Endothelial Progenitor Cells Promote Astrogliosis following Spinal Cord Injury through Jagged1-Dependent Notch Signaling

Transplantation of neural stem/progenitor cells (NS/PCs) promotes functional recovery after spinal cord injury (SCI); however, few studies have examined the optimal site of NS/PC transplantation in the spinal cord. The purpose of this study was to determine the optimal transplantation site of NS/PCs for the treatment of SCI. Wild-type mice were generated with contusive SCI at the T10 level, and NS/PCs were derived from fetal transgenic mice. These NS/PCs ubiquitously expressed ffLuc-cp156 protein (Venus and luciferase fusion protein) and so could be detected by in vivo bioluminescence imaging 9 days postinjury. NS/PCs (low: 250,000 cells per mouse; high: 1 million cells per mouse) were grafted into the spinal cord at the lesion epicenter (E) or at rostral and caudal (RC) sites. Phosphate-buffered saline was injected into E as a control. Motor functional recovery was better in each of the transplantation groups (E-Low, E-High, RC-Low, and RC-High) than in the control group. The photon counts of the grafted NS/PCs were similar in each of the four transplantation groups, suggesting that the survival of NS/PCs was fairly uniform when more than a certain threshold number of cells were transplanted. Quantitative RT-PCR analyses demonstrated that brain-derived neurotropic factor expression was higher in the RC segment than in the E segment, and this may underlie why NS/PCs more readily differentiated into neurons than into astrocytes in the RC group. The location of the transplantation site did not affect the area of spared fibers, angiogenesis, or the expression of any other mediators. These findings indicated that the microenvironments of the E and RC sites are able to support NS/PCs transplanted during the subacute phase of SCI similarly. Optimally, a certain threshold number of NS/PCs should be grafted into the E segment to avoid damaging sites adjacent to the lesion during the injection procedure.

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Human Oligodendrogenic Neural Progenitor Cells Delivered with Chondroitinase ABC Facilitate Functional Repair of Chronic Spinal Cord Injury

Stem Cell Reports ◽

10.1016/j.stemcr.2018.10.017 ◽

2018 ◽

Vol 11 (6) ◽

pp. 1433-1448 ◽

Cited By ~ 27

Author(s):

Satoshi Nori ◽

Mohamad Khazaei ◽

Christopher S. Ahuja ◽

Kazuya Yokota ◽

Jan-Eric Ahlfors ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Progenitor Cells ◽

Neural Progenitor Cells ◽

Neural Progenitor ◽

Chronic Spinal Cord Injury ◽

Chondroitinase Abc ◽

Cord Injury

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Electroacupuncture in the repair of spinal cord injury: inhibiting the Notch signaling pathway and promoting neural stem cell proliferation

Neural Regeneration Research ◽

10.4103/1673-5374.153687 ◽

2015 ◽

Vol 10 (3) ◽

pp. 394 ◽

Cited By ~ 22

Author(s):

Hua-lin Yu ◽

Xin Geng ◽

Tao Sun ◽

Jing-hui Li ◽

Ning Zhao ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Cell Proliferation ◽

Stem Cell ◽

Notch Signaling ◽

Signaling Pathway ◽

Notch Signaling Pathway ◽

Stem Cell Proliferation ◽

Neural Stem Cell Proliferation ◽

Cord Injury

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Long-Term Selective Stimulation of Transplanted Neural Stem/Progenitor Cells for Spinal Cord Injury Improves Locomotor Function

SSRN Electronic Journal ◽

10.2139/ssrn.3858060 ◽

2021 ◽

Author(s):

Momotaro Kawai ◽

Kent Imaizumi ◽

Mitsuru Ishikawa ◽

Shinsuke Shibata ◽

Munehisa Shinozaki ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Progenitor Cells ◽

Locomotor Function ◽

Selective Stimulation ◽

Cord Injury ◽

Neural Stem Progenitor Cells ◽

Stimulation Of

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Adipose mesenchymal stem cell transplantation alleviates spinal cord injury-induced neuroinflammation partly by suppressing the Jagged1/Notch pathway

10.21203/rs.2.17540/v1 ◽

2019 ◽

Author(s):

Zhou Zhilai ◽

Tian Xiaobo ◽

Mo Biling ◽

Xu Huali ◽

Yao Shun ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Stem Cell ◽

Mesenchymal Stem Cell ◽

Notch Signaling ◽

Signaling Pathway ◽

Notch Signaling Pathway ◽

Therapeutic Effects ◽

Mesenchymal Stem Cell Transplantation ◽

Cord Injury

Abstract Background The therapeutic effects of adipose-derived mesenchymal stem cell (ADSC) transplantation have been demonstrated in several models of central nervous system (CNS) injury and are thought to involve the modulation of the inflammatory response. However, the exact underlying molecular mechanism is poorly understood. Activation of the Jagged1/Notch signaling pathway is thought to involve inflammatory and gliotic events in the CNS. Here, we elucidated the effect of ADSC transplantation on the inflammatory reaction after spinal cord injury (SCI) and the potential mechanism mediated by Jagged1/Notch signaling pathway suppression.Methods Using a mouse model of compression SCI, ADSCs and Jagged1 small interfering RNA (siRNA) were injected into the spinal cord. Locomotor function, spinal cord tissue morphology and the levels of various proteins and transcripts were compared between groups.Results ADSC treatment resulted in significant downregulation of proinflammatory mediator expression and reduced ionized calcium binding adapter molecule 1 (Iba1) and ED1 staining in the injured spinal cord, promoting the survival of neurons. These changes were accompanied by improved functional recovery. The augmentation of the Jagged1/Notch signaling pathway after SCI was suppressed by ADSC transplantation. The inhibition of the Jagged1/Notch signaling pathway by Jagged1 siRNA resulted in a decrease in SCI-induced proinflammatory cytokines as well as the activation of microglia. Furthermore, Jagged1 knockdown suppressed the phosphorylation of JAK/STAT3 following SCI.Conclusion The results of this study demonstrated that the therapeutic effects of ADSCs in SCI mice were partly due to Jagged1/notch signaling pathway inhibition and a subsequent reduction in JAK/STAT3 phosphorylation.

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The fate and function of oligodendrocyte progenitor cells after traumatic spinal cord injury

Glia ◽

10.1002/glia.23706 ◽

2019 ◽

Vol 68 (2) ◽

pp. 227-245 ◽

Cited By ~ 5

Author(s):

Greg J. Duncan ◽

Sohrab B. Manesh ◽

Brett J. Hilton ◽

Peggy Assinck ◽

Jason R. Plemel ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Progenitor Cells ◽

Traumatic Spinal Cord Injury ◽

Oligodendrocyte Progenitor Cells ◽

Oligodendrocyte Progenitor ◽

Cord Injury ◽

And Function

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Multipotent Adult Progenitor Cells, but Not Tissue Inhibitor of Matrix Metalloproteinase-3, Increase Tissue Sparing and Reduce Urological Complications following Spinal Cord Injury

Journal of Neurotrauma ◽

10.1089/neu.2018.5727 ◽

2019 ◽

Vol 36 (9) ◽

pp. 1416-1427 ◽

Cited By ~ 1

Author(s):

James M. Jones ◽

Marc A. DePaul ◽

Cynthia R. Gregory ◽

Bradley T. Lang ◽

Hua Xie ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Matrix Metalloproteinase ◽

Progenitor Cells ◽

Tissue Inhibitor ◽

Matrix Metalloproteinase 3 ◽

Multipotent Adult Progenitor Cells ◽

Urological Complications ◽

Cord Injury ◽

Tissue Sparing

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Cytokines Induce Monkey Neural Stem Cell Differentiation through Notch Signaling

BioMed Research International ◽

10.1155/2020/1308526 ◽

2020 ◽

Vol 2020 ◽

pp. 1-13 ◽

Cited By ~ 1

Author(s):

Min Wang ◽

Liming Yu ◽

Lu-Ying Zhu ◽

Hua He ◽

Jie Ren ◽

...

Keyword(s):

Spinal Cord ◽

Stem Cells ◽

Spinal Cord Injury ◽

Neural Stem Cells ◽

Notch Signaling ◽

Stem Cell Differentiation ◽

Leukaemia Inhibitory Factor ◽

Cytokine Signaling ◽

Cord Injury ◽

Theoretical Evidence

The mammalian central nervous system (CNS) has a limited ability to renew the damaged cells after a brain or spinal cord injury whether it is nonhuman primates like monkeys or humans. Transplantation of neural stem cells (NSCs) is a potential therapy for CNS injuries due to their pluripotency and differentiation abilities. Cytokines play an important role in CNS development and repair of CNS injuries. However, the detailed cytokine signaling response in monkey neural stem cells is rarely studied. In our previous research, we isolated NSCs from the adult monkey brain and found the effects of cytokines on monkey NSCs. Now, we further analyzed the regulation mechanisms of cytokines to the proliferation of monkey NSCs such as bone morphogenic protein 4 (BMP4), BMP4/leukaemia inhibitory factor (LIF), or retinoic acid (RA)/Forskolin. The data showed that BMP4 inhibited cell proliferation to arrest, but it did not affect the stemness of NSCs. BMP4/LIF promoted the astrocyte-like differentiation of monkey NSCs, and RA/forskolin induced the neuronal differentiation of monkey NSCs. BMP4/LIF and RA/forskolin induced monkey NSC differentiation by regulating Notch signaling. These results provide some theoretical evidence for NSC therapy to brain or spinal cord injury in regenerative medicine.

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