RT Journal Article
SR Electronic
T1 Anti-Muscarinic Adjunct Therapy Accelerates Functional Human Oligodendrocyte Repair
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 3676
OP 3688
DO 10.1523/JNEUROSCI.3510-14.2015
VO 35
IS 8
A1 Kavitha Abiraman
A1 Suyog U. Pol
A1 Melanie A. O'Bara
A1 Guang-Di Chen
A1 Zainab M. Khaku
A1 Jing Wang
A1 David Thorn
A1 Bansi H. Vedia
A1 Ezinne C. Ekwegbalu
A1 Jun-Xu Li
A1 Richard J. Salvi
A1 Fraser J. Sim
YR 2015
UL http://www.jneurosci.org/content/35/8/3676.abstract
AB Therapeutic repair of myelin disorders may be limited by the relatively slow rate of human oligodendrocyte differentiation. To identify appropriate pharmacological targets with which to accelerate differentiation of human oligodendrocyte progenitors (hOPCs) directly, we used CD140a/O4-based FACS of human forebrain and microarray to hOPC-specific receptors. Among these, we identified CHRM3, a M3R muscarinic acetylcholine receptor, as being restricted to oligodendrocyte-biased CD140a+O4+ cells. Muscarinic agonist treatment of hOPCs resulted in a specific and dose-dependent blockade of oligodendrocyte commitment. Conversely, when hOPCs were cocultured with human neurons, M3R antagonist treatment stimulated oligodendrocytic differentiation. Systemic treatment with solifenacin, an FDA-approved muscarinic receptor antagonist, increased oligodendrocyte differentiation of transplanted hOPCs in hypomyelinated shiverer/rag2 brain. Importantly, solifenacin treatment of engrafted animals reduced auditory brainstem response interpeak latency, indicative of increased conduction velocity and thereby enhanced functional repair. Therefore, solifenacin and other selective muscarinic antagonists represent new adjunct approaches to accelerate repair by engrafted human progenitors.