scholarly journals Transplanted miR-219-overexpressing oligodendrocyte precursor cells promoted remyelination and improved functional recovery in a chronic demyelinated model

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Hong-Bin Fan ◽  
Li-Xia Chen ◽  
Xue-Bin Qu ◽  
Chuan-Lu Ren ◽  
Xiu-Xiang Wu ◽  
...  
Keyword(s):  
Cognitive Function ◽  
Embryonic Stem ◽  
Precursor Cells ◽  
Demyelinating Diseases ◽  
Specific Cell ◽  
Oligodendrocyte Precursor Cells ◽  
Oligodendrocyte Differentiation ◽  
Ultrastructural Studies ◽  
Multiple Differentiation ◽  
Oligodendrocyte Precursor

Abstract Oligodendrocyte precursor cells (OPCs) have the ability to repair demyelinated lesions by maturing into myelin-producing oligodendrocytes. Recent evidence suggests that miR-219 helps regulate the differentiation of OPCs into oligodendrocytes. We performed oligodendrocyte differentiation studies using miR-219-overexpressing mouse embryonic stem cells (miR219-mESCs). The self-renewal and multiple differentiation properties of miR219-mESCs were analyzed by the expression of the stage-specific cell markers Nanog, Oct4, nestin, musashi1, GFAP, Tuj1 and O4. MiR-219 accelerated the differentiation of mESC-derived neural precursor cells (NPCs) into OPCs. We further transplanted OPCs derived from miR219-mESCs (miR219-OPCs) into cuprizone-induced chronically demyelinated mice to observe remyelination, which resulted in well-contained oligodendrocyte grafts that migrated along the corpus callosum and matured to express myelin basic protein (MBP). Ultrastructural studies further confirmed the presence of new myelin sheaths. Improved cognitive function in these mice was confirmed by behavioral tests. Importantly, the transplanted miR219-OPCs induced the proliferation of endogenous NPCs. In conclusion, these data demonstrate that miR-219 rapidly transforms mESCs into oligodendrocyte lineage cells and that the transplantation of miR219-OPCs not only promotes remyelination and improves cognitive function but also enhances the proliferation of host endogenous NPCs following chronic demyelination. These results support the potential of a therapeutic role for miR-219 in demyelinating diseases.

scholarly journals Human Wharton’s Jelly Mesenchymal Stromal Cell-Derived Small Extracellular Vesicles Drive Oligodendroglial Maturation by Restraining MAPK/ERK and Notch Signaling Pathways

2021 ◽  
Vol 9 ◽  
Author(s):  
Marianne S. Joerger-Messerli ◽  
Gierin Thomi ◽  
Valérie Haesler ◽  
Irene Keller ◽  
Patricia Renz ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Mapk Pathway ◽  
Precursor Cells ◽  
Wharton’S Jelly ◽  
Target Cells ◽  
Pathway Enrichment Analysis ◽  
Specific Cell ◽  
Oligodendrocyte Precursor Cells ◽  
Wharton's Jelly ◽  
Oligodendrocyte Precursor

Peripartum cerebral hypoxia and ischemia, and intrauterine infection and inflammation, are detrimental for the precursor cells of the myelin-forming oligodendrocytes in the prematurely newborn, potentially leading to white matter injury (WMI) with long-term neurodevelopmental sequelae. Previous data show that hypomyelination observed in WMI is caused by arrested oligodendroglial maturation rather than oligodendrocyte-specific cell death. In a rat model of premature WMI, we have recently shown that small extracellular vesicles (sEV) derived from Wharton’s jelly mesenchymal stromal cells (WJ-MSC) protect from myelination deficits. Thus, we hypothesized that sEV derived from WJ-MSC directly promote oligodendroglial maturation in oligodendrocyte precursor cells. To test this assumption, sEV were isolated from culture supernatants of human WJ-MSC by ultracentrifugation and co-cultured with the human immortalized oligodendrocyte precursor cell line MO3.13. As many regulatory functions in WMI have been ascribed to microRNA (miR) and as sEV are carriers of functional miR which can be delivered to target cells, we characterized and quantified the miR content of WJ-MSC-derived sEV by next-generation sequencing. We found that WJ-MSC-derived sEV co-localized with MO3.13 cells within 4 h. After 5 days of co-culture, the expression of myelin basic protein (MBP), a marker for mature oligodendrocytes, was significantly increased, while the oligodendrocyte precursor marker platelet-derived growth factor alpha (PDGFRα) was decreased. Notch and MAPK/ERK pathways known to inhibit oligodendrocyte maturation and differentiation were significantly reduced. The pathway enrichment analysis showed that the miR present in WJ-MSC-derived sEV target genes having key roles in the MAPK pathway. Our data strongly suggest that sEV from WJ-MSC directly drive the maturation of oligodendrocyte precursor cells by repressing Notch and MAPK/ERK signaling.

A novel role for thyroid hormone, glucocorticoids and retinoic acid in timing oligodendrocyte development

Development ◽  
1994 ◽  
Vol 120 (5) ◽  
pp. 1097-1108 ◽  
Author(s):  
B.A. Barres ◽  
M.A. Lazar ◽  
M.C. Raff
Keyword(s):  
Cell Proliferation ◽  
Retinoic Acid ◽  
Thyroid Hormone ◽  
Precursor Cells ◽  
Precursor Cell ◽  
Oligodendrocyte Precursor Cells ◽  
Oligodendrocyte Differentiation ◽  
Cell Divisions ◽  
Oligodendrocyte Precursor ◽  
Oligodendrocyte Development

The timing of oligodendrocyte differentiation is thought to depend on an intrinsic clock in oligodendrocyte precursor cells that counts time or cell divisions and limits precursor cell proliferation. We show here that this clock mechanism can be separated into a counting component and an effector component that stops cell proliferation: whereas the counting mechanism is driven by mitogens that activate cell-surface receptors, the effector mechanism depends on hydrophobic signals that activate intracellular receptors, such as thyroid hormones, glucocorticoids and retinoic acid. When purified oligodendrocyte precursor cells are cultured at clonal density in serum-free medium in the presence of mitogens but in the absence of these hydrophobic signals, the cells divide indefinitely and do not differentiate into postmitotic oligodendrocytes. In the absence of mitogens, the precursor cells stop dividing and differentiate prematurely into oligodendrocytes even in the absence of these hydrophobic signals, indicating that these signals are not required for differentiation. The levels of these signals in vivo may normally regulate the timing of oligodendrocyte differentiation, as the maximum number of precursor cell divisions in culture depends on the concentration of such signals and injections of thyroid hormone into newborn rats accelerates oligodendrocyte development. As thyroid hormone, glucocorticoids and retinoic acid have been shown to promote the differentiation of many types of vertebrate cells, it is possible that they help coordinate the timing of differentiation by signalling clocks in precursor cells throughout a developing animal.

scholarly journals Endothelial cells induce proliferation and bone morphogenic protein mediated differentiation of PDGFRα+ human oligodendrocyte precursor cells to astrocytes in trans-well co-culture

2021 ◽  
Author(s):  
Asmita Dasgupta
Keyword(s):  
Endothelial Cells ◽  
Umbilical Vein ◽  
Precursor Cells ◽  
Bmp Signaling ◽  
Demyelinating Diseases ◽  
Oligodendrocyte Precursor Cells ◽  
Human Endothelial Cells ◽  
Humoral Factors ◽  
Astrocytic Differentiation ◽  
Oligodendrocyte Precursor

Abstract Background CD140a /PDGFRα + human oligodendrocyte precursor cells (OPCs) are a lineage of OPCs with proven potential for use in cell therapy against demyelinating diseases. However, little is known about the contribution of human endothelial cells in the biology of PDGFRα + human OPCs in the stem cell niche. Methods Transwell co-culture technique with human umbilical vein endothelial cells (HUVECs) was adopted under proliferative or differentiating conditions to understand the role of endothelial cells in these processes within OPCs. Proliferation was followed by measuring OPC sphere size, count, sphere dissociation followed by cell count and 3H-methyl thymidine incorporation. Differentiation was followed by immunocytochemistry. Taqman gene expression assay for selective soluble factors was performed for the two co-culture partner cells to determine the expression of these factors on the biology of the OPCs in presence of the endothelial cells. Results In co-culture with HUVECs, under proliferative conditions, OPCs show increased proliferation and sphere formation. In contrast, under differentiating conditions, OPCs show increased differentiation to astrocytes, with a concomitant decrease in differentiation to oligodendrocytes, compared to no co-culture controls. Transcript assay for selected humoral factors in the OPCs and HUVECs revealed bone morphogenic proteins (BMPs), endothelin1, growth arrest specific 6 (GAS6), and interleukin 6 (IL6) to be in higher abundance in HUVECs than OPCs. Whereas the OPCs show higher expression for pleiotrophin (PTN), fibroblast growth factor 9 (FGF9), ciliary neurotrophic factor (CNTF), and leukemia inhibitory factor (LIF) compared to the endothelial cells. Among the transcripts analyzed, BMP4 transcripts were the highest in relative abundance in the endothelial cells indicating possibilities of BMPs being the critical mediator of endothelial cell-mediated effects. In agreement to this, Noggin effectively attenuated HUVEC mediated astrocytic differentiation of CD140a /PDGFRα + fetal human OPCs. Conclusion Based on the above results, the study concludes that human endothelial cells can significantly alter the biology of PDGFαR + fetal human OPCs mediated by humoral factors to induce increased proliferation and BMP mediated astrocytic differentiation. It can be secondarily inferred from these conclusions that using pharmacological inhibitors of BMP signaling along with the PDGFRα + fetal OPC transplantation may make these cells more effective in remyelination therapy.

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