Microenvironmental modulation in tandem with human stem cell transplantation enhances functional recovery after chronic complete spinal cord injury

Fehlings, 2018, Rho inhibitor VX-210 in acute traumatic subaxial cervical spinal cord injury: design of the SPinal cord injury rho INhibition InvestiGation (SPRING) clinical trial, J. Neurotrauma, 35, 1049, 10.1089/neu.2017.5434 Honmou, 2021, Intravenous infusion of auto serum-expanded autologous mesenchymal stem cells in spinal cord injury patients: 13 case series, Clin. Neurol. Neurosurg., 203, 10.1016/j.clineuro.2021.106565 Grossman, 2014, A prospective, multicenter, phase I matched-comparison group trial of safety, pharmacokinetics, and preliminary efficacy of riluzole in patients with traumatic spinal cord injury, J. Neurotrauma, 31, 239, 10.1089/neu.2013.2969 Curtis, 2018, A first-in-human, phase I study of neural stem cell transplantation for chronic spinal cord injury, Cell Stem Cell, 22, 941, 10.1016/j.stem.2018.05.014 Ghobrial, 2017, Human neural stem cell transplantation in chronic cervical spinal cord injury: functional outcomes at 12 Months in a phase II clinical trial, Neurosurgery, 64, 87, 10.1093/neuros/nyx242 Nagoshi, 2020, Phase I/II study of intrathecal administration of recombinant human hepatocyte growth factor in patients with acute spinal cord injury: a double-blind, randomized clinical trial of safety and efficacy, J. Neurotrauma, 37, 1752, 10.1089/neu.2019.6854 Sugai, 2021, First-in-human clinical trial of transplantation of iPSC-derived NS/PCs in subacute complete spinal cord injury: study protocol, Regen Ther., 18, 321, 10.1016/j.reth.2021.08.005 Burda, 2014, Reactive gliosis and the multicellular response to CNS damage and disease, Neuron, 81, 229, 10.1016/j.neuron.2013.12.034 Wanner, 2013, Glial scar borders are formed by newly proliferated, elongated astrocytes that interact to corral inflammatory and fibrotic cells via STAT3-dependent mechanisms after spinal cord injury, J. Neurosci., 33, 12870, 10.1523/JNEUROSCI.2121-13.2013 Dias, 2018, Reducing pericyte-derived scarring promotes recovery after spinal cord injury, Cell, 173, 153, 10.1016/j.cell.2018.02.004 Jones, 2022, Spinal cord injury elicits expression of keratan sulfate proteoglycans by macrophages, reactive microglia, and oligodendrocyte progenitors, J. Neurosci., 22, 4611, 10.1523/JNEUROSCI.22-11-04611.2002 Silver, 2004, Regeneration beyond the glial scar, Nat. Rev. Neurosci., 5, 146, 10.1038/nrn1326 Nishimura, 2013, Time-dependent changes in the microenvironment of injured spinal cord affects the therapeutic potential of neural stem cell transplantation for spinal cord injury, Mol. Brain, 6, 3, 10.1186/1756-6606-6-3 Sofroniew, 2018, Dissecting spinal cord regeneration, Nature, 557, 343, 10.1038/s41586-018-0068-4 Anderson, 2018, Required growth facilitators propel axon regeneration across complete spinal cord injury, Nature, 561, 396, 10.1038/s41586-018-0467-6 Kumamaru, 2013, Therapeutic activities of engrafted neural stem/precursor cells are not dormant in the chronically injured spinal cord, Stem Cell., 31, 1535, 10.1002/stem.1404 Keirstead, 2005, Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants remyelinate and restore locomotion after spinal cord injury, J. Neurosci., 25, 4694, 10.1523/JNEUROSCI.0311-05.2005 Karimi-Abdolrezaee, 2010, Synergistic effects of transplanted adult neural stem/progenitor cells, chondroitinase, and growth factors promote functional repair and plasticity of the chronically injured spinal cord, J. Neurosci., 30, 1657, 10.1523/JNEUROSCI.3111-09.2010 Tashiro, 2016, Functional recovery from neural stem/progenitor cell transplantation combined with treadmill training in mice with chronic spinal cord injury, Sci. Rep., 6, 10.1038/srep30898 Wang, 2011, Chondroitinase combined with rehabilitation promotes recovery of forelimb function in rats with chronic spinal cord injury, J. Neurosci., 31, 9332, 10.1523/JNEUROSCI.0983-11.2011 Liu, 2019, Different functional bio-scaffolds share similar neurological mechanism to promote locomotor recovery of canines with complete spinal cord injury, Biomaterials, 214, 10.1016/j.biomaterials.2019.119230 Ceto, 2020, Neural stem cell grafts form extensive synaptic networks that integrate with host circuits after spinal cord injury, Cell Stem Cell, 27, 430, 10.1016/j.stem.2020.07.007 Cummings, 2005, Human neural stem cells differentiate and promote locomotor recovery in spinal cord-injured mice, Proc. Natl. Acad. Sci. U. S. A., 102, 14069, 10.1073/pnas.0507063102 Okubo, 2018, Treatment with a gamma-secretase inhibitor promotes functional recovery in human iPSC- derived transplants for chronic spinal cord injury, Stem Cell Rep., 11, 1416, 10.1016/j.stemcr.2018.10.022 Ogino, 2018, Efficacy of the dual controlled release of HGF and bFGF impregnated with a collagen/gelatin scaffold, J. Surg. Res., 221, 173, 10.1016/j.jss.2017.08.051 Takemoto, 2008, Preparation of collagen/gelatin sponge scaffold for sustained release of bFGF, Tissue Eng. Part A, 14, 1629, 10.1089/ten.tea.2007.0215 Fan, 2017, A modified collagen scaffold facilitates endogenous neurogenesis for acute spinal cord injury repair, Acta Biomater., 51, 304, 10.1016/j.actbio.2017.01.009 Li, 1992, Peripheral nerve repair with collagen conduits, Clin. Mater., 9, 195, 10.1016/0267-6605(92)90100-8 Kitamura, 2019, Application of hepatocyte growth factor for acute spinal cord injury: the road from basic studies to human treatment, Int. J. Mol. Sci., 20, 10.3390/ijms20051054 Yamane, 2018, Collagen-Binding hepatocyte growth factor (HGF) alone or with a gelatin- furfurylamine hydrogel enhances functional recovery in mice after spinal cord injury, Sci. Rep., 8, 917, 10.1038/s41598-018-19316-y Umekage, 2019, Overview: an iPS cell stock at CiRA, Inflamm. Regen., 39 Kawasaki, 2018, Growth cone phosphoproteomics reveals that GAP-43 phosphorylated by JNK is a marker of axon growth and regeneration, iScience, 29, 190, 10.1016/j.isci.2018.05.019 Sakakibara, 1996, Mouse-Musashi-1, a neural RNA-binding protein highly enriched in the mammalian CNS stem cell, Dev. Biol., 176, 230, 10.1006/dbio.1996.0130 Basso, 1995, A sensitive and reliable locomotor rating scale for open field testing in rats, J. Neurotrauma, 12, 1, 10.1089/neu.1995.12.1 Shibata, 2021, Treadmill training based on the overload principle promotes locomotor recovery in a mouse model of chronic spinal cord injury, Exp. Neurol., 345, 10.1016/j.expneurol.2021.113834 Kamata, 2021, A robust culture system to generate neural progenitors with gliogenic competence from clinically relevant induced pluripotent stem cells for treatment of spinal cord injury, Stem. Cells Transl. Med., 10, 398, 10.1002/sctm.20-0269 Nori, 2011, Grafted human-induced pluripotent stem-cell-derived neurospheres promote motor functional recovery after spinal cord injury in mice, Proc. Natl. Acad. Sci. U. S. A., 108, 16825, 10.1073/pnas.1108077108 Asboth, 2018, Cortico-reticulo-spinal circuit reorganization enables functional recovery after severe spinal cord contusion, Nat. Neurosci., 21, 576, 10.1038/s41593-018-0093-5 Kitagawa, 2022, Modulation by DREADD reveals the therapeutic effect of human iPSC-derived neuronal activity on functional recovery after spinal cord injury, Stem Cell Rep., 17, 127, 10.1016/j.stemcr.2021.12.005 Shibata, 2019, Large-area fluorescence and electron microscopic correlative imaging with multibeam scanning electron microscopy, Front. Neural Circ., 13, 29, 10.3389/fncir.2019.00029 Kajikawa, 2020, Cell therapy for spinal cord injury by using human iPSC-derived region-specific neural progenitor cells, Mol. Brain, 13, 120, 10.1186/s13041-020-00662-w Li, 2020, Microglia-organized scar-free spinal cord repair in neonatal mice, Nature, 587, 613, 10.1038/s41586-020-2795-6 Ransohoff, 2016, A polarizing question: do M1 and M2 microglia exist?, Nat. Neurosci., 19, 987, 10.1038/nn.4338 Orr, 2018, Spinal cord injury scarring and inflammation: therapies targeting glial and inflammatory responses, Neurotherapeutics, 15, 541, 10.1007/s13311-018-0631-6 Kigerl, 2009, Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord, J. Neurosci., 29, 13435, 10.1523/JNEUROSCI.3257-09.2009 Hammond, 2019, Single-cell RNA sequencing of microglia throughout the mouse lifespan and in the injured brain reveals complex cell-state changes, Immunity, 50, 253, 10.1016/j.immuni.2018.11.004 Li, 2019, Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing, Neuron, 101, 207, 10.1016/j.neuron.2018.12.006 Jeong, 2012, Hepatocyte growth factor reduces astrocytic scar formation and promotes axonal growth beyond glial scars after spinal cord injury, Exp. Neurol., 233, 312, 10.1016/j.expneurol.2011.10.021 Nakamura, 2010, The discovery of hepatocyte growth factor (HGF) and its significance for cell biology, life sciences and clinical medicine, Proc. Jpn. Acad. Ser. B Phys. Biol. Sci., 86, 588, 10.2183/pjab.86.588 Song, 2019, TGF-Beta secretion by M2 macrophages induces glial scar formation by activating astrocytes in vitro, J. Mol. Neurosci., 69, 324, 10.1007/s12031-019-01361-5 Liu, 2011, Experimental investigation of HGF inhibiting glial scar in vitro, Cell. Mol. Neurobiol., 31, 259, 10.1007/s10571-010-9616-7 Mizuno, 2005, HGF reduces advancing lung fibrosis in mice: a potential role for MMP- dependent myofibroblast apoptosis, Faseb. J., 19, 580, 10.1096/fj.04-1535fje Yaekashiwa, 1997, Simultaneous or delayed administration of hepatocyte growth factor equally represses the fibrotic changes in murine lung injury induced by bleomycin, A morphologic study, Am. J. Respir. Crit. Care Med., 156, 1937, 10.1164/ajrccm.156.6.9611057 Göritz, 2011, A pericyte origin of spinal cord scar tissue, Science333, 6039, 238, 10.1126/science.1203165 Shibahara, 2020, Pericyte-mediated tissue repair through PDGFRbeta promotes peri-infarct astrogliosis, oligodendrogenesis, and functional recovery after acute ischemic stroke, eNeuro, 7, 10.1523/ENEURO.0474-19.2020 Riew, 2018, PDGFR-β-Positive perivascular adventitial cells expressing nestin contribute to fibrotic scar formation in the striatum of 3-NP intoxicated rats, Front. Mol. Neurosci., 11, 402, 10.3389/fnmol.2018.00402 Barnabé-Heider, 2008, Stem cells for spinal cord repair, Cell Stem Cell, 3, 16, 10.1016/j.stem.2008.06.011 Gevaert, 2007, Deletion of the transient receptor potential cation channel TRPV4 impairs murine bladder voiding, J. Clin. Invest., 117, 3453, 10.1172/JCI31766 Assinck, 2020, Transplantation of skin precursor-derived Schwann cells yields better locomotor outcomes and reduces bladder pathology in rats with chronic spinal cord injury, Stem Cell Rep., 15, 140, 10.1016/j.stemcr.2020.05.017 Fandel, 2016, Transplanted human stem cell-derived interneuron precursors mitigate mouse bladder dysfunction and central neuropathic pain after spinal cord injury, Cell Stem Cell, 19, 544, 10.1016/j.stem.2016.08.020 Wognum, 2009, An exploratory pathways analysis of temporal changes induced by spinal cord injury in the rat bladder wall: insights on remodeling and inflammation, PLoS One, 4, 10.1371/journal.pone.0005852 Foditsch, 2017, Structural changes of the urinary bladder after chronic complete spinal cord injury in minipigs, Int. Neurourol. J., 21, 12, 10.5213/inj.1732666.333 Okubo, 2016, Pretreatment with a gamma-secretase inhibitor prevents tumor-like overgrowth in human iPSC-derived transplants for spinal cord injury, Stem Cell Rep., 7, 649, 10.1016/j.stemcr.2016.08.015 Potas, 2006, Augmented locomotor recovery after spinal cord injury in the athymic nude rat, J. Neurotrauma, 23, 660, 10.1089/neu.2006.23.660