Human Schwann cells exhibit long‐term cell survival, are not tumorigenic and promote repair when transplanted into the contused spinal cord

The transplantation of rodent Schwann cells (SCs) provides anatomical and functional restitution in a variety of spinal cord injury (SCI) models, supporting the recent translation of SCs to phase 1 clinical trials for human SCI. Whereas human (Hu)SCs have been examined experimentally in a complete SCI transection paradigm, to date the reported behavior of SCs when transplanted after a clinically relevant contusive SCI has been restricted to the use of rodent SCs. Here, in a xenotransplant, contusive SCI paradigm, the survival, biodistribution, proliferation and tumorgenicity as well as host responses to HuSCs, cultured according to a protocol analogous to that developed for clinical application, were investigated. HuSCs persisted within the contused nude rat spinal cord through 6 months after transplantation (longest time examined), exhibited low cell proliferation, displayed no evidence of tumorigenicity and showed a restricted biodistribution to the lesion. Neuropathological examination of the CNS revealed no adverse effects of HuSCs. Animals exhibiting higher numbers of surviving HuSCs within the lesion showed greater volumes of preserved white matter and host rat SC and astrocyte ingress as well as axon ingrowth and myelination. These results demonstrate the safety of HuSCs when employed in a clinically relevant experimental SCI paradigm. Further, signs of a potentially positive influence of HuSC transplants on host tissue pathology were observed. These findings show that HuSCs exhibit a favorable toxicity profile for up to 6 months after transplantation into the contused rat spinal cord, an important outcome for FDA consideration of their use in human clinical trials.

[1]  K. Anderson,et al.  Safety of Autologous Human Schwann Cell Transplantation in Subacute Thoracic Spinal Cord Injury. , 2017, Journal of neurotrauma.

[2]  Kim D Anderson,et al.  The Use of Autologous Schwann Cells to Supplement Sciatic Nerve Repair with a Large Gap: First in Human Experience , 2016, Cell transplantation.

[3]  J. Dutton,et al.  T cell deficiency in spinal cord injury: altered locomotor recovery and whole-genome transcriptional analysis , 2015, BMC Neuroscience.

[4]  R. Franco-Bourland,et al.  Temporal changes of spinal subarachnoid space patency after graded spinal cord injury in rats. , 2015, Injury.

[5]  D. Pearse,et al.  Permissive Schwann Cell Graft/Spinal Cord Interfaces for Axon Regeneration , 2015, Cell transplantation.

[6]  G. Raisman,et al.  Functional Regeneration of Supraspinal Connections in a Patient with Transected Spinal Cord following Transplantation of Bulbar Olfactory Ensheathing Cells with Peripheral Nerve Bridging , 2014, Cell transplantation.

[7]  Xiao-Ming Xu,et al.  Long-term survival, axonal growth-promotion, and myelination of Schwann cells grafted into contused spinal cord in adult rats , 2014, Experimental Neurology.

[8]  J. Schwab,et al.  The paradox of chronic neuroinflammation, systemic immune suppression, autoimmunity after traumatic chronic spinal cord injury , 2014, Experimental Neurology.

[9]  BissoyiA.,et al.  Targeting cryopreservation-induced cell death: a review. , 2014 .

[10]  E. Itoi,et al.  Combination of Engineered Schwann Cell Grafts to Secrete Neurotrophin and Chondroitinase Promotes Axonal Regeneration and Locomotion after Spinal Cord Injury , 2014, The Journal of Neuroscience.

[11]  Spinal Cord Injury Facts and Figures at a Glance , 2014, The journal of spinal cord medicine.

[12]  D. Pearse,et al.  Combining Neurotrophin-Transduced Schwann Cells and Rolipram to Promote Functional Recovery from Subacute Spinal Cord Injury , 2013, Cell transplantation.

[13]  Linghui Yang,et al.  OECs transplantation results in neuropathic pain associated with BDNF regulating ERK activity in rats following cord hemisection , 2013, BMC Neuroscience.

[14]  I. Weissman,et al.  Tumorigenicity as a clinical hurdle for pluripotent stem cell therapies , 2013, Nature Medicine.

[15]  U. Rutishauser,et al.  Extensive cell migration, axon regeneration, and improved function with polysialic acid‐modified Schwann cells after spinal cord injury , 2012, Glia.

[16]  M. Yekaninejad,et al.  Safety of intramedullary Schwann cell transplantation for postrehabilitation spinal cord injuries: 2-year follow-up of 33 cases. , 2011, Journal of neurosurgery. Spine.

[17]  K. Segawa,et al.  Treatment of Human Mesenchymal Stem Cells with Angiotensin Receptor Blocker Improved Efficiency of Cardiomyogenic Transdifferentiation and Improved Cardiac Function via Angiogenesis , 2011, Stem cells.

[18]  J. Kocsis,et al.  Species-specific control of cellular proliferation and the impact of large animal models for the use of olfactory ensheathing cells and Schwann cells in spinal cord repair , 2011, Experimental Neurology.

[19]  C. Murry,et al.  Developing vasculature and stroma in engineered human myocardium. , 2011, Tissue engineering. Part A.

[20]  Norman R. Saunders,et al.  Spatio-Temporal Progression of Grey and White Matter Damage Following Contusion Injury in Rat Spinal Cord , 2010, PloS one.

[21]  M. Ghosh,et al.  Suspension matrices for improved Schwann-cell survival after implantation into the injured rat spinal cord. , 2010, Journal of neurotrauma.

[22]  J. Fawcett,et al.  Schwann cell migration is integrin‐dependent and inhibited by astrocyte‐produced aggrecan , 2010, Glia.

[23]  T. Ozawa,et al.  Effect of cryopreservation on cell proliferation and immunogenicity of transplanted human heart cells. , 2010, Annals of thoracic and cardiovascular surgery : official journal of the Association of Thoracic and Cardiovascular Surgeons of Asia.

[24]  J. Fawcett,et al.  Astrocyte-Produced Ephrins Inhibit Schwann Cell Migration via VAV2 Signaling , 2010, The Journal of Neuroscience.

[25]  C. Muñoz-Quiles,et al.  Chronic Spinal Injury Repair by Olfactory Bulb Ensheathing Glia and Feasibility for Autologous Therapy , 2009, Journal of neuropathology and experimental neurology.

[26]  S. Kuroda,et al.  TRANSPLANTED BONE MARROW STROMAL CELLS PROMOTE AXONAL REGENERATION AND IMPROVE MOTOR FUNCTION IN A RAT SPINAL CORD INJURY MODEL , 2009, Neurosurgery.

[27]  V. Rahimi-Movaghar,et al.  Treatment of chronic thoracic spinal cord injury patients with autologous Schwann cell transplantation: An interim report on safety considerations and possible outcomes , 2008, Neuroscience Letters.

[28]  Charles Tator,et al.  Transplanted adult spinal cord–derived neural stem/progenitor cells promote early functional recovery after rat spinal cord injury , 2008, Neuroscience.

[29]  A. Gorio,et al.  Viability-Dependent Promoting Action of Adult Neural Precursors in Spinal Cord Injury , 2008, Molecular medicine.

[30]  M. Rubio,et al.  Adult olfactory bulbs from primates provide reliable ensheathing glia for cell therapy , 2008, Glia.

[31]  Hao Peng,et al.  Migration and distribution of bone marrow stromal cells in injured spinal cord with different transplantation techniques. , 2008, Chinese journal of traumatology = Zhonghua chuang shang za zhi.

[32]  H. Keirstead,et al.  The extent of myelin pathology differs following contusion and transection spinal cord injury. , 2007, Journal of neurotrauma.

[33]  Charles Tator,et al.  Bone marrow-derived mesenchymal stromal cells for the repair of central nervous system injury , 2007, Bone Marrow Transplantation.

[34]  Andrés Hurtado,et al.  Early necrosis and apoptosis of Schwann cells transplanted into the injured rat spinal cord , 2007, The European journal of neuroscience.

[35]  D. Pearse,et al.  Transplantation of Schwann cells and/or olfactory ensheathing glia into the contused spinal cord: Survival, migration, axon association, and functional recovery , 2007, Glia.

[36]  Tony J Collins,et al.  ImageJ for microscopy. , 2007, BioTechniques.

[37]  D. Pearse,et al.  Schwann Cell Transplantation Improves Reticulospinal Axon Growth and Forelimb Strength after Severe Cervical Spinal Cord Contusion , 2007, Cell transplantation.

[38]  S. Kurpad,et al.  Pain with no gain: Allodynia following neural stem cell transplantation in spinal cord injury , 2006, Experimental Neurology.

[39]  R. Walker,et al.  Quantification of immunohistochemistry—issues concerning methods, utility and semiquantitative assessment I , 2006, Histopathology.

[40]  R M Levenson,et al.  Quantification of immunohistochemistry—issues concerning methods, utility and semiquantitative assessment II , 2006, Histopathology.

[41]  Yaniv Ziv,et al.  Synergy between immune cells and adult neural stem/progenitor cells promotes functional recovery from spinal cord injury , 2006, Proceedings of the National Academy of Sciences.

[42]  Ján Rosocha,et al.  Transplants of Human Mesenchymal Stem Cells Improve Functional Recovery After Spinal Cord Injury in the Rat , 2006, Cellular and Molecular Neurobiology.

[43]  U. Deschl,et al.  Purification and in vitro characterization of adult canine olfactory ensheathing cells , 2006, Cell and Tissue Research.

[44]  D. Burke,et al.  Dural repair reduces connective tissue scar invasion and cystic cavity formation after acute spinal cord laceration injury in adult rats. , 2006, Journal of neurotrauma.

[45]  M. Oudega,et al.  Degenerative and spontaneous regenerative processes after spinal cord injury. , 2006, Journal of neurotrauma.

[46]  M. Fehlings,et al.  Delayed Transplantation of Adult Neural Precursor Cells Promotes Remyelination and Functional Neurological Recovery after Spinal Cord Injury , 2006, The Journal of Neuroscience.

[47]  P. Wood,et al.  Labeled Schwann cell transplantation: Cell loss, host Schwann cell replacement, and strategies to enhance survival , 2006, Glia.

[48]  D. Pearse,et al.  Survival, Integration, and Axon Growth Support of Glia Transplanted into the Chronically Contused Spinal Cord , 2005, Cell transplantation.

[49]  J. Shumsky,et al.  Axon growth and recovery of function supported by human bone marrow stromal cells in the injured spinal cord exhibit donor variations , 2005, Brain Research.

[50]  Jonas Frisén,et al.  Allodynia limits the usefulness of intraspinal neural stem cell grafts; directed differentiation improves outcome , 2005, Nature Neuroscience.

[51]  M. Frame,et al.  N-cadherin differentially determines Schwann cell and olfactory ensheathing cell adhesion and migration responses upon contact with astrocytes , 2005, Molecular and Cellular Neuroscience.

[52]  M. Oudega,et al.  Transplantation of Schwann cells and olfactory ensheathing glia after spinal cord injury: does pretreatment with methylprednisolone and interleukin-10 enhance recovery? , 2004, Journal of neurotrauma.

[53]  L. Brunnberg,et al.  [Cultivation and expansion of canine Schwann cells using reexplantation]. , 2004, Berliner und Munchener tierarztliche Wochenschrift.

[54]  M. Filbin,et al.  cAMP and Schwann cells promote axonal growth and functional recovery after spinal cord injury , 2004, Nature Medicine.

[55]  C. Ide,et al.  Bone marrow stromal cells infused into the cerebrospinal fluid promote functional recovery of the injured rat spinal cord with reduced cavity formation , 2004, Experimental Neurology.

[56]  M. Zurita,et al.  Functional recovery in chronic paraplegia after bone marrow stromal cells transplantation , 2004, Neuroreport.

[57]  Cheng He,et al.  Olfactory ensheathing cells genetically modified to secrete GDNF to promote spinal cord repair. , 2003, Brain : a journal of neurology.

[58]  H. Okano,et al.  Transplantation of in vitro‐expanded fetal neural progenitor cells results in neurogenesis and functional recovery after spinal cord contusion injury in adult rats , 2002, Journal of neuroscience research.

[59]  M. Oudega,et al.  Schwann Cell But Not Olfactory Ensheathing Glia Transplants Improve Hindlimb Locomotor Performance in the Moderately Contused Adult Rat Thoracic Spinal Cord , 2002, The Journal of Neuroscience.

[60]  K. Remes Cell therapy , 2002, Journal of the Neurological Sciences.

[61]  Scott R. Whittemore,et al.  Pluripotent Stem Cells Engrafted into the Normal or Lesioned Adult Rat Spinal Cord Are Restricted to a Glial Lineage , 2001, Experimental Neurology.

[62]  E. Wisse,et al.  Participation of CD45, NKR-P1A and ANK61 antigen in rat hepatic NK cell (pit cell)mediated target cell cytotoxicity. , 2000, World journal of gastroenterology.

[63]  O. Rutgeerts,et al.  Natural killer cell- and macrophage mediated discordant guinea pig-->rat xenograft rejection in the absence of complement, xenoantibody and T cell immunity. , 2000, Transplantation.

[64]  Chelyshev IuA,et al.  [The development, phenotypic characteristics and communications of Schwann cells]. , 2000 .

[65]  L. Noble,et al.  Vascular events after spinal cord injury: contribution to secondary pathogenesis. , 2000, Physical therapy.

[66]  G. Keilhoff,et al.  [Cultivating human Schwann cells for tissue engineering of peripheral nerves]. , 2000, Handchirurgie, Mikrochirurgie, Plastische Chirurgie.

[67]  Johannes Gerdes,et al.  The Ki‐67 protein: From the known and the unknown , 2000, Journal of cellular physiology.

[68]  Jesús Avila,et al.  Functional Recovery of Paraplegic Rats and Motor Axon Regeneration in Their Spinal Cords by Olfactory Ensheathing Glia , 2000, Neuron.

[69]  P. Aebischer,et al.  Regrowth of axons into the distal spinal cord through a Schwann‐cell‐seeded mini‐channel implanted into hemisected adult rat spinal cord , 1999, The European journal of neuroscience.

[70]  J. Guest,et al.  Influence of IN‐1 antibody and acidic FGF‐fibrin glue on the response of injured corticospinal tract axons to human Schwann cell grafts , 1997, Journal of neuroscience research.

[71]  J. Guest,et al.  The Ability of Human Schwann Cell Grafts to Promote Regeneration in the Transected Nude Rat Spinal Cord , 1997, Experimental Neurology.

[72]  M. Waer,et al.  Natural killer cell- and macrophage-mediated rejection of concordant xenografts in the absence of T and B cell responses. , 1997, Journal of immunology.

[73]  R. Bunge,et al.  Improved method for harvesting human Schwann cells from mature peripheral nerve and expansion in vitro , 1996, Glia.

[74]  P. Aebischer,et al.  A Combination of BDNF and NT-3 Promotes Supraspinal Axonal Regeneration into Schwann Cell Grafts in Adult Rat Thoracic Spinal Cord , 1995, Experimental Neurology.

[75]  M. Sliwkowski,et al.  The influence of heregulins on human Schwann cell proliferation , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[76]  N. Kleitman,et al.  Axonal regeneration into Schwann cell‐seeded guidance channels grafted into transected adult rat spinal cord , 1995, The Journal of comparative neurology.

[77]  K. Muraszko,et al.  Sources of Human Schwann Cells and the Influence of Donor Age , 1994, Experimental Neurology.

[78]  R. Bunge,et al.  Studies of Myelin Formation after Transplantation of Human Schwann Cells into the Severe Combined Immunodeficient Mouse , 1994, Experimental Neurology.

[79]  P. Aebischer,et al.  The functional characteristics of Schwann cells cultured from human peripheral nerve after transplantation into a gap within the rat sciatic nerve , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[80]  M. Bunge,et al.  Induction of axon growth into schwann cell implants grafted into lesioned adult rat spinal cord , 1991, Experimental Neurology.

[81]  A. Blight Mechanical factors in experimental spinal cord injury. , 1988, The Journal of the American Paraplegia Society.

[82]  H. Konno,et al.  Evolution of tissue damage in compressive spinal cord injury in rats. , 1987, Journal of neurosurgery.

[83]  D. Pettijohn,et al.  Redistribution of the nuclear mitotic apparatus protein (NuMA) during mitosis and nuclear assembly. Properties of purified NuMA protein. , 1986, Experimental cell research.

[84]  L. Noble,et al.  Blood-spinal cord barrier response to transection , 1983, Experimental Neurology.

[85]  B. Kruijt,et al.  The athymic nude rat. II. Immunological characteristics. , 1980, Clinical immunology and immunopathology.

[86]  J. Baust,et al.  Biobanking: The Future of Cell Preservation Strategies. , 2015, Advances in experimental medicine and biology.

[87]  S. Sarangi,et al.  Targeting cryopreservation-induced cell death: a review. , 2014, Biopreservation and biobanking.

[88]  P. Wood,et al.  Realizing the maximum potential of Schwann cells to promote recovery from spinal cord injury. , 2012, Handbook of clinical neurology.

[89]  L. Shields,et al.  Post-traumatic syringomyelia: CSF hydrodynamic changes following spinal cord injury are the driving force in the development of PTSM. , 2012, Handbook of clinical neurology.

[90]  M. Bunge,et al.  Schwann cell transplantation: a repair strategy for spinal cord injury? , 2012, Progress in brain research.

[91]  Devin L Jindrich,et al.  OEG implantation and step training enhance hindlimb-stepping ability in adult spinal transected rats. , 2008, Brain : a journal of neurology.

[92]  杜飞,et al.  Migration and distribution of bone marrow stromal cells in injured spinal cord with different transplantation techniques , 2008 .

[93]  D. Yoon,et al.  Effect of human mesenchymal stem cell transplantation combined with growth factor infusion in the repair of injured spinal cord. , 2006, Acta neurochirurgica. Supplement.

[94]  M. Oudega,et al.  Neurotrophins BDNF and NT-3 promote axonal re-entry into the distal host spinal cord through Schwann cell-seeded mini-channels. , 2001, The European journal of neuroscience.

[95]  A. Crang,et al.  Remyelination of demyelinated CNS axons by transplanted human schwann cells: the deleterious effect of contaminating fibroblasts. , 2001, Cell transplantation.

[96]  K. I. Saitkulov,et al.  [The development, phenotypic characteristics and communications of Schwann cells]. , 2000, Uspekhi fiziologicheskikh nauk.

[97]  Aqing Chen,et al.  Bridging Schwann cell transplants promote axonal regeneration from both the rostral and caudal stumps of transected adult rat spinal cord , 1997, Journal of neurocytology.

[98]  J. Rutkowski,et al.  Purification and expansion of human Schwann cells in vitro , 1995, Nature Medicine.

[99]  J. A. Gruner,et al.  A monitored contusion model of spinal cord injury in the rat. , 1992, Journal of neurotrauma.

[100]  E. Lotzová,et al.  Successful heterotransplantation of human colon cancer cells to athymic animals is related to tumor cell differentiation and growth kinetics and to host natural killer cell activity. , 1986, Invasion & metastasis.

[101]  M. Festing,et al.  The athymic nude rat. , 1979, Folia biologica.