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Sensory neurons influence the expression of cell adhesion factors by cutaneous cells in vitro and in vivo
Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
2001 (English)In: Journal of Neurocytology, ISSN 0300-4864, E-ISSN 1573-7381, Vol. 30, no 4, 327-336 p.Article in journal (Refereed) Published
Abstract [en]

Dorsal root ganglion (DRG) neurons co-cultured with skin-derived fibroblast-like cells (FLCs) show a strong neurite outgrowth. However, when physical contact between FLCs and neurons is prevented with membrane inserts, the DRG neurons exhibit a low survival and a deficient neurite growth. This indicates that cell adhesion molecules influence neuronal survival and neurite growth in co-cultures. The aim of the present study is to find out if selected adhesion molecules are expressed by cultivated FLCs with and without nervous influences, and/or by normal and denervated whole skin. RT-PCR data show that cultured FLCs and denervated skin express L1, N-CAM, N-cadherin and ninjurin, but not neurofascin or TAG-1. However, cultured FLCs exposed to DRG homogenates and innervated skin express N-cadherin only. Following application of neutralizing L1-, N-cadherin- and ninjurin-antibodies (but not N-CAM-antibodies) in the culture medium the mean number of surviving neurons is decreased. Co-cultures incubated with L1-, N-cadherin- or ninjurin-antibodies all show significantly less neurite outgrowth compared to controls. In conclusion, the findings in this paper indicate (i) that FLCs cultured in vitro and denervated whole skin express the cell adhesion factors L1, N-CAM, N-cadherin and ninjurin, (ii) that FLCs treated with neural molecules and innervated whole skin express N-cadherin only, (iii) that L1, N-cadherin and ninjurin are important for DRG neurons co-cultured with FLCs in vitro in terms of survival and neurite extension and (iv) that there may exist subpopulations of DRG-neurons with different sensitivities for N-cadherin- and ninjurin-antibodies.

Place, publisher, year, edition, pages
2001. Vol. 30, no 4, 327-336 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-25115DOI: 10.1023/A:1014460413884Local ID: 9548OAI: oai:DiVA.org:liu-25115DiVA: diva2:245441
Note

On the day of the defence day the status of this article was accepted.

Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
In thesis
1. Factors influencing nerve growth in situ and in vitro
Open this publication in new window or tab >>Factors influencing nerve growth in situ and in vitro
2001 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [sv]

Bakgranden till denna doktorsavhaodling är den problematik som uppstår efter en perifer nervskada, roreträdesvis i relation till handen eftersom den har så stor betydelse i vårt dagliga liv. En haod utan känsel fungerar dåligt och än sänne fungerar en handprotes. Problemet idag är inte att få nervtrådarna att växa efter en skada utan att få dem att växa rätt. Dagens mikrokirurgiska behandling av nervskador är mycket förfinad. Vi kan inte vänta oss att en fortsatt utveckling av mikrokirurgin på ett dramatiskt sätt skall bidra till en rorbättring av vår rormåga att leda utväxande nervtrådar till deras mål organ. Därror är det viktigt att studera de molekylära faktorer som bidrar till styrning av nervväxt För att studera detta har jag använt mig av två olika modeller. Först gjorde jag en experimentell studie på vuxen råtta. Frågeställningen var om man med lljälp av filtrat gjorda från två olika målorgan (muskel och hud) kan styra utväxaode nervtrådar att växa åt rätt håll. Detta visade sig vara möjligt, och frågan väcktes då hur samspelet mellao nerv och målorgao såg ut på cellnivå. För att besvara den frågan utvecklade jag en in vitro-modell där jag odlade känselnervceller tillsammans med bindvävsceller från huden (känselcellemas målorgan). Jag har använt denna odlingsmodell i tre arbeten ror att undersöka hur vissa kända molekyler påverkar nervväxt. I ett arbete beskriver jag effekter av lösta molekyler (neurotrofiner) på nervväxt I ett annat arbete studeras betydelsen av molekyler som är bundna till cellytor (celladhesionsmolekyler) för nervväxt. En tredje studie rör effekter av ämnen som flisätts vid inflammation (cytokiner) på nervväxt. Sammanfattningsvis har denna avhaodling bidragit till att öka vår kunskap om olika faktorer som är viktiga för nervväxt I en framtid kommer vi förhoppningsvis attkunna sätta ihop all den konskap om nervväxt som just nu ackumul eras på olika håll i världen till en aovändbar helhet och tillämpa den vid behaodlingen av perifera nervskador.

Abstract [en]

Since peripheral nerves extend over long distances and follow a partly superficial course they are often subjected to injuries. This is especially true for major nerves in the extremities. Axotomized neurons can regenerate the divided axon, provided that a distal stump is available. However, successful microsurgical anastomosis of the stumps does not mean that each regenerating axon grows into the appropriate band of Biingner and back to the relevant target. In fact, regeneration often results in a neuron/target mis-match and an unsatisfactory functional restoration. Erratic regeneration is a serious therapeutic problem which can not be solved by a refined microsurgery. To improve the precision of axonal regeneration the nerve fibers have to be guided to their target organ via siguals at the cellular level. The general aim of this thesis was to identify some factors of importance for neurite growth in situ and in vitro.

The results of axon sorting experiments and retrograde tracing showed that adult rat sciatic motor axons regenerating into a Y-tube grew more readily into a branch containing muscle-derived molecules than into a branch containing skin-derived molecules. Regenerating sciatic sensory axons emerging from large perikarya were emiched in a branch with muscle-derived molecules and sensory axons from small perikarya were enriched in a branch with skin-derived molecules.

Experiments in vitro showed that skin-derived fibroblast-like cells (sFLCs) stimulate neurite formation from young DRG neurons. The nemites formed terminal-like networks iu close relation to iudividual sFLCs. RPA-analysis showed that sFLCs cultivated iu vitro expressed NGF, BDNF, NT-3 and NT-4 and that DRG neurons eocultured with transfected 3T3 cells were iuflueuced by neurotrophlns produced by these cells. A picture similar to the wild-type pattern was seeu iu co-cultures with 3T3 cells overexpressing NT-3.

Cell surface molecules appeared to play ao importaot role in the control of neuritogenesis from DRG neurons eo-cultured with sFLCs. RT-PCR analysis showed that sFLCs expressed the adhesion factors N-CAM, L1, N-cadherin, and ninjurin if cultured alone and N-cadherin only if DRG extract was added to the culture. Denervated and innervated whole skin samples differed similarly. Application of antibodies showed that adhesion factors L1, N-cadherin and ninjurin are important for survival of and neuritogenesis from DRG neurons co-cultured with sFLCs.

It was also found that sFLCs and perichondrial (p) FLCs expressed receptors for the cytokines IL-1ß, IL-6, LIF and that these cytokines affected DRG neurons eocultivated with both FLC types, in tenns of survival and/or neuritogenesis. The cytokine effects on DRG neurons eo-cultured with FLCs were influenced by cytokine concentration and by the origin of the FLCs. Some cytokine effects were mediated via NGF.

Altogether, these results show that nerve growth can be experimentally influenced by target-derived molecules in situ and by neurotrophins, cell adhesion molecules and cytokines in vitro. In the future, these and other factors may conceivably be used as tools for treatment of nerve injuries.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet, 2001. 92 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 693
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-25667 (URN)10043 (Local ID)91-7219-988-1 (ISBN)10043 (Archive number)10043 (OAI)
Public defence
2001-11-02, Berzeliussalen, Universitetssjukhuset, Linköping, 09:00 (Swedish)
Opponent
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2015-09-18Bibliographically approved

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