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  • 1.
    Glavaski-Joksimovic, A.
    et al.
    Karolinska University Hospital, Stockholm, Sweden.
    Thonabulsombat, C.
    Karolinska University Hospital, Stockholm, Sweden.
    Wendt, M.
    Karolinska University Hospital, Stockholm, Sweden.
    Eriksson, M.
    Karolinska University Hospital, Stockholm, Sweden.
    Ma, H.
    Karolinska University Hospital, Stockholm, Sweden.
    Olivius, Petri
    Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
    Morphological differentiation of tau–green fluorescent protein embryonic stem cells into neurons after co-culture with auditory brain stem slices2009In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 162, no 2, p. 472-481Article in journal (Refereed)
    Abstract [en]

    Most types of congenital and acquired hearing loss are caused by loss of sensory hair cells in the inner ear and their respective afferent neurons. Replacement of spiral ganglion neurons (SGN) would therefore be one prioritized step in an attempt to restore sensory neuronal hearing loss. To initiate an SGN repair paradigm we previously transplanted embryonic neuronal tissue and stem cells (SC) into the inner ear in vivo. The results illustrated good survival of the implant. One such repair, however, would not have any clinical significance unless central connections from the implanted SIGN could be established. For the purpose of evaluating the effects of cell transplantation on cochlear nucleus (CN) neurons we have established organotypic brain stem (BS) cultures containing the CN. At present we have used in vitro techniques to study the survival and differentiation of tau-green fluorescent protein (GFP) mouse embryonic stem cells (MESC) as a mono- or co-culture with BS slices. For the co-culture, 300 mu m thick auditory BS slices encompassing the CN were prepared from postnatal Sprague-Dawley rats. The slices were propagated using the membrane interface method and the CN neurons labeled with Dil. After 5 +/- 2 days in culture a tau-GFP MESC suspension was deposited next to CN in the BS slice. Following deposition the MESC migrated towards the CN. One and two weeks after transplantation the co-cultures were fixed and immunostained with antibodies raised against neuroprogenitor, neuronal, glial and synaptic vesicle protein markers. Our experiments with the tau-GFP MESC and auditory BS co-cultures show a significant MESC survival but also differentiation into neuronal cells. The findings illustrate the significance of SC and auditory BS co-cultures regarding survival, migration, neuronal differentiation and connections.

  • 2.
    Glavaski-Joksimovic, Aleksandra
    et al.
    Karolinska University Hospital, Stockholm, Sweden.
    Thonabulsombat, Charoensri
    Karolinska University Hospital, Stockholm, Sweden.
    Wendt, Malin
    Karolinska University Hospital, Stockholm, Sweden.
    Eriksson, Mikael
    Karolinska University Hospital, Stockholm, Sweden.
    Palmgren, Björn
    Karolinska University Hospital, Stockholm, Sweden.
    Jonsson, Anna
    Karolinska University Hospital, Stockholm, Sweden.
    Olivius, Petri
    Karolinska University Hospital, Stockholm, Sweden.
    Survival, migration, and differentiation of Sox1-GFP embryonic stem cells in coculture with an auditory brainstem slice preparation2008In: Cloning and Stem Cells, ISSN 1536-2302, E-ISSN 1557-7457, Vol. 10, no 1, p. 75-87Article in journal (Refereed)
    Abstract [en]

    The poor regeneration capability of the mammalian hearing organ has initiated different approaches to enhance its functionality after injury. To evaluate a potential neuronal repair paradigm in the inner ear and cochlear nerve we have previously used embryonic neuronal tissue and stem cells for implantation in vivo and in vitro. At present, we have used in vitro techniques to study the survival and differentiation of Sox1-green fluorescent protein (GFP) mouse embryonic stem (ES) cells as a monoculture or as a coculture with rat auditory brainstem slices. For the coculture, 300 mu m-thick brainstem slices encompassing the cochlear nucleus and cochlear nerve were prepared from postnatal SD rats. The. slices were propagated using the membrane interface method and the cochlear nuclei were prelabeled with DiI. After some days in culture a suspension of Sox1 cells was deposited next to the brainstem slice. Following. deposition Sox1 cells migrated toward the brainstem and onto the cochlear nucleus. GFP was not detectable in undifferentiated ES cells but became evident during neural differentiation.. Up to 2 weeks after transplantation the cocultures were fixed. The undifferentiated cells were evaluated with antibodies against progenitor cells whereas the differentiated cells were determined with neuronal and glial markers. The morphological and immunohistochemical data indicated that Sox1 cells in monoculture differentiated into a higher percentage of glial cells than neurons. However, when a coculture was used a significantly lower percentage of Sox1 cells differentiated into glial cells. The results demonstrate that a coculture of Sox1 cells and auditory brainstem present a useful model to study stem cell differentiation.

  • 3.
    Herlenius, E.
    et al.
    Karolinska University Hospital, Stockholm, Sweden.
    Thonabulsombat, C.
    Karolinska University Hospital, Stockholm, Sweden.
    Forsberg, D.
    Karolinska University Hospital, Stockholm, Sweden.
    Jäderstad, J.
    Karolinska University Hospital, Stockholm, Sweden.
    Jäderstad, L.M.
    Karolinska University Hospital, Stockholm, Sweden.
    Björk, L.
    Karolinska University Hospital, Stockholm, Sweden.
    Olivius, Petri
    Karolinska University Hospital, Sweden .
    Functional stem cell integration assessed by organotypic slice cultures2012In: Current Protocols in Stem Cell Biology, ISSN 1941-7322, Vol. 1, no SUPPL.23Article in journal (Refereed)
    Abstract [en]

    Re-formation or preservation of functional, electrically active neural networks has been proffered as one of the goals of stem cell-mediated neural therapeutics. A primary issue for a cell therapy approach is the formation of functional contacts between the implanted cells and the host tissue. Therefore, it is of fundamental interest to establish protocols that allow us to delineate a detailed time course of grafted stem cell survival, migration, differentiation, integration, and functional interaction with the host. One option for in vitro studies is to examine the integration of exogenous stem cells into an existing active neuronal network in ex vivo organotypic cultures. Organotypic cultures leave the structural integrity essentially intact while still allowing the microenvironment to be carefully controlled. This allows detailed studies over time of cellular responses and cellcell interactions, which are not readily performed in vivo. This unit describes procedures for using organotypic slice cultures as ex vivo model systems for studying neural stem cell and embryonic stem cell engraftment and communication with CNS host tissue.

  • 4.
    Hertegard, S.
    et al.
    Karolinska University Hospital, Huddinge, Stockholm, Sweden.
    Cedervall, J.
    Karolinska Institutet, Stockholm, Sweden.
    Svensson, B.
    Östersunds Hospital, Sweden.
    Forsberg, K.
    University of Umeå, Sweden.
    Maurer, F. H. J.
    Lund University, Sweden.
    Vidovska, D.
    Lund University, Sweden;.
    Olivius, Petri
    Karolinska University Hospital, Solna, Stockholm, Sweden.
    Ährlund-Richter, L.
    Karolinska Institutet, Stockholm, Sweden.
    Le Blanc, K.
    Karolinska University Hospital Huddinge and Karolinska Institutet, Stockholm, Sweden.
    Viscoelastic and histologic properties in scarred rabbit vocal folds after mesenchymal stem cell injection2006In: The Laryngoscope, ISSN 0023-852X, E-ISSN 1531-4995, Vol. 116, no 7, p. 1248-1254Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE/HYPOTHESIS:

    The aim of this study was to analyze the short-term viscoelastic and histologic properties of scarred rabbit vocal folds after injection of human mesenchymal stem cells (MSC) as well as the degree of MSC survival. Because MSCs are antiinflammatory and regenerate mesenchymal tissues, can MSC injection reduce vocal fold scarring after injury?

    STUDY DESIGN:

    Twelve vocal folds from 10 New Zealand rabbits were scarred by a localized resection and injected with human MSC or saline. Eight vocal folds were left as controls.

    MATERIAL AND METHODS:

    After 4 weeks, 10 larynges were stained for histology and evaluation of the lamina propria thickness. Collagen type I content was analyzed from six rabbits. MSC survival was analyzed by fluorescent in situ hybridization staining from three rabbits. Viscoelasticity for 10 vocal folds was analyzed in a parallel-plate rheometer.

    RESULTS:

    The rheometry on fresh-frozen samples showed decreased dynamic viscosity and lower elastic modulus (P<.01) in the scarred samples injected with MSC as compared with the untreated scarred group. Normal controls had lower dynamic viscosity and elastic modulus as compared with the scarred untreated and treated vocal folds (P<.01). Histologic analysis showed a higher content of collagen type 1 in the scarred samples as compared with the normal vocal folds and with the scarred folds treated with MSC. MSCs remained in all samples analyzed.

    CONCLUSIONS:

    The treated scarred vocal folds showed persistent MSC. Injection of scarred rabbit vocal folds with MSC rendered improved viscoelastic parameters and less signs of scarring expressed as collagen content in comparison to the untreated scarred vocal folds.

     

  • 5.
    Hu, Z.
    et al.
    Karolinska Institute, Stockholm, Sweden.
    Ulfendahl, M.
    Karolinska Institute, Stockholm, Sweden.
    Olivius, Petri
    Karolinska Institute/Karolinska University Hospital, Stockholm, Sweden .
    NGF stimulates extensive neurite outgrowth from implanted dorsal root ganglion neurons following transplantation into the adult rat inner ear2005In: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 18, no 1, p. 184-192Article in journal (Refereed)
    Abstract [en]

    Neuronal tissue transplantation is a potential way to replace degenerated spiral ganglion neurons (SGNs) since these cells cannot regenerate in adult mammals. To investigate whether nerve growth factor (NGF) can stimulate neurite outgrowth from implanted neurons, mouse embryonic dorsal root ganglion (DRG) cells expressing enhanced green fluorescent protein (EGFP) were transplanted into the scala tympani of adult rats with a supplement of NGF or artificial perilymph. DRG neurons were observed in the cochlea for up to 6 weeks postoperatively. A significant difference was identified in the number of DRG neurons between the NGF and non-NGF groups. In the NGF group, extensive neurite projections from DRGs were found penetrating the osseous modiolus towards the spiral ganglion. These results suggest the possibility that embryonic neuronal implants may become integrated within the adult auditory nervous system. In combination with a cochlear prosthesis, a neuronal implantation strategy may provide a possibility for further treatment of profoundly deaf patients.

  • 6.
    Hu, Zhengqing
    et al.
    Karolinska Institute, Stockholm, Sweden.
    Ulfendahl, Mats
    Karolinska Institute, Stockholm, Sweden.
    Prieskorn, Diane M.
    University of Michigan, Ann Arbor, MI, USA .
    Olivius, Petri
    Karolinska Institute/Karolinska University Hospital, Stockholm, Sweden .
    Miller, Josef M.
    University of Michigan, Ann Arbor, MI, USA .
    Functional Evaluation of a Cell Replacement Therapy in the Inner Ear2009In: Otology and Neurotology, ISSN 1531-7129, E-ISSN 1537-4505, Vol. 30, no 4, p. 551-558Article in journal (Refereed)
    Abstract [en]

    HYPOTHESIS:

    Cell replacement therapy in the inner ear will contribute to the functional recovery of hearing loss.

    BACKGROUND:

    Cell replacement therapy is a potentially powerful approach to replace degenerated or severely damaged spiral ganglion neurons. This study aimed at stimulating the neurite outgrowth of the implanted neurons and enhancing the potential therapeutic of inner ear cell implants.

    METHODS:

    Chronic electrical stimulation (CES) and exogenous neurotrophic growth factor (NGF) were applied to 46 guinea pigs transplanted with embryonic dorsal root ganglion (DRG) neurons 4 days postdeafening. The animals were evaluated with the electrically evoked auditory brainstem responses (EABRs) at experimental Days 7, 11, 17, 24, and 31. The animals were euthanized at Day 31, and the inner ears were dissected for immunohistochemistry investigation.

    RESULTS:

    Implanted DRG cells, identified by enhanced green fluorescent protein fluorescence and a neuronal marker, were found close to Rosenthal canal in the adult inner ear for up to 4 weeks after transplantation. Extensive neurite projections clearly, greater than in nontreated animals, were observed to penetrate the bony modiolus and reach the spiral ganglion region in animals supplied with CES and/or NGF. There was, however, no significant difference in the thresholds of EABRs between DRG-transplanted animals supplied with CES and/or NGF and DRG-transplanted animals without CES or NGF supplement.

    CONCLUSION:

    The results suggest that CES and/or NGF can stimulate neurite outgrowth from implanted neurons, although based on EABR measurement, these interventions did not induce functional connections to the central auditory pathway. Additional time or novel approaches may enhance functional responsiveness of implanted cells in the adult cochlea

  • 7.
    Jiao, Yu
    et al.
    Karolinska University Hospital.
    Novozhilova, Ekaterina
    Karolinska University Hospital.
    Karlen, Alexandra
    Karolinska Institute.
    Muhr, Jonas
    Karolinska Institute.
    Olivius, Petri
    Linköping University, Department of Clinical and Experimental Medicine, Neurobiology. Linköping University, Faculty of Health Sciences. Karolinska University Hospital.
    Olfactory ensheathing cells promote neurite outgrowth from co-cultured brain stem slice2011In: EXPERIMENTAL NEUROLOGY, ISSN 0014-4886, Vol. 229, no 1, p. 65-71Article in journal (Refereed)
    Abstract [en]

    Cell therapy aiming at the replacement of degenerated neurons is a very attractive approach. By using an established in vitro organotypic brain stem (BS) slice culture we screen for candidate donor cells, some of them being further functionally assessed in in vivo models of sensorineural hearing loss. Both in vitro and in vivo systems show that implanted cells face challenges of survival, targeted migration, differentiation and functional integration with the host tissue. Low success rates are possibly due to the lack of necessary neurotrophic factors, adhesion molecules and guiding cues. Olfactory ensheathing cells (OECs) have been shown to express a number of neurotrophic factors and to promote axonal growth through cell to cell interactions. In the present study we co-cultured OECs with organotypic BS slice in order to see if OECs can serve as a facilitator when screening candidate donor cells in an organotypic culture setup. Here we show that OECs when co-cultured with the auditory BS slice not only promote neurite outgrowth from the cochlear nucleus (CN) region of the BS slice but also support cells by having BS slice axons growing along their processes. These findings further suggest that OECs may enhance survival and targeted migration of candidate donor cells suitable for cell therapy in vitro and in vivo. This article is part of a Special Issue entitled: Understanding olfactory ensheathing glia and their prospect for nervous system repair.

  • 8.
    Jiao, Yu
    et al.
    Karolinska University Hospital, Sweden; Karolinska University Hospital, Sweden; Capital Medical University, Peoples R China.
    Palmgren, Bjorn
    Karolinska University Hospital, Sweden; Karolinska University Hospital, Sweden.
    Novozhilova, Ekaterina
    Karolinska University Hospital, Sweden; Karolinska University Hospital, Sweden.
    Englund Johansson, Ulrica
    Lund University, Sweden.
    Spieles-Engemann, Anne L.
    Karolinska University Hospital, Sweden; Karolinska University Hospital, Sweden.
    Kale, Ajay
    Karolinska University Hospital, Sweden; Karolinska University Hospital, Sweden.
    Stupp, Samuel I.
    Northwestern University, IL 60208 USA; Northwestern University, IL 60208 USA; Northwestern University, IL 60208 USA; Northwestern University, IL 60208 USA.
    Olivius, Petri
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology in Linköping. Karolinska University Hospital, Sweden.
    BDNF Increases Survival and Neuronal Differentiation of Human Neural Precursor Cells Cotransplanted with a Nanofiber Gel to the Auditory Nerve in a Rat Model of Neuronal Damage2014In: BioMed Research International, ISSN 2314-6133, E-ISSN 2314-6141, Vol. 2014, p. 1-11Article in journal (Refereed)
    Abstract [en]

    Objectives. To study possible nerve regeneration of a damaged auditory nerve by the use of stem cell transplantation. Methods. We transplanted HNPCs to the rat AN trunk by the internal auditory meatus (IAM). Furthermore, we studied if addition of BDNF affects survival and phenotypic differentiation of the grafted HNPCs. A bioactive nanofiber gel (PA gel), in selected groups mixed with BDNF, was applied close to the implanted cells. Before transplantation, all rats had been deafened by a round window niche application of beta-bungarotoxin. This neurotoxin causes a selective toxic destruction of the AN while keeping the hair cells intact. Results. Overall, HNPCs survived well for up to six weeks in all groups. However, transplants receiving the BDNF-containing PA gel demonstrated significantly higher numbers of HNPCs and neuronal differentiation. At six weeks, a majority of the HNPCs had migrated into the brain stem and differentiated. Differentiated human cells as well as neurites were observed in the vicinity of the cochlear nucleus. Conclusion. Our results indicate that human neural precursor cells (HNPC) integration with host tissue benefits from additional brain derived neurotrophic factor (BDNF) treatment and that these cells appear to be good candidates for further regenerative studies on the auditory nerve (AN).

  • 9.
    Kaiser, Andreas
    et al.
    Karolinska University Hospital, Sweden .
    Kale, Ajay
    Karolinska University Hospital, Sweden .
    Novozhilova, Ekaterina
    Karolinska University Hospital, Sweden .
    Siratirakun, Piyaporn
    Karolinska University Hospital, Sweden .
    Aquino, Jorge B.
    Karolinska Institute, Sweden .
    Thonabulsombat, Charoensri
    Mahidol University, Thailand .
    Ernfors, Patrilz
    Karolinska Institute, Sweden .
    Olivius, Petri
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology in Linköping.
    Brain stern slice conditioned medium contains endogenous BDNF and GDNF that affect neural crest boundary cap cells in co-culture2014In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1566, p. 12-23Article in journal (Refereed)
    Abstract [en]

    Conditioned medium (CM), made by collecting medium after a few days in cell culture and then re-using it to further stimulate other cells, is a known experimental concept since the 1950s. Our group has explored this technique to stimulate the performance of cells in culture in general, and to evaluate stem- and progenitor cell aptitude for auditory nerve repair enhancement in particular. As compared to other mediums, all primary endpoints in our published experimental settings have weighed in favor of conditioned culture medium, where we have shown that conditioned culture medium has a stimulatory effect on cell survival. In order to explore the reasons for this improved survival we set out to analyze the conditioned culture medium. We utilized ELISA kits to investigate whether brain stem (BS) slice CM contains any significant amounts of brain-derived neurotrophic factor (BDNF) and glial cell derived neurotrophic factor (GDNF). We further looked for a donor cell with progenitor characteristics that would be receptive to BDNF and GDNF. We chose the well-documented boundary cap (BC) progenitor cells to be tested in our in vitro co-culture setting together with cochlear nucleus (CN) of the BS. The results show that BS CM contains BDNF and GDNF and that survival of BC cells, as well as BC cell differentiation into neurons, were enhanced when BS CM were used. Altogether, we conclude that BC cells transplanted into a BDNF and GDNF rich environment could be suitable for treatment of a traumatized or degenerated auditory nerve.

  • 10.
    Novozhilova, E.
    et al.
    Karolinska University Hospital, Sweden; Karolinska University Hospital, Sweden.
    Englund-Johansson, U.
    Lund University, Sweden.
    Kale, A.
    Karolinska University Hospital, Sweden; Karolinska University Hospital, Sweden.
    Jiao, Y.
    Karolinska University Hospital, Sweden; Karolinska University Hospital, Sweden; Capital Medical University, Peoples R China.
    Olivius, Petri
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology in Linköping.
    EFFECTS OF ROCK INHIBITOR Y27632 AND EGFR INHIBITOR PD168393 ON HUMAN NEURAL PRECURSORS CO-CULTURED WITH RAT AUDITORY BRAINSTEM EXPLANT2015In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 287, p. 43-54Article in journal (Refereed)
    Abstract [en]

    Hearing function lost by degeneration of inner ear spiral ganglion neurons (SGNs) in the auditory nervous system could potentially be compensated by cellular replacement using suitable donor cells. Donor cell-derived neuronal development with functional synaptic formation with auditory neurons of the cochlear nucleus (CN) in the brainstem is a prerequisite for a successful transplantation. Here a rat auditory brainstem explant culture system was used as a screening platform for donor cells. The explants were co-cultured with human neural precursor cells (HNPCs) to determine HNPCs developmental potential in the presence of environmental cues characteristic for the auditory brainstem region in vitro. We explored effects of pharmacological inhibition of GTPase Rho with its effector Rho-associated kinase (ROCK) and epidermal growth factor receptor (EGFR) signaling on the co-cultures. Pharmacological agents ROCK inhibitor Y27632 and EGFR blocker PD168393 were tested. Effect of the treatment on explant penetration by green fluorescent protein (GFP)-labeled HNPCs was evaluated based on the following criteria: number of GFP-HNPCs located within the explant; distance migrated by the GFP-HNPCs deep into the explant; length of the GFP+/neuronal class III beta-tubulin (TUJ1)+ processes developed and phenotypes displayed. In a short 2-week co-culture both inhibitors had growth-promoting effects on HNPCs, prominent in neurite extension elongation. Significant enhancement of migration and in-growth of HNPCs into the brain slice tissue was only observed in Y27632-treated co-cultures. Difference between Y27632- and PD168393-treated HNPCs acquiring neuronal fate was significant, though not different from the fates acquired in control co-culture. Our data suggest the presence of inhibitory mechanisms in the graft-host environment of the auditory brainstem slice co-culture system with neurite growth arresting properties which can be modulated by administration of signaling pathways antagonists. Therefore the co-culture system can be utilized for screens of donor cells and compounds regulating neuronal fate determination. (C) 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

  • 11.
    Novozhilova, Ekaterina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Olivius, Petri
    Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology in Linköping.
    Siratirakun, Piyaporn
    Karolinska University Hospital, Sweden.
    Lundberg, Cecilia
    Lund University, Sweden.
    Englund-Johansson, Ulrica
    Lund University, Sweden.
    Neuronal Differentiation and Extensive Migration of Human Neural Precursor Cells following Co-Culture with Rat Auditory Brainstem Slices2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 3Article in journal (Refereed)
    Abstract [en]

    Congenital or acquired hearing loss is often associated with a progressive degeneration of the auditory nerve (AN) in the inner ear. The AN is composed of processes and axons of the bipolar spiral ganglion neurons (SGN), forming the connection between the hair cells in the inner ear cochlea and the cochlear nuclei (CN) in the brainstem (BS). Therefore, replacement of SGNs for restoring the AN to improve hearing function in patients who receive a cochlear implantation or have severe AN malfunctions is an attractive idea. A human neural precursor cell (HNPC) is an appropriate donor cell to investigate, as it can be isolated and expanded in vitro with maintained potential to form neurons and glia. We recently developed a post-natal rodent in vitro auditory BS slice culture model including the CN and the central part of the AN for initial studies of candidate cells. Here we characterized the survival, distribution, phenotypic differentiation, and integration capacity of HNPCs into the auditory circuitry in vitro. HNPC aggregates (spheres) were deposited adjacent to or on top of the BS slices or as a monoculture (control). The results demonstrate that co-cultured HNPCs compared to monocultures (1) survive better, (2) distribute over a larger area, (3) to a larger extent and in a shorter time-frame form mature neuronal and glial phenotypes. HNPC showed the ability to extend neurites into host tissue. Our findings suggest that the HNPC-BS slice co-culture is appropriate for further investigations on the integration capacity of HNPCs into the auditory circuitry.

  • 12.
    Palmgren, Bjorn
    et al.
    Karolinska University Hospital.
    Jiao, Yu
    Karolinska University Hospital.
    Novozhilova, Ekaterina
    Karolinska University Hospital.
    Stupp, Samuel I
    Northwestern University.
    Olivius, Petri
    Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology in Linköping. Karolinska University Hospital, Sweden .
    Survival, migration and differentiation of mouse tau-GFP embryonic stem cells transplanted into the rat auditory nerve2012In: Experimental Neurology, ISSN 0014-4886, E-ISSN 1090-2430, Vol. 235, no 2, p. 599-609Article in journal (Refereed)
    Abstract [en]

    Stem cells have been investigated as treatment for a variety of diagnoses such as Parkinsons disease, Alzheimers disease and spinal cord injuries. Here, we investigated the possibility of using stem cells as a replacement therapy for lesions of the auditory nerve (AN). We transplanted tau-GFP mouse embryonic stem cells into the AN either by the internal auditory meatus or via the modiolus in rats that had been previously deafened by application of beta-bungarotoxin to the round window niche. We investigated the effect of brain derived neurotrophic factor (BDNF) on cell transplant survival and differentiation. Additionally chondroitinase ABC (ChABC), a digestive enzyme that cleaves the core chondroitin sulfate proteoglycans, was used in order to promote possible migration of cells and axons through the transitional zone. A bioactive isoleucine-lysine-valine-alanine-valine (IKVAV) peptide amphiphile (PA) nanofiber gel was applied around the cell injection site. This nanofiber gel has been shown to promote neural differentiation and other similar gels have been used to encapsulate and release proteins. Three weeks after injection, transplanted cells were found in the scala tympani, the modiolus, the AN trunk and the brain stem. As compared to cell transplantation and gel only, BDNF content in the PA gel increased cell survival and neuronal differentiation. In the animals treated with ChABC we observed extensive migration of cells through the transitional zone to or from the CNS.

  • 13.
    Palmgren, Bjorn
    et al.
    Karolinska University Hospital.
    Jin, Zhe
    Uppsala University.
    Jiao, Yu
    Karolinska University Hospital.
    Kostyszyn, Beata
    Karolinska University Hospital.
    Olivius, Petri
    Linköping University, Department of Clinical and Experimental Medicine, Neurobiology. Linköping University, Faculty of Health Sciences. Karolinska University Hospital.
    Horseradish peroxidase dye tracing and embryonic statoacoustic ganglion cell transplantation in the rat auditory nerve trunk2011In: BRAIN RESEARCH, ISSN 0006-8993, Vol. 1377, p. 41-49Article in journal (Refereed)
    Abstract [en]

    At present severe damage to hair cells and sensory neurons in the inner ear results in non-treatable auditory disorders. Cell implantation is a potential treatment for various neurological disorders and has already been used in clinical practice. In the inner ear, delivery of therapeutic substances including neurotrophic factors and stem cells provide strategies that in the future may ameliorate or restore hearing impairment. In order to describe a surgical auditory nerve trunk approach, in the present paper we injected the neuronal tracer horseradish peroxidase (HRP) into the central part of the nerve by an intra cranial approach. We further evaluated the applicability of the present approach by implanting statoacoustic ganglion (SAG) cells into the same location of the auditory nerve in normal hearing rats or animals deafened by application of p-bungarotoxin to the round window niche. The HRP results illustrate labeling in the cochlear nucleus in the brain stem as well as peripherally in the spiral ganglion neurons in the cochlea. The transplanted SAGs were observed within the auditory nerve trunk but no more peripheral than the CNS-PNS transitional zone. Interestingly, the auditory nerve injection did not impair auditory function, as evidenced by the auditory brainstem response. The present findings illustrate that an auditory nerve trunk approach may well access the entire auditory nerve and does not compromise auditory function. We suggest that such an approach might compose a suitable route for cell transplantation into this sensory cranial nerve.

  • 14.
    Palmgren, Björn
    et al.
    Karolinska University Hospital, Stockholm, Sweden.
    Jin, Zhe
    Uppsala University, Sweden .
    Ma, Hongmin
    Karolinska University Hospital, Stockholm, Sweden.
    Jiao, Yu
    Karolinska University Hospital, Stockholm, Sweden.
    Olivius, Petri
    Karolinska University Hospital, Stockholm, Sweden.
    β-Bungarotoxin application to the round window: An in vivo deafferentation model of the inner ear2010In: Hearing Research, ISSN 0378-5955, E-ISSN 1878-5891, Vol. 265, no 1-2, p. 70-76Article in journal (Refereed)
    Abstract [en]

    Hearing impairment can be caused by a primary lesion to the spiral ganglion neurons (SGNs) with the hair cells kept intact, for example via tumours, trauma or auditory neuropathy. To mimic these conditions in animal models various methods of inflicting damage to the inner ear have been used. However, only a few methods have a selective effect on the SGNs, which is of importance since it might be clinically more relevant to study hearing impairment with the hair cells undamaged. beta-Bungarotoxin is a venom of the Taiwan banded krait, which in vitro has been shown to induce apoptosis in neurons, leaving remaining cochlear cells intact. We wanted to create an in vivo rat model of selective damage to primary auditory neurons. Under deep anaesthesia, 41 rats received beta-Bungarotoxin or saline to the round window niche. At postoperative intervals between days 3 and 21 auditory brainstem response (ABR) measurement, immunohistochemistry, SGN quantification and cochlear surface preparation were performed. The results in the beta-Bungarotoxin-treated ears, as compared with sham-operated ears, show significantly increased ABR thresholds at all postoperative intervals, illustrating a severe to profound hearing loss at all tested frequencies (3.5, 7, 16 and 28 kHz). Quantification of the SGNs showed no obvious reduction in neuronal numbers until 14 days postoperatively. Between days 14 and 21 a significant reduction in SGN numbers was observed. Cochlear surface preparation and immunohistochemistry showed that the hair cells were intact. Our results illustrate that in vivo application of beta-Bungarotoxin to the round window niche is a feasible way of deafening rats by SGN reduction while the hair cells are kept intact.

  • 15.
    Qiu, Jianxin
    et al.
    Karlinska Hospital, Stockholm, Sweden.
    Olivius, Petri
    Karlinska Hospital, Stockholm, Sweden.
    Tong, Bushen
    Karlinska Hospital, Stockholm, Sweden.
    Borg, Erik
    Örebro University, Sweden.
    Duan, Maoli
    Karlinska Hospital, Stockholm, Sweden.
    Ventral approach to rat inner ear preserves cochlear function2007In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 127, no 3, p. 240-243Article in journal (Refereed)
    Abstract [en]

    CONCLUSION:

    This technique enabled us to visualize the cochlea without causing damage.

    OBJECTIVE:

    The mammalian inner ear is difficult to approach surgically. This is particularly true in the cases of the rat and mouse, which both have small cochleae. Rat and mouse research is particularly important because their genomes are well characterized, and significantly similar to that of the human. The aim of the present study was to develop a method of accessing the rat cochlea without affecting its function.

    MATERIALS AND METHODS:

    In the ventral approach, a small hole was made for access to the scala tympani. Cochlear function was assessed through auditory brainstem response (ABR) threshold measurements.

    RESULTS:

    The ventral approach enabled the direct visualization of the tympanic bulla. Thus, the tympanic bulla could be easily opened in a manner that was benign to cochlear function. There was no significant difference in ABR threshold before and after surgery.

  • 16.
    Rahman, Anisur
    et al.
    Karolinska Institute/Karolinska University Hospital, Stockholm, Sweden.
    Olivius, Petri
    Karolinska Institute/Karolinska University Hospital, Stockholm, Sweden.
    Dirckx, Joris
    University of Antwerp, Groenenburgerlaan, Belgium .
    Von Unge, Magnus
    Karolinska Institute/Karolinska University Hospital, Stockholm, Sweden.
    Hultcrantz, Malou
    Karolinska Institute/Karolinska University Hospital, Stockholm, Sweden.
    Stem cells and enhanced healing of chronic tympanic membrane perforation2008In: Acta Oto-Laryngologica, ISSN 0001-6489, E-ISSN 1651-2251, Vol. 128, no 4, p. 352-359Article in journal (Refereed)
    Abstract [en]

    CONCLUSIONS:

    Important information about the basic reparative process of tympanic membrane (TM) healing is shown, which can be incorporated for further clinical understanding. This provides a basis for the exploration of stem cell treatment for TM perforations and holds promise for future improvements.

    OBJECTIVES:

    This study aimed to analyse the healing of TM perforation by using stem cells and the stiffness of the membrane was tested in an acute and long-term study.

    MATERIALS AND METHODS:

    Sprague-Dawley rats were used in a model of TM perforation. The perforation was performed with a laser system. Stem cells were applied and the healing time and morphological analysis were performed with light and transmission electron microscope. Stiffness was examined by moiré interferometry.

    RESULTS:

    The stiffness of the perforated and healed TM was restored after just 2 weeks. In the chronic perforation model, mesenchymal stem cells enhanced the healing.

  • 17.
    Rahman, Anisur
    et al.
    Karolinska University Hospital and Institute, Stockholm, Sweden.
    von Unge, Magnus
    Karolinska University Hospital and Institute, Stockholm, Sweden.
    Olivius, Petri
    Karolinska University Hospital and Institute, Stockholm, Sweden.
    Dirckx, Joris
    University of Antwerp, Belgium.
    Hultcrantz, Malou
    Karolinska University Hospital and Institute, Stockholm, Sweden.
    Healing time, long-term result and effects of stem cell treatment in acute tympanic membrane perforation2007In: International Journal of Pediatric Otorhinolaryngology, ISSN 0165-5876, E-ISSN 1872-8464, Vol. 71, no 7, p. 1129-1137Article in journal (Refereed)
    Abstract [en]

    Objective

    The incidence of otitis media in children between the age of 2 and 6 years is well documented. Repeated attacks may cause acute and chronic perforations. The surgical treatment for repairing chronic perforation is quite uncomfortable for the patients of this age group because of the invasiveness of this treatment. The aim of this study was to determine the long-term influence of embryonic stem cells on acute perforations and the effect of gelatin as a vehicle for applied stem cells. The possibility of teratogenic effects of the stem cells was also observed.

    Methods

    Bilateral laser myringotomy was performed in 17 adult Sprague–Dawley rats, divided into two groups. Gelatin, a substance suitable as vehicle for bioactive material was used bilaterally around the perforation in group A, to serve as a scaffold for repairing tissue. The stem cells were used in the right tympanic membrane perforation leaving the left tympanic membrane as a control. The animals in group B received the same treatment except for the use of gelatin and in addition received an immuno-suppressive agent. After half a year of observation the mechanical stiffness of the tympanic membrane was measured by moiré interferometry for group B and the morphological study was performed by light microscopy for both groups A and B and electron microscopy for group A.

    Results

    Stem cell treated ears did not show any enhanced healing of the perforation although a marked thickening of the lamina propria was observed compared with control group. After half a year the strength and the stiffness of the tympanic membrane was almost the same for both treated and untreated ears. No evidence of teratoma was found after half a year.

    Conclusion

    This study suggests that the stem cells stimulate the proliferation of connective tissue and fibers in the lamina propria, possibly mediated by secreted substances, although the stiffness properties do not seem to be altered. The use of gelatin does not seem to enhance the healing process of the tympanic membrane perforation.

  • 18.
    Regala, C.
    et al.
    Karolinska Hospital, Stockholm, Sweden.
    Duan, M.
    Karolinska Hospital, Stockholm, Sweden.
    Zou, J.
    Karolinska Hospital, Stockholm, Sweden.
    Salminen, M.
    Karolinska Institutet, Stockholm, Sweden.
    Olivius, Petri
    Karolinska Hospital, Stockholm, Sweden.
    Xenografted fetal dorsal root ganglion, embryonic stem cell and adult neural stem cell survival following implantation into the adult vestibulocochlear nerve2005In: Experimental Neurology, ISSN 0014-4886, E-ISSN 1090-2430, Vol. 193, no 2, p. 326-333Article in journal (Refereed)
    Abstract [en]

    Sensorineural hearing loss is a disabling condition. In the post-embryonic and adult mammalian inner ear, the regeneration of auditory hair cells, spiral ganglion neurons or their axons does not occur naturally. This decrease in excitable neurons limits the success of auditory rehabilitation.

    Allografts and xenografts have shown promise in the treatment of a variety of neurological diseases. Fetal dorsal root ganglion (DRG) neurons can extend functional connections in the rat spinal cord. Embryonic stem cells (ES cells) and adult neural stem cells (ANSC) have the potential to differentiate into neurons.

    We have implanted embryonic days (E) 13–16 fetal mouse DRGs from transgenic mouse lines that express Enhanced Green Fluorescent Protein (EGFP) or lacZ reporter genes, EGFP-expressing ES cells or lacZ-expressing ANSC into the injured vestibulocochlear nerve of adult rats and guinea pigs. Survival of the implants was assessed 2 to 4 weeks postoperatively. For further evaluation of the differentiation of the implanted ES-cells, we double labeled with the mouse-specific neuronal antibody Thy 1.2.

    The rats implanted with EGFP- or lacZ-expressing DRGs showed labeled DRGs after sacrifice. In addition, EGFP-positive nerve fibers were seen growing within the proximal nerve. The results from the EGFP ES cells and lacZ ANSC revealed reporter-expressing cells at the site of injection in the vestibulocochlear nerve of the host rats and guinea pigs but also within the brain stem. Thy 1.2 profiles were seen among the EGFP ES cells within the 8th cranial nerve.

    The findings of this study indicate that the vestibulocochlear nerve of adult rats and guinea pigs will support xenotransplants of embryonic DRG, ES cells and ANSC. This may have future clinical applicability in recreating a neuronal conduit following neuronal injury between the inner ear and the central nervous system (CNS).

  • 19.
    Thonabulsombat, Charoensri
    et al.
    Mahidol University, Salaya, Phutthamonthon, Nakorn Pathom, Thailand.
    Johansson, Saga
    King's College London, UK.
    Spenger, Christian
    Karolinska University Hospital, MR Center, Stockholm, Sweden.
    Ulfendahl, Mats
    Karolinska University Hospital, Stockholm, Sweden.
    Olivius, Petri
    Karolinska University Hospital, Stockholm, Sweden.
    Implanted embryonic sensory neurons project axons toward adult auditory brainstem neurons in roller drum and Stoppini co-cultures2007In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1170, p. 48-58Article in journal (Refereed)
    Abstract [en]

    Previously we have shown in vivo the survival, migration and integration of embryonic dorsal root ganglion (DRG) neurons that were grafted into the inner ear and peripheral auditory nervous system. In order to evaluate relevant factors determining integration of sensory neurons further into the central auditory nervous system, complementary in vitro techniques are necessary. The advantages of in vitro systems are that a large number of factors including various grafts and different conditions can be efficiently examined for. Hence, we co-cultured 300 mu m thick postnatal rat brainstem slices containing the cochlear nucleus including the central part of the 8th cranial nerve with mouse embryonic DRG neurons. The organotypic co-cultures were either grown on coverslips using the roller drum method described by Gahwiler or on membranes according to the interface method described by Stoppini. Neurons in the cochlear nucleus were labeled, with DiI. The results demonstrate that (1) brainstem slices survive for up to 5 weeks in culture, and that (2) co-cultures of embryonic sensory neurons and brainstern show a high degree of neuronal survival, and that (3) survival and axonal outgrowth from the implanted embryonic neurons are dependant on the presence of the brainstern slice rather than on exogenous NGF and that (4) implanted embryonic neurons send axons toward neurons in the cochlear nucleus. (c) 2007 Published by Elsevier B.V.

  • 20.
    Ulfendahl, Mats
    et al.
    Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Hu, Zhengqing
    Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Olivius, Petri
    Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Duan, Maoli
    Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Wei, Dongguang
    Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    A cell therapy approach to substitute neural elements in the inner ear2007In: Physiology and Behavior, ISSN 0031-9384, E-ISSN 1873-507X, Vol. 92, no 1-2, p. 75-79Article in journal (Refereed)
    Abstract [en]

    Three different donor tissues were tested for their capacity to survive, integrate and differentiate in the adult inner ear. Surviving embryonic dorsal root ganglion cells were found within the spiral ganglion neuron region and along the auditory nerve fibers. In the presence of exogenous nerve growth factor (NGF), the dorsal root ganglion cells formed extensive growth of neurites that seemed to contact the host neurons. Adult neural stem cells survived relative poorly in the inner car whereas embryonic stem cells showed a somewhat greater capacity for survival and integration. Overall, the survival rate of implanted tissue was quite low in the cochlea. It is concluded that an inner ear cell therapy approach based on the implantation of exogenous cells will require that important survival factors are identified and supplied. In addition, it is possible that the physical properties of the cochlea, e.g., fluid-filled compartments and very limited space for cell proliferation, are unfavorable, at least in the normal cochlea.

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