{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T09:19:34Z","timestamp":1788599974117,"version":"build-2803163510"},"reference-count":48,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2024,12,13]],"date-time":"2024-12-13T00:00:00Z","timestamp":1734048000000},"content-version":"vor","delay-in-days":12,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82371383"],"award-info":[{"award-number":["82371383"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CNS Neurosci Ther"],"published-print":{"date-parts":[[2024,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>In 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\u2010MSC) sheets in this model. Furthermore, the mechanisms underlying the vascular repair effect of hUC\u2010MSC sheets following SCI were investigated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A temperature\u2010responsive cell culture method was employed for the preparation of hUC\u2010MSC sheets. The extracellular matrix (ECM) produced by hUC\u2010MSCs 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&amp;E) staining method. Subsequently, endothelial cells were cultivated with the conditioned medium (CM) obtained from hUC\u2010MSCs or hUC\u2010MSC sheets. The pro\u2010angiogenic impact of the conditioned medium of hUC\u2010MSCs (MSC\u2010CM) and the conditioned medium of hUC\u2010MSC sheets (CS\u2010CM) was evaluated through the utilization of the CCK\u20108 assay, endothelial wound healing assay, and tube formation assay in an in\u00a0vitro context. The development of glial scars, blood vessels, neurons, and axons in hUC\u2010MSCs and hUC\u2010MSC sheets was assessed through immunofluorescence staining.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In comparison to hUC\u2010MSCs, hUC\u2010MSC 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\u2010angiogenic growth factors. During the course of the experiment, it was observed that the secretion of uPAR was the most pronounced among the pro\u2010angiogenic factors present in MSC\u2010CM and CS\u2010CM. This finding was subsequently corroborated in subsequent experiments, wherein uPAR was demonstrated to promote angiogenesis via the PI3K\/Akt signaling pathway.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The creation of cell sheets not only significantly enhances the biological function of hUC\u2010MSCs but also effectively retains the cells locally in spinal cord injury. Therefore, the transplantation of hUC\u2010MSC sheets can maximize the function of hUC\u2010MSCs, greatly reducing glial scar formation, enhancing vascular formation, and promoting the regeneration of neurons and axons. Additionally, the research findings prove that hUC\u2010MSC sheets activate the PI3K\/Akt signaling pathway through uPAR secretion to enhance angiogenesis. The transfer of the entire extracellular matrix by hUC\u2010MSC sheets, in the absence of the introduction of additional exogenous or synthetic biomaterials, serves to further augment their potential for clinical application.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cns.70163","type":"journal-article","created":{"date-parts":[[2024,12,13]],"date-time":"2024-12-13T12:06:32Z","timestamp":1734091592000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Cell Sheets Formation Enhances Therapeutic Effects of Human Umbilical Cord Mesenchymal Stem Cells on Spinal Cord Injury"],"prefix":"10.1111","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4311-3801","authenticated-orcid":false,"given":"Yulin","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Spine Surgery Affiliated Hospital of Nantong University  Nantong China"},{"name":"Medical School of Nantong University  Nantong 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