RNA Profiling of Mouse Ependymal Cells after Spinal Cord Injury Identifies the Oncostatin Pathway as a Potential Key Regulator of Spinal Cord Stem Cell Fate

Ependymal cells reside in the adult spinal cord and display stem cell properties in vitro. They proliferate after spinal cord injury and produce neurons in lower vertebrates but predominantly astrocytes in mammals. The mechanisms underlying this glial-biased differentiation remain ill-defined. We addressed this issue by generating a molecular resource through RNA profiling of ependymal cells before and after injury. We found that these cells activate STAT3 and ERK/MAPK signaling post injury and downregulate cilia-associated genes and FOXJ1, a central transcription factor in ciliogenesis. Conversely, they upregulate 510 genes, seven of them more than 20-fold, namely Crym, Ecm1, Ifi202b, Nupr1, Rbp1, Thbs2 and Osmr—the receptor for oncostatin, a microglia-specific cytokine which too is strongly upregulated after injury. We studied the regulation and role of Osmr using neurospheres derived from the adult spinal cord. We found that oncostatin induced strong Osmr and p-STAT3 expression in these cells which is associated with reduction of proliferation and promotion of astrocytic versus oligodendrocytic differentiation. Microglial cells are apposed to ependymal cells in vivo and co-culture experiments showed that these cells upregulate Osmr in neurosphere cultures. Collectively, these results support the notion that microglial cells and Osmr/Oncostatin pathway may regulate the astrocytic fate of ependymal cells in spinal cord injury.

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Reaction of ependymal cells to spinal cord injury: a potential role for oncostatin pathway and microglial cells

10.1101/2021.02.12.428106 ◽

2021 ◽

Author(s):

R. Chevreau ◽

H Ghazale ◽

C Ripoll ◽

C Chalfouh ◽

Q Delarue ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Glial Cells ◽

Mapk Signaling ◽

Central Canal ◽

Microglial Cells ◽

Ependymal Cells ◽

Rna Profiling ◽

Cord Injury

AbstractEpendymal cells with stem cell properties reside in the adult spinal cord around the central canal. They rapidly activate and proliferate after spinal cord injury, constituting a source of new cells. They produce neurons and glial cells in lower vertebrates but they mainly generate glial cells in mammals. The mechanisms underlying their activation and their glial-biased differentiation in mammals remain ill-defined. This represents an obstacle to control these cells. We addressed this issue using RNA profiling of ependymal cells before and after injury. We found that these cells activate STAT3 and ERK/MAPK signaling during injury and downregulate cilia-associated genes and FOXJ1, a central transcription factor in ciliogenesis. Conversely, they upregulate 510 genes, six of them more than 20 fold, namely Crym, Ecm1, Ifi202b, Nupr1, Rbp1, Thbs2 and Osmr. OSMR is the receptor for the inflammatory cytokine oncostatin (OSM) and we studied its regulation and role using neurospheres derived from ependymal cells. We found that OSM induces strong OSMR and p-STAT3 expression together with proliferation reduction and astrocytic differentiation. Conversely, production of oligodendrocyte-lineage OLIG1+ cells was reduced. OSM is specifically expressed by microglial cells and was strongly upregulated after injury. We observed microglial cells apposed to ependymal cells in vivo and co-cultures experiments showed that these cells upregulate OSMR in neurosphere cells. Collectively, these results support the notion that microglial cells and OSMR/OSM pathway regulate ependymal cells in injury. In addition, the generated high throughput data provides a unique molecular resource to study how ependymal cell react to spinal cord lesion.

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Faculty Opinions recommendation of Regeneration of dorsal column fibers into and beyond the lesion site following adult spinal cord injury.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1001592.11054 ◽

2001 ◽

Author(s):

Marie Filbin

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Dorsal Column ◽

Lesion Site ◽

Cord Injury ◽

Adult Spinal Cord

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Stem Cell Transplantation: A Promising Therapy for Spinal Cord Injury

Current Stem Cell Research & Therapy ◽

10.2174/1574888x14666190823144424 ◽

2020 ◽

Vol 15 (4) ◽

pp. 321-331 ◽

Cited By ~ 2

Author(s):

Zhe Gong ◽

Kaishun Xia ◽

Ankai Xu ◽

Chao Yu ◽

Chenggui Wang ◽

...

Keyword(s):

Spinal Cord ◽

Stem Cells ◽

Spinal Cord Injury ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Therapeutic Potential ◽

Embryonic Stem ◽

Current Status ◽

Cord Injury

Spinal Cord Injury (SCI) causes irreversible functional loss of the affected population. The incidence of SCI keeps increasing, resulting in huge burden on the society. The pathogenesis of SCI involves neuron death and exotic reaction, which could impede neuron regeneration. In clinic, the limited regenerative capacity of endogenous cells after SCI is a major problem. Recent studies have demonstrated that a variety of stem cells such as induced Pluripotent Stem Cells (iPSCs), Embryonic Stem Cells (ESCs), Mesenchymal Stem Cells (MSCs) and Neural Progenitor Cells (NPCs) /Neural Stem Cells (NSCs) have therapeutic potential for SCI. However, the efficacy and safety of these stem cellbased therapy for SCI remain controversial. In this review, we introduce the pathogenesis of SCI, summarize the current status of the application of these stem cells in SCI repair, and discuss possible mechanisms responsible for functional recovery of SCI after stem cell transplantation. Finally, we highlight several areas for further exploitation of stem cells as a promising regenerative therapy of SCI.

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Knockdown of long non-coding RNA LEF1-AS1 attenuates apoptosis and inflammatory injury of microglia cells following spinal cord injury

Journal of Orthopaedic Surgery and Research ◽

10.1186/s13018-020-02041-6 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Sheng-Yu Cui ◽

Wei Zhang ◽

Zhi-Ming Cui ◽

Hong Yi ◽

Da-Wei Xu ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Cell Viability ◽

Microglial Cells ◽

Protective Effects ◽

Loss Of Function ◽

Sprague Dawley ◽

Cord Injury ◽

Apoptosis And Inflammation

Abstract Background Spinal cord injury (SCI) is associated with health burden both at personal and societal levels. Recent assessments on the role of lncRNAs in SCI regulation have matured. Therefore, to comprehensively explore the function of lncRNA LEF1-AS1 in SCI, there is an urgent need to understand its occurrence and development. Methods Using in vitro experiments, we used lipopolysaccharide (LPS) to treat and establish the SCI model primarily on microglial cells. Gain- and loss of function assays of LEF1-AS1 and miR-222-5p were conducted. Cell viability and apoptosis of microglial cells were assessed via CCK8 assay and flow cytometry, respectively. Adult Sprague-Dawley (SD) rats were randomly divided into four groups: Control, SCI, sh-NC, and sh-LEF-AS1 groups. ELISA test was used to determine the expression of TNF-α and IL-6, whereas the protein level of apoptotic-related markers (Bcl-2, Bax, and cleaved caspase-3) was assessed using Western blot technique. Results We revealed that LncRNA LEF1-AS1 was distinctly upregulated, whereas miR-222-5p was significantly downregulated in LPS-treated SCI and microglial cells. However, LEF1-AS1 knockdown enhanced cell viability, inhibited apoptosis, as well as inflammation of LPS-mediated microglial cells. On the contrary, miR-222-5p upregulation decreased cell viability, promoted apoptosis, and inflammation of microglial cells. Mechanistically, LEF1-AS1 served as a competitive endogenous RNA (ceRNA) by sponging miR-222-5p, targeting RAMP3. RAMP3 overexpression attenuated LEF1-AS1-mediated protective effects on LPS-mediated microglial cells from apoptosis and inflammation. Conclusion In summary, these findings ascertain that knockdown of LEF1-AS1 impedes SCI progression via the miR-222-5p/RAMP3 axis.

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Pentapeptide IKVAV-engineered hydrogels for neural stem cell attachment

Biomaterials Science ◽

10.1039/d0bm01454k ◽

2021 ◽

Author(s):

Yixia Yin ◽

Wenwu Wang ◽

Qi Shao ◽

Binbin Li ◽

Dan Yu ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Stem Cell ◽

Neural Stem Cell ◽

Cell Attachment ◽

Injury Repair ◽

Cord Injury ◽

Proliferation Ability

A IKVAV-functionalized hydrogel is developed. It not only enhances neural stem cell (NSC) attachment, growth, and differentiation, but also maintains the proliferation ability of the NSC spheroids in the hydrogel for spinal cord injury repair.

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