Morphological and Functional Characterization of Predifferentiation of Myelinating Glia-like Cells from Human Bone Marrow Stromal Cells through Activation of F3/Notch Signaling in Mouse Retina

¹ Department of Clinical Research, Singapore General Hospital, Singapore.; Department of Anatomy, Beijing University of Traditional Chinese Medicine, Beijing, China.; Department of Anatomy, Shanxi Medical University, Shanxi, China.
² Department of Clinical Research, Singapore General Hospital, Singapore.; Institute of Neuroscience, Nantong University, Nantong, China.
³ Department of Clinical Research, Singapore General Hospital, Singapore.
⁴ Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.; Division of Life Science and Biotechnology, Ocean University of China, Qingdao, China.
⁵ Department of Anatomy, Beijing University of Traditional Chinese Medicine, Beijing, China.
⁶ Institute of Neuroscience, Nantong University, Nantong, China.
⁷ Centre of Molecular Medicine, Singapore.
⁸ Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
⁹ Department of Clinical Research, Singapore General Hospital, Singapore.; Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.; Institute of Molecular and Cell Biology, Singapore.

^* To whom correspondence should be addressed. E-mail: xiao.zhi.cheng{at}sgh.com.sg.

	Abstract

Recently, we have demonstrated that F3/contactin and NB-3 are trans-acting extracellular ligands of Notch that promote differentiation of neural stem cells and oligodendrocyte precursor cells into mature oligodendrocytes (OLs). Here, we demonstrate that human bone marrow stromal cells (hBMSCs) can be induced to differentiate into cells with myelinating glial cell characteristics in mouse retina after predifferentiation in vitro. Isolated CD90 (+) hBMSCs treated with -mercaptoethanol for 1 day and retinoic acid for 3 days in culture changed into myelinating glia-like cells (MGLCs). More cells expressed NG2, an early OLs marker, after treatment but expression of O4, a mature OLs marker, was negligible. Subsequently, the population of O4 (+) cells was significantly increased after the MGLCs were predifferentiated in culture in the presence of either F3/contactin or multiple factors, including forskolin, basic-FGF, PDGF and heregulin, in vitro for another 3 days. Notably, 2 months after transplantation into mouse retina, the predifferentiated cells changed morphologically into cells resembling mature MGLCs and expressing O4 and myelin basic protein (MBP), two mature myelinating glial cell markers. The cells sent out processes to contact and wrap axons, an event which normally occurs during early stages of myelination, in the retina. The results suggest that CD90 (+) hBMSCs are capable of morphological and functional differentiation into MGLCs in vivo through predifferentiation by triggering F3/Notch signaling in vitro.

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