DMT48
Nurown (MSC-NTF) Cells Maintain Neurotrophic and Immunomodulatory Effects with S1P Modulator Siponimod
MSC-NTF cells (NurOwn®) are autologous bone-marrow derived mesenchymal stem cells (MSC) induced to secrete high levels of neurotrophic factors (NTFs). MSC-NTF cells were evaluated in a phase 2 clinical study in progressive MS (NCT 03799718 demonstrating consistent increases in CSF biomarkers of neuroprotection (VEGF-A, HGF, LIF, Fetuin-A, Follistatin, and NCAM-1). Sphingosine 1-phosphate (S1P) receptor modulators that internalize S1P1 receptors, thereby inhibiting efflux of lymphocytes from lymph nodes and thymus, may show direct neuroprotective effects,1 and in a the EAE mouse model2 were shown to promote survival and functionality of MSCs with synergistic effects.
Objectives:
In this study we evaluated the interaction of the S1P modulator siponimod with MSC-NTF cell-induced neurite outgrowth in a human neuroblastoma cell line, and on immunomodulatory effects on human activated peripheral blood mononuclear cells (PBMC).
Methods:
MSC-NTF cells were generated from the Bone Marrow of healthy donors. Human neuroblastoma cell line SH-SY5Y neurons were co-cultured with MSC-NTF cells by Transwell inserts with or without the addition of siponimod. Neuronal cells were imaged for three days using the Incucyte S3 live imaging system, and neurite length was calculated using the Neurotrack module. For the immunomodulatory assay, MSC-NTF cells were co-cultured with activated PBMC with or without the addition of siponimod. Secretion of inflammatory cytokines was detected.
Results:
After three days, MSC-NTF cells consistently induced neurite outgrowth of SH-SY5Y cells that was similar in the presence or absence of siponimod at various concentrations. MSC-MTF cells inhibited IFN-γ and TNF-α secretion by 80%. Similar results were obtained with the addition of siponimod.
Conclusions:
The ability of MSC-NTF cells to induce neurite extension and inhibit inflammatory cytokine secretion is not modified in the presence of siponimod, an S1P modulator recently approved for the treatment of SPMS. This suggests that co-administration of siponimod does not interfere with known measures of MSC-NTF cell neuroprotection and immunomodulation and may guide future efforts to optimize this innovative autologous mesenchymal cellular therapy in progressive MS.
References:
- Zhang Y, Mol Therap 2017
- Kassis I, Immunology Letters 2021