Exosomal miR-673-5p from fibroblasts promotes Schwann cell-mediated peripheral neuron myelination by targeting the TSC2/mTORC1/SREBP2 axis

Abstract

Peripheral myelination is a complicated process, wherein Schwann cells (SCs) promote the formation of the myelin sheath around the axons of peripheral neurons. Fibroblasts are the second resident cells in the peripheral nerves; however, the precise function of fibroblasts in SC-mediated myelination has rarely been examined. Here, we show that exosomes derived from fibroblasts boost myelination-related gene expression in SCs. We used exosome sequencing, together with bioinformatic analysis, to demonstrate that exosomal microRNA miR-673-5p is capable of stimulating myelin gene expression in SCs. Subsequent functional studies revealed that miR-673-5p targets the regulator of mechanistic target of the rapamycin (mTOR) complex 1 (mTORC1) tuberous sclerosis complex 2 in SCs, leading to the activation of downstream signaling pathways including mTORC1 and sterol-regulatory element binding protein 2. In vivo experiments further confirmed that miR-673-5p activates the tuberous sclerosis complex 2/mTORC1/sterol-regulatory element binding protein 2 axis, thus promoting the synthesis of cholesterol and related lipids and subsequently accelerating myelin sheath maturation in peripheral nerves. Overall, our findings revealed exosome-mediated cross talk between fibroblasts and SCs that plays a pivotal role in peripheral myelination. We propose that exosomes derived from fibroblasts and miR-673-5p might be useful for promoting peripheral myelination in translational medicine. Peripheral myelination is a complicated process, wherein Schwann cells (SCs) promote the formation of the myelin sheath around the axons of peripheral neurons. Fibroblasts are the second resident cells in the peripheral nerves; however, the precise function of fibroblasts in SC-mediated myelination has rarely been examined. Here, we show that exosomes derived from fibroblasts boost myelination-related gene expression in SCs. We used exosome sequencing, together with bioinformatic analysis, to demonstrate that exosomal microRNA miR-673-5p is capable of stimulating myelin gene expression in SCs. Subsequent functional studies revealed that miR-673-5p targets the regulator of mechanistic target of the rapamycin (mTOR) complex 1 (mTORC1) tuberous sclerosis complex 2 in SCs, leading to the activation of downstream signaling pathways including mTORC1 and sterol-regulatory element binding protein 2. In vivo experiments further confirmed that miR-673-5p activates the tuberous sclerosis complex 2/mTORC1/sterol-regulatory element binding protein 2 axis, thus promoting the synthesis of cholesterol and related lipids and subsequently accelerating myelin sheath maturation in peripheral nerves. Overall, our findings revealed exosome-mediated cross talk between fibroblasts and SCs that plays a pivotal role in peripheral myelination. We propose that exosomes derived from fibroblasts and miR-673-5p might be useful for promoting peripheral myelination in translational medicine. Myelination is a complicated biological process which involves the formation of a myelin sheath around nerve cell axons so as to insulate them from the surroundings and thus favoring electrical impulses passing along the axon. Schwann cells (SCs) and oligodendrocytes are the two main glial cells responsible for myelination in the peripheral nervous system and central nervous system (CNS). Myelin membranes are mainly composed of proteins and lipids, including cholesterol, galactosphingolipids, and saturated long-chain fatty acids, which account for at least 70% of the dry weight of myelin membranes (1Garbay B. Heape A.M. Sargueil F. Cassagne C. Myelin synthesis in the peripheral nervous system.Prog. Neurobiol. 2000; 61: 267-304Google Scholar). Defects in lipid synthesis in SCs or oligodendrocytes are often associated with various neuropathies such as Smith-Lemli-Opitz-syndrome, Refsum’s disease, and Tangier disease (2Bosio A. Binczek E. Stoffel W. Functional breakdown of the lipid bilayer of the myelin membrane in central and peripheral nervous system by disrupted galactocerebroside synthesis.Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 13280-13285Google Scholar, 3Coetzee T. Fujita N. Dupree J. Shi R. Blight A. Suzuki K. Suzuki K. Popko B. Myelination in the absence of galactocerebroside and sulfatide: Normal structure with abnormal function and regional instability.Cell. 1996; 86: 209-219Google Scholar, 4Saher G. Brugger B. Lappe-Siefke C. Mobius W. Tozawa R. Wehr M.C. Wieland F. Ishibashi S. Nave K.A. High cholesterol level is essential for myelin membrane growth.Nat. Neurosci. 2005; 8: 468-475Google Scholar). In accordance, any interruption in lipid synthesis has been shown to impair the structure and function of myelin in both the peripheral nervous system and CNS (5Liu X. Peng S. Zhao Y. Zhao T. Wang M. Luo L. Yang Y. Sun C. AMPK negatively regulates peripheral myelination via activation of c-jun.Mol. Neurobiol. 2017; 54: 3554-3564Google Scholar, 6Norrmen C. Figlia G. Lebrun-Julien F. Pereira J.A. Trotzmuller M. Kofeler H.C. Rantanen V. Wessig C. van Deijk A.L. Smit A.B. Verheijen M.H. Ruegg M.A. Hall M.N. Suter U. mTORC1 controls PNS myelination along the mTORC1-RXRgamma-SREBP-lipid biosynthesis axis in Schwann cells.Cell Rep. 2014; 9: 646-660Google Scholar, 7Peterson T.R. Sengupta S.S. Harris T.E. Carmack A.E. Kang S.A. Balderas E. Guertin D.A. Madden K.L. Carpenter A.E. Finck B.N. Sabatini D.M. mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway.Cell. 2011; 146: 408-420Google Scholar, 8Sawade L. Grandi F. Mignanelli M. Patino-Lopez G. Klinkert K. Langa-Vives F. Di Guardo R. Echard A. Bolino A. Haucke V. Rab35-regulated lipid turnover by myotubularins represses mTORC1 activity and controls myelin growth.Nat. Commun. 2020; 11: 2835Google Scholar, 9Dimas P. Montani L. Pereira J.A. Moreno D. Trotzmuller M. Gerber J. Semenkovich C.F. Kofeler H.C. Suter U. CNS myelination and remyelination depend on fatty acid synthesis by oligodendrocytes.Elife. 2019; 8e44702Google Scholar, 10Clarke B.A. Majumder S. Zhu H. Lee Y.T. Kono M. Li C. Khanna C. Blain H. Schwartz R. Huso V.L. Byrnes C. Tuymetova G. Dunn T.M. Allende M.L. Proia R.L. The Ormdl genes regulate the sphingolipid synthesis pathway to ensure proper myelination and neurologic function in mice.Elife. 2019; 8e51067Google Scholar, 11Montani L. Pereira J.A. Norrmen C. Pohl H.B.F. Tinelli E. Trotzmuller M. Figlia G. Dimas P. von Niederhausern B. Schwager R. Jessberger S. Semenkovich C.F. Kofeler H.C. Suter U. De novo fatty acid synthesis by Schwann cells is essential for peripheral nervous system myelination.J. Cell Biol. 2018; 217: 1353-1368Google Scholar, 12Viader A. Sasaki Y. Kim S. Strickland A. Workman C.S. Yang K. Gross R.W. Milbrandt J. Aberrant Schwann cell lipid metabolism linked to mitochondrial deficits leads to axon degeneration and neuropathy.Neuron. 2013; 77: 886-898Google Scholar). Fibroblasts are widely distributed in many types of tissues, and their main task is to synthesize and organize matrix proteins (13LeBleu V.S. Neilson E.G. Origin and functional heterogeneity of fibroblasts.FASEB J. 2020; Scholar, Wang X. S. E. N. J. V. and in and Scholar). Fibroblasts in are as be such as and fibroblasts in and X. E. to 2019; Scholar, S. E. L. A. F. K. R. Li X. K. L. Y. B.A. M. in fibroblasts is linked to in and 2019; Scholar, the of 2017; Scholar, C.F. M. Li Y. M. R. Wang X. A. A. of cells from 2017; Scholar). In peripheral SCs and fibroblasts are the two main types of for and The of peripheral Scholar). to SCs, fibroblasts are derived from cells M. S.A. Lee D. cells in peripheral to fibroblasts in to Schwann Scholar). fibroblasts in peripheral of by cell R. S. Wang X. X. S. Cell in peripheral by Scholar). fibroblasts been as resident cells in the peripheral for a to the precise of fibroblasts are has been shown that in signaling between fibroblasts and SCs cell and the of axons the S. S. P. M. M. signaling peripheral nerve Schwann cell Scholar). are with of to R. V.S. The and of 2020; Scholar). and lipids, exosomes been shown to various essential in X. B.A. X. W. A. P. A. K. M. L. Y. between and in 2020; Scholar, C. T. M. X. G. L. C. R.W. matrix and disease in the 2019; Scholar, K.L. A. K. D. K. exosomes 2020; Scholar). to the for fibroblasts and SCs in peripheral we that exosomes might be a for of such as myelination. In the we the between fibroblasts and SCs, and that exosomes promote myelin gene expression in SCs. by revealed that exosomal miR-673-5p is a for myelin gene expression in SCs. that miR-673-5p targets the axis of mechanistic target of the rapamycin complex 1 in SCs and thus cholesterol synthesis for myelin our revealed a cross talk between fibroblasts and SCs in peripheral nerve myelination and that exosomal miR-673-5p is a pivotal in Peripheral myelination in and is in 2 Peripheral nerve and myelin structure of Scholar). the of fibroblasts in peripheral we the of by fibroblasts the myelination process in nerves. shown in and expression in along with myelin that fibroblasts from activation to in peripheral nerve fibroblasts been shown to in various biological to proper of peripheral S. S. P. M. M. signaling peripheral nerve Schwann cell Scholar, B. Y. S. T. Wang Y. G. F. X. Schwann cell pathway peripheral nerve Scholar, P. A. F. E. E. G. R. Schwann cell and are by by 2013; Scholar, L. U. M. B. on Schwann cell J. Cell Biol. Scholar). we that fibroblasts in peripheral myelination. we fibroblasts from the to a of for S. of cells to Cell Rep. 2017; 9: Scholar). confirmed that the of fibroblasts Myelination is essential process for the peripheral that is by SCs (1Garbay B. Heape A.M. Sargueil F. Cassagne C. Myelin synthesis in the peripheral nervous system.Prog. Neurobiol. 2000; 61: 267-304Google Scholar). We the of fibroblasts in myelination by SCs. SCs with cell from and myelin gene expression examined. has been as a second in the of myelination G. D. Schwann cell galactocerebroside by of used as a The that the myelin gene including and the from fibroblasts such is a of exosome Zhao N. F. T. by cell exosomal as a for we that exosomes in the in myelin gene we exosomes from peripheral nerve fibroblasts and their on myelin gene expression in SCs. that the exosome the from fibroblasts in and the in the of and that is capable of exosome we the exosomes by The revealed that the exosomes a of exosomes R. V.S. The and of 2020; Scholar, G. N. T.E. M.A. the via 2019; Scholar). further the of we and the two of exosomes R. V.S. The and of 2020; Scholar, X. B.A. X. W. A. P. A. K. M. L. Y. between and in 2020; Scholar). of that to the and in the exosomes is resident that is often used as a of exosomes H. Li X. Zhao J. Wang Y. J. W. L. X. Y. J. of activity by and 2019; Scholar). In accordance, the expression of in exosomes in both exosomes and the exosomes be by SCs exosomes myelin gene expression further we for a for myelin gene expression Schwann cell Biol. Scholar). The that expression in SCs by exosomes the that peripheral exosomes are capable of myelin gene expression in SCs, their in peripheral myelination. In exosomes including acid lipids, acids, and A.M. J. R. of exosome 2019; Scholar). studies shown that are the main that various of exosomes W. M. G. Y. A. J. A. W. Li P. exosomal in vivo and in 2017; Scholar, H. A. J. A. A. C. E. L. The of 2019; Scholar, T. Y. Y. Li C. Y. J. F. Luo exosomal regulates 2019; Scholar, N. L. L. Yang G. J. Wang C. Y. Wang S. Y. J. K. Kim in 2017; 11: Scholar, T. M.A. M. M. C. R. P. regulate gene expression in 2017; Scholar, Y. Kim B. J. C. D. cells control exosomal 2017; Scholar). we our on exosomal and with and a of Functional revealed that We the main biological in SCs the mTOR signaling pathway in both bioinformatic a protein plays a pivotal role in a of from protein synthesis to Sabatini D.M. mTOR signaling in and 2017; Scholar). mTOR has two protein mTORC1 and mTOR complex 2 H. B. Yang mTOR and 2013; Scholar). has been that mTORC1 is for proper peripheral myelination C. Figlia G. Lebrun-Julien F. Pereira J.A. Trotzmuller M. Kofeler H.C. Rantanen V. Wessig C. van Deijk A.L. Smit A.B. Verheijen M.H. Ruegg M.A. Hall M.N. Suter U. mTORC1 controls PNS myelination along the mTORC1-RXRgamma-SREBP-lipid biosynthesis axis in Schwann cells.Cell Rep. 2014; 9: 646-660Google Scholar, 8Sawade L. Grandi F. Mignanelli M. Patino-Lopez G. Klinkert K. Langa-Vives F. Di Guardo R. Echard A. Bolino A. Haucke V. Rab35-regulated lipid turnover by myotubularins represses mTORC1 activity and controls myelin growth.Nat. Commun. 2020; 11: 2835Google Scholar, C. Figlia G. P. Pereira J.A. S. Suter U. mTORC1 is in to promote and Schwann cell Neurosci. 2018; Scholar, G. Norrmen C. Pereira J.A. Gerber D. Suter U. function of the axis in myelination of the peripheral nervous 2017; Scholar, M. A. R. by regulates myelin activation of which mTORC1 activity in Neurosci. 2017; Scholar). in the we the mTORC1 pathway responsible for the myelin gene expression in SCs by SCs with exosomes and of mTORC1 J. J. activation of and signaling by the protein Scholar). that rapamycin myelin gene expression in SCs, and the myelin gene expression by exosomes by rapamycin that mTORC1 is a for the of exosomes on myelination in SCs. which in exosomes activates mTORC1 and thus myelin gene expression in SCs, we the of mTORC1 sclerosis 1 and 2 are widely as of mTOR Sabatini D.M. mTOR signaling in and 2017; Scholar, M. L. X. Wang H. W. Wang H. of by tuberous sclerosis controls and of Commun. Scholar). the mTOR signaling we and to the The target genes of in SCs of targets and the and the we that exosomal and miR-673-5p are that target We further in SCs with the exosomes and that the of the by the exosomes we the of in of SCs. The that the expression of and miR-673-5p for and miR-673-5p We myelin gene SCs with the by as by the in gene expression expression by however, the expression by the of in process examined. we that expression by by further expression in SCs and that negatively regulates myelin gene expression in SCs. further which exosomal targets we the and for including and the miR-673-5p and expression miR-673-5p as a functional in exosomes and thus the on myelin gene expression in SCs. further we SCs with miR-673-5p or that the expression by the on the the further expression the expression by miR-673-5p of mTORC1 by rapamycin in in expression that by miR-673-5p is responsible for the myelin gene expression in SCs by element binding proteins are the two main downstream targets of mTORC1 C. Figlia G. Lebrun-Julien F. Pereira J.A. Trotzmuller M. Kofeler H.C. Rantanen V. Wessig C. van Deijk A.L. Smit A.B. Verheijen M.H. Ruegg M.A. Hall M.N. Suter U. mTORC1 controls PNS myelination along the mTORC1-RXRgamma-SREBP-lipid biosynthesis axis in Schwann cells.Cell Rep. 2014; 9: 646-660Google Scholar, 7Peterson T.R. Sengupta S.S. Harris T.E. Carmack A.E. Kang S.A. Balderas E. Guertin D.A. Madden K.L. Carpenter A.E. Finck B.N. Sabatini D.M. mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway.Cell. 2011; 146: 408-420Google Scholar, J. Zhu J. J. X. activation of signaling via Natl. Acad. Sci. U. S. A. 2020; Scholar). we and their target genes in the nerves. The that miR-673-5p the expression of in the at and a at expression by miR-673-5p a the downstream of such as and by miR-673-5p for expression by miR-673-5p at and a target gene of by miR-673-5p at and further that is a downstream of we SCs with miR-673-5p and and The miR-673-5p miR-673-5p expression in SCs by the and expression by the we a downstream target of regulator of and fatty acid Scholar). in by the miR-673-5p or and are responsible for novo cholesterol biosynthesis of the of cholesterol and fatty acid synthesis in the Scholar, S. S. J. M. C. T. J. A. H. in and two are associated with in and Scholar, Shi A. Wang Y. W. Sun M. Zhao X. Luo J. W. cholesterol biosynthesis via the 2020; we that cholesterol and related lipids in might be by we of the with miR-673-5p The that a of lipids, including and by the miR-673-5p and and are the main in myelin sheath formation S. M. and of lipids in Scholar). we the of lipids on and that by miR-673-5p in both and and We cholesterol in the nerves. shown in in with the miR-673-5p the level of cholesterol in the that exosomal miR-673-5p targets leading to the activation of mTORC1 and downstream such as and is a that controls the expression of cholesterol and lipid genes of the of cholesterol and fatty acid synthesis in the Scholar). is a in the cholesterol we that exosomal miR-673-5p in SCs, leading to the activation of mTORC1 and downstream targets such as and the biosynthesis of cholesterol and related lipids in SCs is which myelination in the nerves. with miR-673-5p The at such as and a of expression by the miR-673-5p and by the miR-673-5p The expression of myelin genes such as and and to we and expression in The that both and by miR-673-5p at and and revealed that the myelin sheath in in miR-673-5p which further confirmed by the and axons by we with to miR-673-5p the of exosomes myelination in nerves; for the of myelin the of and the of myelin by exosomes and that exosomes a on peripheral in which exosomal miR-673-5p is a myelination in nerves. miR-673-5p via at the of 2 The at as and to further of of from and of axons in from and of axons nerve at 2 are as by exosomes peripheral myelination in of exosomes derived from fibroblasts via 2 The at as and to of of from and the of myelin the of and the of myelin by exosomes are as by In peripheral fibroblasts are the second resident cells SCs The of peripheral Scholar). the precise role of fibroblasts in proper of peripheral is In the we a cross talk between fibroblasts and SCs for peripheral which is by exosomes derived from exosomal miR-673-5p targets leading to the activation of mTORC1 and downstream in SCs. a fatty acid and cholesterol synthesis in SCs which in the myelin sheath Fibroblasts are the cells responsible for the matrix by matrix including and (13LeBleu V.S. Neilson E.G. Origin and functional heterogeneity of fibroblasts.FASEB J. 2020; Scholar, Wang X. S. E. N. J. V. and in and Scholar). are many types of fibroblasts in on in and gene expression (13LeBleu V.S. Neilson E.G. Origin and functional heterogeneity of fibroblasts.FASEB J. 2020; Scholar, Wang X. S. E. N. J. V. and in and Scholar). of has role in various such as and (13LeBleu V.S. Neilson E.G. Origin and functional heterogeneity of fibroblasts.FASEB J. 2020; Scholar, Wang X. S. E. N. J. V. and in and Scholar). fibroblasts account for of peripheral nerve resident cells The of peripheral is their in the of peripheral nerves. Peripheral nerve resident fibroblasts been shown to via the signaling pathway in peripheral nerve S. S. P. M. M. signaling peripheral nerve Schwann cell Scholar). In that fibroblasts a from in peripheral nerve S. S. P. M. M. signaling peripheral nerve Schwann cell Scholar). In with we that activation with the process of peripheral nerve which fibroblasts a role in our experiments revealed that exosomes myelin gene expression and fatty acid and cholesterol synthesis in SCs and thus favoring peripheral nerve myelination. mTOR is a protein that two mTORC1 and mTOR complex 2. mTORC1 is responsible for and biosynthesis of lipids, and of novo synthesis by signaling mTOR and 2013; Scholar, G. mTORC1 synthesis control of the mitochondrial Scholar, L. Wang T. Sabatini D.M. for of of which are that myelination is process, mTORC1 be in the myelination. of mTORC1 in SCs or oligodendrocytes myelin sheath maturation C. Figlia G. Lebrun-Julien F. Pereira J.A. Trotzmuller M. Kofeler H.C. Rantanen V. Wessig C. van Deijk A.L. Smit A.B. Verheijen M.H. Ruegg M.A. Hall M.N. Suter U. mTORC1 controls PNS myelination along the mTORC1-RXRgamma-SREBP-lipid biosynthesis axis in Schwann cells.Cell Rep. 2014; 9: 646-660Google Scholar, J. of or has on and CNS myelination.J. Neurosci. 2014; Scholar, F. L. Norrmen C. Trotzmuller M. Kofeler H. Ruegg M.A. Hall M.N. Suter U. mTORC1 activity in oligodendrocytes is for CNS myelination.J. Neurosci. 2014; Scholar, B. E. Milbrandt J. mTORC1 of Schwann cells and myelin of Schwann Natl. Acad. Sci. U. S. A. 2017; Scholar). is capable of a protein that activates mTOR J. The cell J. Scholar, K. Li Y. T. K.L. is a target of activity and regulates mTOR Scholar). of a on myelination. of or myelination in the L. D.M. H. K. A. M. of tuberous of and and Neurosci. Scholar, Li Yang Lee of associated with in a of tuberous sclerosis complex Scholar). In a that the of in cells axon remyelination and myelin L. of tuberous sclerosis in cells axon remyelination and myelin a Neurosci. 2017; Scholar). findings that has in myelination and In with has been that mTORC1 in SCs the of peripheral however, mTORC1 is myelination G. Norrmen C. Pereira J.A. Gerber D. Suter U. function of the axis in myelination of the peripheral nervous 2017; Scholar). In the we with miR-673-5p to and that nerve myelination are with the of in as the myelination process Peripheral nerve and myelin structure of myelination in be in of mTORC1 by in SCs myelination. a downstream target of in by is a that regulates the synthesis and of fatty and cholesterol H. R. lipid 2017; Scholar). has been shown that in the plays a pivotal role in myelin formation X. S. C. M.N. J. C. T. L. Wang Y. Y. F. J. regulates cholesterol Scholar). of protein fatty acid and cholesterol synthesis in which myelin formation and H. M. K.L. Kim protein in 2017; Scholar). is a gene by and plays essential role in cholesterol biosynthesis control of the and to Biol. 2020; Scholar). In the we that both and by of in nerves. the synthesis of fatty and cholesterol in the be We that the of fatty and cholesterol in by be used to the myelin the of AMPK protein and lipid synthesis in nerves; in peripheral myelination is in (5Liu X. Peng S. Zhao Y. Zhao T. Wang M. Luo L. Yang Y. Sun C. AMPK negatively regulates peripheral myelination via activation of c-jun.Mol. Neurobiol. 2017; 54: 3554-3564Google Scholar). De novo fatty acid synthesis in SCs plays essential role in peripheral myelination L. Pereira J.A. Norrmen C. Pohl H.B.F. Tinelli E. Trotzmuller M. Figlia G. Dimas P. von Niederhausern B. Schwager R. Jessberger S. Semenkovich C.F. Kofeler H.C. Suter U. De novo fatty acid synthesis by Schwann cells is essential for peripheral nervous system myelination.J. Cell Biol. 2018; 217: 1353-1368Google Scholar). of signaling in SCs leads to a in fatty and cholesterol, which in in the peripheral Strickland A. Milbrandt J. signaling in Schwann cells myelination and a 2020; Scholar). our revealed a cross talk between fibroblasts and SCs myelination in peripheral nerves; exosomes derived from fibroblasts by SCs and which in myelin gene expression and myelin sheath exosomal miR-673-5p targets and of mTORC1 in SCs, leading to mTORC1 activation and downstream including and cholesterol and lipid synthesis in SCs is which myelination in nerves. findings between fibroblasts and SCs in the myelination process which for the of cholesterol and lipid biosynthesis in SCs myelination. The nerve of used to as the with for and for at The cells with with 1 the and with with the 2 with with The of as by for of the the fibroblasts cells and with The cells of two used to The fibroblasts with for a of cells with for and of cells with for the cell to and at is that the synthesis and of as a control used to The cell at at and cells in the The to at for 2 at with for 2 at the in used to exosome and The used to the of the protein and the control by exosomal in SCs, exosomes with the cell the exosomes in and by for 2 at exosomes in from exosomes with a exosome and protein Cell at for at The for protein for by and to membranes with the including or for at in with and with the second for 1 at further with system SCs from the of with and and with with The SCs by and as E. G. Li X. K. A. The of matrix activates cell signaling and of cells by binding to Neurosci. Scholar). of SCs in at expression of and expression in SCs, cells the for the 1 of or with and to the The to The a from Kim J. J. R. K. of is by and membrane Cell Biol. Scholar). The a from M.N. J. of the tuberous sclerosis gene as a target of the Scholar). 1 of SCs by with a to cell on The two with at and V. regulate SCs with or to the The used and A. miR-673-5p and control at miR-673-5p via at the of 2 the of by the of The of Y. Wang Y. J. Yang L. C. X. Wang Y. Peng S. X. Sun C. Yang Y. peripheral nerve by 2017; Scholar). cells with for in cells in and for 1 at by with at The in cells with the for 1 at the cells with for at the in in and on a The with including at for The further with the or the or the at Cell and with a The nerve in with and in and in of The in and and with and The a from to the of myelin sheath the of myelin and the of nerve with a including axons Y. K. G. J. Peng S. X. Sun C. 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