

ABSTRACT: The transplantation of mesenchymal stem cell (MSC) sheets derived from human umbilical cords (hUCs) was investigated in this study as a potential application in treating myocardial infarction (MI). Two groups of hUC-MSC sheets were formed by populating LunaGel^TM, which are 3D scaffolds of photo-crosslinkable gelatin-based hydrogel with two different cell densities. An MI model was created by ligating the left anterior descending coronary artery of healthy BALB/c mice. After two weeks, the cell sheets were applied directly to the MI area and the efficacy of the treatment was evaluated over the next two weeks by monitoring the mice's weight, evaluating the left ventricle ejection fraction, and assessing the histology of the heart tissue at the end of the experiment. Higher cell density showed significantly greater efficiency in MI mice treatment in terms of weight gain and the recovery of ejection fraction. The heart tissue of the groups receiving cell sheets showed human-CD44-positive staining and reduced fibrosis and apoptosis. In conclusion, the hUC-MSC sheets ameliorated heart MI injury in mice and the efficacy of the cell sheets improved as the number of cells increased.

SUBMITTER: Bui TQ

PROVIDER: S-EPMC10452263 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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The Efficacy of Transplanting Human Umbilical Cord Mesenchymal Stem Cell Sheets in the Treatment of Myocardial Infarction in Mice.

Bui Thang Quoc TQ Binh Nguyen Trong NT Pham Truc Le-Buu TL Le Van Trinh T Truong Nhung Hai NH Nguyen Dang Phu-Hai DP Luu Thao Thi-Thu TT Nguyen-Xuan Pham Trang T Cam Tran Tu T Nguyen Huyen Thuong-Thi HT Thuy-Trinh Nhu N Tran Phong Anh PA

Biomedicines 20230803 8

The transplantation of mesenchymal stem cell (MSC) sheets derived from human umbilical cords (hUCs) was investigated in this study as a potential application in treating myocardial infarction (MI). Two groups of hUC-MSC sheets were formed by populating LunaGel<sup>TM</sup>, which are 3D scaffolds of photo-crosslinkable gelatin-based hydrogel with two different cell densities. An MI model was created by ligating the left anterior descending coronary artery of healthy BALB/c mice. After two weeks, ...[more]

PMID: 37626684

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Project description:Objectives:Osteoarthritis (OA) is a chronic disease of degenerative joints. Mesenchymal stem cells (MSCs) have been used for cartilage regeneration in OA. We investigated the therapeutic potential of human umbilical cord-derived MSCs (HUCMSCs) with hyaluronic acid (HA) hydrogel transplanted into a porcine OA preclinical model. Materials and Methods:The HUCMSCs were characterized with respect to morphology, surface markers, and differentiation capabilities. Quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) was used to examine gene expressions in a HUCMSC-HA coculture. Two healthy female minipigs weighing 30-40 kg and aged approximately 4 months were used in this large animal study. A full-thickness chondral injury was created in the trochlear groove of each of the pig's rear knees. After 3 weeks, a second osteochondral defect was created. Then, 1.5 mL of a HUCMSC (5 × 106 cells) and HA composite (4%) was transplanted into the chondral-injured area in the right knee of each pig. Using the same surgical process, an osteochondral defect (untreated) was created in the left knee as a control. The pigs were sacrificed 12 weeks after transplantation. Macroscopic and microscopic histologies, qRT-PCR, and immunostaining evaluated the degree of chondral degradation. Results:The HUCMSCs exhibited typical MSC characteristics, including spindle morphology, expression of surface markers (positive for CD29, CD4, CD73, CD90, and human leukocyte antigen [HLA]-ABC; negative for CD34, CD45, and HLA-DR), and multipotent differentiation (adipogenesis, osteogenesis, and chondrogenesis). More extensive proliferation of HUCMSCs was noted with 4% and 25% of HA than without HA. Expression of COL2A1 and aggrecan in the HUCMSC-derived chondrocytes was increased when HA was included. The treated knees showed significant gross and histological improvements in hyaline cartilage regeneration when compared to the control knees. The International Cartilage Repair Society histological score was higher for the treated knees than the control knees. Conclusion:Our findings suggest that cartilage regeneration using a mixture of HUCMSCs and HA in a large animal model may be an effective treatment for OA, and this study is a stepping stone toward the future clinical trials.

Project description:BackgroundIn recent years, the utilization of stem cell therapy and cell sheet technology has emerged as a promising approach for addressing spinal cord injury (SCI). However, the most appropriate cell type and mechanism of action remain unclear at this time. This study sought to develop an SCI rat model and evaluate the therapeutic effects of human umbilical cord mesenchymal stem cell (hUC-MSC) sheets in this model. Furthermore, the mechanisms underlying the vascular repair effect of hUC-MSC sheets following SCI were investigated.MethodsA temperature-responsive cell culture method was employed for the preparation of hUC-MSC sheets. The extracellular matrix (ECM) produced by hUC-MSCs serves two distinct yet interrelated purposes. Firstly, it acts as a biologically active scaffold for transplanted cells, facilitating their attachment and proliferation. Secondly, it provides mechanical support and bridges spinal cord stumps, thereby facilitating the restoration of spinal cord function. The formation of the cavity within the spinal cord was evaluated using the Hematoxylin and Eosin (H&E) staining method. Subsequently, endothelial cells were cultivated with the conditioned medium (CM) obtained from hUC-MSCs or hUC-MSC sheets. The pro-angiogenic impact of the conditioned medium of hUC-MSCs (MSC-CM) and the conditioned medium of hUC-MSC sheets (CS-CM) was evaluated through the utilization of the CCK-8 assay, endothelial wound healing assay, and tube formation assay in an in vitro context. The development of glial scars, blood vessels, neurons, and axons in hUC-MSCs and hUC-MSC sheets was assessed through immunofluorescence staining.ResultsIn comparison to hUC-MSCs, hUC-MSC sheets demonstrated a more pronounced capacity to facilitate vascular formation and induce the regeneration of newborn neurons at the SCI site, while also reducing glial scar formation and significantly enhancing motor function in SCI rats. Notably, under identical conditions, the formation of cell sheets has been associated with a paracrine increase in the ability of the cells themselves to secrete pro-angiogenic growth factors. During the course of the experiment, it was observed that the secretion of uPAR was the most pronounced among the pro-angiogenic factors present in MSC-CM and CS-CM. This finding was subsequently corroborated in subsequent experiments, wherein uPAR was demonstrated to promote angiogenesis via the PI3K/Akt signaling pathway.ConclusionThe creation of cell sheets not only significantly enhances the biological function of hUC-MSCs but also effectively retains the cells locally in spinal cord injury. Therefore, the transplantation of hUC-MSC sheets can maximize the function of hUC-MSCs, greatly reducing glial scar formation, enhancing vascular formation, and promoting the regeneration of neurons and axons. Additionally, the research findings prove that hUC-MSC sheets activate the PI3K/Akt signaling pathway through uPAR secretion to enhance angiogenesis. The transfer of the entire extracellular matrix by hUC-MSC sheets, in the absence of the introduction of additional exogenous or synthetic biomaterials, serves to further augment their potential for clinical application.

Project description:Stem cell-based therapy has been used to treat ischaemic heart diseases for two decades. However, optimal cell types and transplantation methods remain unclear. This study evaluated the therapeutic effects of human umbilical cord mesenchymal stem cell (hUCMSC) sheet on myocardial infarction (MI).MethodshUCMSCs expressing luciferase were generated by lentiviral transduction for in vivo bio-luminescent imaging tracking of cells. We applied a temperature-responsive cell culture surface-based method to form the hUCMSC sheet. Cell retention was evaluated using an in vivo bio-luminescent imaging tracking system. Unbiased transcriptional profiling of infarcted hearts and further immunohistochemical assessment of monocyte and macrophage subtypes were used to determine the mechanisms underlying the therapeutic effects of the hUCMSC sheet. Echocardiography and pathological analyses of heart sections were performed to evaluate cardiac function, angiogenesis and left ventricular remodelling.ResultsWhen transplanted to the infarcted mouse hearts, hUCMSC sheet significantly improved the retention and survival compared with cell suspension. At the early stage of MI, hUCMSC sheet modulated inflammation by decreasing Mcp1-positive monocytes and CD68-positive macrophages and increasing Cx3cr1-positive non-classical macrophages, preserving the cardiomyocytes from acute injury. Moreover, the extracellular matrix produced by hUCMSC sheet then served as bioactive scaffold for the host cells to graft and generate new epicardial tissue, providing mechanical support and routes for revascularsation. These effects of hUCMSC sheet treatment significantly improved the cardiac function at days 7 and 28 post-MI.ConclusionshUCMSC sheet formation dramatically improved the biological functions of hUCMSCs, mitigating adverse post-MI remodelling by modulating the inflammatory response and providing bioactive scaffold upon transplantation into the heart.Translational perspectiveDue to its excellent availability as well as superior local cellular retention and survival, allogenic transplantation of hUCMSC sheets can more effectively acquire the biological functions of hUCMSCs, such as modulating inflammation and enhancing angiogenesis. Moreover, the hUCMSC sheet method allows the transfer of an intact extracellular matrix without introducing exogenous or synthetic biomaterial, further improving its clinical applicability.

Project description:Background Human umbilical cord mesenchymal stem cells (hUC-MSCs) have been widely used due to their multipotency, a broad range of sources, painless collection, and compliance with standard amplification. Cell sheet technology is a tissue engineering methodology requiring scaffolds free, and it provides an effective method for cell transplantation. To improve the therapeutic efficacy, we combined hUC-MSCs with cell sheet technology to evaluate the safety and efficacy of hUC-MSC sheets in preclinical studies using appropriate animal models. Methods hUC-MSC sheets were fabricated by hUC-MSCs from a cell bank established by a standard operation process and quality control. Cytokine secretion, immunoregulation, and angiopoiesis were evaluated in vitro. Oncogenicity and cell diffusion assays of hUC-MSC sheets were conducted to verify the safety of hUC-MSCs sheet transplantation in mice. To provide more meaningful animal experimental data for clinical trials, porcine myocardial infarction (MI) models were established by constriction of the left circumflex, and hUC-MSC sheets were transplanted onto the ischemic area of the heart tissue. Cardiac function was evaluated and compared between the experimental and MI groups. Results The in vitro results showed that hUC-MSC sheets could secrete multiple cellular factors, including VEGF, HGF, IL-6, and IL-8. Peripheral blood mononuclear cells had a lower proliferation rate and lower TNF-α secretion when co-cultured with hUC-MSC sheets. TH1 cells had a smaller proportion after activation. In vivo safety results showed that the hUC-MSCs sheet had no oncogenicity and was mainly distributed on the surface of the ischemic myocardial tissue. Echocardiography showed that hUC-MSC sheets effectively improved the left ventricular ejection fraction (LVEF), and the LVEF significantly changed (42.25 ± 1.23% vs. 66.9 ± 1.10%) in the hUC-MSC transplantation group compared with the MI group (42.52 ± 0.65% vs. 39.55 ± 1.97%) at 9 weeks. The infarct ratio of the hUC-MSCs sheet transplantation groups was also significantly reduced (14.2 ± 4.53% vs. 4.00 ± 2.00%) compared with that of the MI group. Conclusion Allogeneic source and cell bank established by the standard operation process and quality control make hUC-MSCs sheet possible to treat MI by off-the-shelf drug with universal quality instead of individualized medical technology. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-02919-8.

Project description:BackgroundMesenchymal stem cells (MSCs) possess powerful immunomodulatory ability. This study aimed to assess the efficacy and safety of human umbilical cord-derived mesenchymal stem cells (UMSCs) in patients with ulcerative colitis (UC) and to explore the potential mechanisms.MethodsThis prospective, self-controlled clinical study was conducted at Henan Provincial People's Hospital. Patients with moderate-to-severe active UC, unresponsive to traditional drugs were continuously enrolled from September 2018 to March 2023. UMSCs were administered intravenously monthly for two months at a cell dosage of 1 × 106 per kg. The primary outcome was a clinical response at 2 months. The levels of cytokines and progerin in the plasma of the patients were analyzed using enzyme-linked immunosorbent assay kits, and longitudinal data was analyzed using generalized estimation equation.ResultsForty-one patients were enrolled and received UMSC therapy. At 2 months, 73.2% (30/41) of patients achieved a clinical response, and 41.5% (17/41) achieved a clinical remission. At 6 months, 2 patients were lost to follow-up; the corresponding figures were 70.0% (25/41) and 34.2% (14/41), respectively. After UMSC therapy, the Mayo score, Mayo endoscopy score, mean and maximum values of Ulcerative Colitis Endoscopic Index of Severity and Nancy index were significantly reduced compared with baseline values. Additionally, the levels of progerin and inflammatory markers, such as interleukin (IL)-1β, IL-6, IL-8, IL-12, and IL-17 A decreased, while hemoglobin, albumin, and IL-10/IL-17 A ratio increased, particularly in the response group. Multiple stepwise logistic regression analysis showed age was an independent risk factor affecting efficacy (odds ratio, 0.875 (95% confidence interval (0.787, 0.972)); the area under the receiver operating characteristic curve for age was 0.79. No serious adverse events were observed during or after UMSC therapy.ConclusionUMSCs are safe and effective for patients with UC, with age being an independent risk factor affecting efficacy. Mechanistically, UMSC treatment may ameliorate cell senescence and suppress the secretion of pro-inflammatory cytokines.Trial registrationThe study was retrospectively registered at www.chictr.org.cn/ (ChiCTR1900026035) on September 18, 2019.

Dataset Information

The Efficacy of Transplanting Human Umbilical Cord Mesenchymal Stem Cell Sheets in the Treatment of Myocardial Infarction in Mice.

Publications

The Efficacy of Transplanting Human Umbilical Cord Mesenchymal Stem Cell Sheets in the Treatment of Myocardial Infarction in Mice.

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