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Lithium Reversibly Inhibits Schwann Cell Proliferation and Differentiation Without Inducing Myelin Loss

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Abstract

This study was undertaken to examine the bioactivity, specificity, and reversibility of lithium’s action on the growth, survival, proliferation, and differentiation of cultured Schwann cells (SCs). In isolated SCs, lithium promoted a state of cell cycle arrest that featured extensive cell enlargement and c-Jun downregulation in the absence of increased expression of myelin-associated markers. In addition, lithium effectively prevented mitogen-induced S-phase entry without impairing cell viability. When lithium was administered together with differentiating concentrations of cyclic adenosine monophosphate (cAMP) analogs, a dramatic inhibition of the expression of the master regulator of myelination Krox-20 was observed. Likewise, lithium antagonized the cAMP-dependent expression of various myelin markers such as protein zero, periaxin, and galactocerebroside and allowed SCs to maintain high levels of expression of immature SC markers even in the presence of high levels of cAMP and low levels of c-Jun. Most importantly, the inhibitory action of lithium on SC proliferation and differentiation was shown to be dose dependent, specific, and reversible upon removal of lithium compounds. In SC-neuron cultures, lithium suppressed myelin sheath formation while preserving axonal integrity, SC-axon contact, and basal lamina formation. Lithium was unique in its ability to prevent the onset of myelination without promoting myelin degradation or SC dedifferentiation. To conclude, our results underscored an unexpected antagonistic action of lithium on SC mitogenesis and myelin gene expression. We suggest that lithium represents an attractive pharmacological agent to safely and reversibly suppress the onset of SC proliferation, differentiation, and myelination while maintaining the integrity of pre-existing myelinated fibers.

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Acknowledgements

We thank the excellent technical support provided by Jennifer Soto and Ketty Bacallao with neuronal cell cultures. We kindly acknowledge the assistance provided by Vladimir Camarena and Gaofeng Wang with IncuCyte microscopy, Melissa Carballosa with ImageJ software, and Yan Shi with automated fluorescence microscopy. This work was supported by NIH-NINDS (NS084326), The Craig H. Neilsen Foundation, The Miami Project to Cure Paralysis, and The Buoniconti Fund. G.P. was a recipient of a CONICET/BecAr fellowship (Argentina).

Authors’ Contributions

G.P. and P.V.M. designed the study and wrote the manuscript; G.P., R.B, and N.D.A performed experiments; G.P., N.D.A., P.S., and P.V.M. analyzed and interpreted data. All authors read and approved the final manuscript.

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  1. The Miami Project to Cure Paralysis and the Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL, USA

    Gonzalo Piñero, Randall Berg, Natalia Denise Andersen & Paula Virginia Monje

  2. Universidad de Buenos Aires. CONICET, Instituto de Química y Fisicoquímica Biológicas (IQUIFIB), Buenos Aires, Argentina

    Gonzalo Piñero & Patricia Setton-Avruj

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Piñero, G., Berg, R., Andersen, N. et al. Lithium Reversibly Inhibits Schwann Cell Proliferation and Differentiation Without Inducing Myelin Loss. Mol Neurobiol 54, 8287–8307 (2017). https://doi.org/10.1007/s12035-016-0262-z

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