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Modulation of oligodendrocyte precursor cells differentiation fate during CNS remyelination

Final Report Summary - MODOPCFATE (Modulation of oligodendrocyte precursor cells differentiation fate during CNS remyelination.)

Demyelination is a pathological process that occurs in the central nervous system when due to genetic defects or pathological insults myelin sheaths responsible for the integrity of axons and guidance of signal are destroyed. Natural, endogenous response to demyelination is remyelination, the regenerative process in which myelin is restored to demyelinated axons, is carried by oligodendrocyte precursor cells (OPCs). Our studies demonstrated that depending on microenvironmental clues in injured tissues oligodendrocyte precursors can differentiate along a classic pathway into oligodendrocytes or on an alternative pathway into Schwann cells and astrocytes. We observed that Schwann cells derived from OPCs in the central nervous system occupied almost exclusively tissue around blood vessels in astrocyte deficient areas. Therefore, we postulated the occurrence of specific niches or microenvironments that modulate OPC fate. The aim of project was to identify the factors and their downstream effectors that significantly discriminate vascular and non-vascular niche and determine the fate of oligodendrocyte precursor cells. With different in vitro and in vivo approaches we investigated the biology of oligodendrocyte precursor cells (OPCs), multipotent cells with stem-like characteristic. In particular, we investigated the role of microenvironmental clues in controlling of OPCs differentiation, the process which is crucial for reconstitution of injured central nervous system white matter. Moreover, we explored mutual interactions between OPCs and other cells in the injured tissue – microglial cells, reactive astrocytes and blood vessel endothelium. With laser capture microdissection we dissected tissue from vascular and non-vascular regions of lesion areas at 6, 10 and 14 days after bilateral stereotaxic injection of ethidium bromide into the brain white matter of adult rats and performed microarrays to profile the whole transcriptome of both niches separately. This approach allowed us to distinguish between mRNAs that are enriched within two separate environmental niches within the same lesion area. The study identified 138 differentially expressed transcripts. Comparative bioinformatic analysis of global gene expression combined with signaling transduction pathway structure and genes function analysis revealed specific candidate signaling pathways differentially expressed in local peri-vascular niche compared to non-vascular one. Results of RT-PCR-based validation of microarray data have proven that expression gradient of BMP4, BMP7, their antagonist Sostdc1, as well as Wnt2b, Wnt6, Dhh and Scube1 act as the major regulators of OPCs fate in the vascular niche. We have compared BMPs pathway components (BMP proteins, their receptors, and antagonists) in the predefined niches during the tissue reconstruction and proposed the hypothesis predicted that spatiotemporal differences in the expression of BMPs and their inhibitors are the most important factors in alternative OPC differentiation into Schwann cells. To address the above we investigated the possibility of modulation OPCs fate by delivery of BMPs or BMPs receptors’ antagonists into the lesions undergoing active remyelination. The experiments are ongoing, we expect that BMPs will favour differentiation into Schwann cells while the extent of the oligodendrocyte-mediated remyelination will be increased at the lesions exposed to inhibitory factors.
A key aspect of neural repair is that none of observed cellular and molecular events are occurring in isolation. We observe that migrating OPCs preferentially associate with blood vessels, and on the other hand, the blood vessels undergo substantial regeneration in course of remyelination. These two processes are integrated forming a neurovascular niche during tissue reorganization. Our analysis shown that unique properties of tissue around blood vessels differ from the rest of the lesion which can be one of the factors favoring OPCs alternative differentiation in this area of lesion.
The gain-of-function and loss-of-function in vitro experiments verifying which endothelial-derived factors prompt OPCs proliferation and alternative differentiation are a subject of our currently on-going project which is an original concept based on promising results obtained during our work on reported project. Our data can potentially have an impact on the current understanding of the phenomenon of remyelination by endogenous multipotential precursors as well as influence the development of new therapeutic opportunities by selectively targeting cellular plasticity-related phenomena. In the long-term perspective, we expect that modulation of signals from the vascular environment may be crucial for the development of therapeutic strategies targeting both enhancement of endogenous remyelination and tissue regeneration after transplantation of exogenous cells.