97b477405e074709bee7cb578cf989c7 pmc_34073117.pdf 649e3e87b3b2f9b9a82a1f47689d1b1cefe520d5 pmc_34073117.pdf 977798c4a99fc852f84f2eb8c77f816980308333a53fd6086ebd7f5c09fad622 pmc_34073117.pdf Title: Human-Induced Neural and Mesenchymal Stem Cell Therapy Combined with a Curcumin Nanoconjugate as a Spinal Cord Injury Treatment Subject: We currently lack effective treatments for the devastating loss of neural function associated with spinal cord injury (SCI). In this study, we evaluated a combination therapy comprising human neural stem cells derived from induced pluripotent stem cells (iPSC-NSC), human mesenchymal stem cells (MSC), and a pH-responsive polyacetal–curcumin nanoconjugate (PA-C) that allows the sustained release of curcumin. In vitro analysis demonstrated that PA-C treatment protected iPSC-NSC from oxidative damage in vitro, while MSC co-culture prevented lipopolysaccharide-induced activation of nuclear factor-B (NF-B) in iPSC-NSC. Then, we evaluated the combination of PA-C delivery into the intrathecal space in a rat model of contusive SCI with stem cell transplantation. While we failed to observe significant improvements in locomotor function (BBB scale) in treated animals, histological analysis revealed that PA-C-treated or PA-C and iPSC-NSC + MSC-treated animals displayed significantly smaller scars, while PA-C and iPSC-NSC + MSC treatment induced the preservation of -III Tubulin-positive axons. iPSC-NSC + MSC transplantation fostered the preservation of motoneurons and myelinated tracts, while PA-C treatment polarized microglia into an anti-inflammatory phenotype. Overall, the combination of stem cell transplantation and PA-C treatment confers higher neuroprotective effects compared to individual treatments. Keywords: spinal cord injury; stem cells; curcumin; neuroprotection; polymer–drug conjugate Author: Pablo Bonilla, Joaquim Hernandez, Esther Giraldo, Miguel A. González-Pérez, Ana Alastrue-Agudo, Hoda Elkhenany, María J. Vicent, Xavier Navarro, Michael Edel and Victoria Moreno-Manzano Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Tue Jun 1 12:34:32 2021 CEST ModDate: Tue Jun 1 12:48:33 2021 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 25 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 5991133 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- IEFSKB+VnURWPalladioL Type 1 Custom yes yes no 10 0 QPZFHW+EURM10 Type 1 Builtin yes yes no 15 0 DFKHDH+URWPalladioL-Ital Type 1 Custom yes yes no 19 0 EPDEFT+URWPalladioL-Bold Type 1 Custom yes yes no 24 0 WZGGRA+URWPalladioL-Roma Type 1 Custom yes yes no 28 0 IOJCNK+VnURWPalladioL-Bold Type 1 Custom yes yes no 32 0 IRWHZX+TimesNewRomanPSMT Type 1C WinAnsi yes yes no 40 0 CKUPDE+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 43 0 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DCJEPN+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 290 0 MPUDFL+PazoMath Type 1 Builtin yes yes no 310 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2023-05-27 02:44:09 CEST RepresentationInformation: pmc_34073117.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2023-03-31 12:14:05 CEST Size: 5991133 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 648 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@44c8afef Item: Title: Results Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Children: Item: Title: Cultured iPSC-NSC Express Neuronal, Astroglial, and Oligodendrocyte-Specific Lineage Markers Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Item: Title: PA-C Treatment Increases iPSC-NSC Viability, Enhances Neurite Elongation, but Fails to Induce Neural and Glial Differentiation Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: PA-C Protects iPSC-NSC against Hydrogen Peroxide-Induced Toxicity Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: PA-C Treatment and MSC Prevent NF-B Translocation to the Nucleus of LPS-Treated iPSC-NSC Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: Functional Locomotor Recovery after SCI in Response to Individual Treatments and Combination Therapies Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: PA-C and PA-C Combined with iPSC-NSC + MSC Transplantation Preserve -III-Tubulin Positive Fibers, Limit Inhibitory Scar Size, and Increase Functional Synapse Number after SCI Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: PA-C Combined with iPSC-NSC + MSC Transplantation Induces White Matter Sparing after SCI Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Item: Title: PA-C and PA-C Combined with iPSC-NSC + MSC Transplantation Promotes Microglia Polarization toward an Anti-Inflammatory Profile Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: Discussion Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: Materials and Methods Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Children: Item: Title: Human iPSC-NSC and MSC Culture Conditions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Item: Title: Analysis of Cell Viability, Differentiation, and Neurite Outgrowth in iPSC-NSC Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@a38d7a3 Item: Title: NF-B Activation Assay in iPSC-NSC + MSC Co-Cultures Treated with PA-C Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77f99a05 Item: Title: Immunocytochemistry Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@63440df3 Item: Title: RNA Extraction, cDNA Synthesis, and RT2 Profiler PCR Human Neurogenesis Array Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@3aeaafa6 Item: Title: Contusive Spinal Cord Injury, Cell Transplantation, and PA-C Delivery In Vivo Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@76a3e297 Item: Title: Functional In Vivo Locomotion Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4d3167f4 Item: Title: Histological Studies of Spinal Cords Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@ed9d034 Item: Title: Ethical Statement Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@6121c9d6 Item: Title: Statistical Analyses Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@87f383f Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4eb7f003 Info: Title: Human-Induced Neural and Mesenchymal Stem Cell Therapy Combined with a Curcumin Nanoconjugate as a Spinal Cord Injury Treatment Author: Pablo Bonilla, Joaquim Hernandez, Esther Giraldo, Miguel A. González-Pérez, Ana Alastrue-Agudo, Hoda Elkhenany, María J. Vicent, Xavier Navarro, Michael Edel and Victoria Moreno-Manzano Subject: We currently lack effective treatments for the devastating loss of neural function associated with spinal cord injury (SCI). In this study, we evaluated a combination therapy comprising human neural stem cells derived from induced pluripotent stem cells (iPSC-NSC), human mesenchymal stem cells (MSC), and a pH-responsive polyacetal curcumin nanoconjugate (PA-C) that allows the sustained release of curcumin. In vitro analysis demonstrated that PA-C treatment protected iPSC-NSC from oxidative damage in vitro, while MSC co-culture prevented lipopolysaccharide-induced activation of nuclear factor-B (NF-B) in iPSC-NSC. Then, we evaluated the combination of PA-C delivery into the intrathecal space in a rat model of contusive SCI with stem cell transplantation. While we failed to observe significant improvements in locomotor function (BBB scale) in treated animals, histological analysis revealed that PA-C-treated or PA-C and iPSC-NSC + MSC-treated animals displayed significantly smaller scars, while PA-C and iPSC-NSC + MSC treatment induced the preservation of -III Tubulin-positive axons. iPSC-NSC + MSC transplantation fostered the preservation of motoneurons and myelinated tracts, while PA-C treatment polarized microglia into an anti-inflammatory phenotype. Overall, the combination of stem cell transplantation and PA-C treatment confers higher neuroprotective effects compared to individual treatments. 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