Intravenous C16 and angiopoietin-1 improve the efficacy of placenta-derived mesenchymal stem cell therapy for EAE

Scientific Reports, Mar 2018

The placenta has emerged as an attractive source of mesenchymal stem cells (MSCs) because of the absence of ethical issues, non-invasive access, and abundant yield. However, inflammatory cell invasion into grafts negatively impacts the survival and efficacy of transplanted cells. Previous studies have shown that synthetic C16 peptide can competitively block the transmigration of leukocytes into the central nerve system, while angiopoietin-1 (Ang-1) can inhibit inflammation-induced blood vessel leakage and inflammatory cell infiltration in rats with experimental allergic encephalomyelitis (EAE). In this study, we investigated the effects of intravenous administration of C16 and Ang-1 on the efficacy of placenta-derived MSC (PMSC) transplantation in a rat model of EAE. We found that, compared with PMSCs alone, treatment with PMSCs along with intravenously administered C16 and Ang-1 was more effective at ameliorating demyelination/neuronal loss and neurological dysfunction, reducing inflammatory cell infiltration, perivascular edema, and reactive astrogliosis (p < 0.05). Mechanistic studies revealed that intravenous C16 and Ang-1 increased PMSC engraftment in the central nervous system and promoted expression of the neurotropic proteins brain-derived neurotrophic factor, growth-associated protein 43, and p75 neurotrophin receptor as well as the neuronal-glial lineage markers neurofilament protein 200 and myelin basic protein in the engrafted PMSCs.

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Intravenous C16 and angiopoietin-1 improve the efficacy of placenta-derived mesenchymal stem cell therapy for EAE

Abstract The placenta has emerged as an attractive source of mesenchymal stem cells (MSCs) because of the absence of ethical issues, non-invasive access, and abundant yield. However, inflammatory cell invasion into grafts negatively impacts the survival and efficacy of transplanted cells. Previous studies have shown that synthetic C16 peptide can competitively block the transmigration of leukocytes into the central nerve system, while angiopoietin-1 (Ang-1) can inhibit inflammation-induced blood vessel leakage and inflammatory cell infiltration in rats with experimental allergic encephalomyelitis (EAE). In this study, we investigated the effects of intravenous administration of C16 and Ang-1 on the efficacy of placenta-derived MSC (PMSC) transplantation in a rat model of EAE. We found that, compared with PMSCs alone, treatment with PMSCs along with intravenously administered C16 and Ang-1 was more effective at ameliorating demyelination/neuronal loss and neurological dysfunction, reducing inflammatory cell infiltration, perivascular edema, and reactive astrogliosis (p < 0.05). Mechanistic studies revealed that intravenous C16 and Ang-1 increased PMSC engraftment in the central nervous system and promoted expression of the neurotropic proteins brain-derived neurotrophic factor, growth-associated protein 43, and p75 neurotrophin receptor as well as the neuronal-glial lineage markers neurofilament protein 200 and myelin basic protein in the engrafted PMSCs. Introduction The autoimmune disease multiple sclerosis (MS) affects the central nervous system (CNS) and has great socio-economic impact in developed countries1. In MS, the immune system attacks the protective sheath (myelin) of nerve fibers, eventually leading to permanent nerve damage and neurological disability2. Mesenchymal stem cells (MSCs) have demonstrated immunoregulatory and neuroprotective functions in animal models of MS, and thus, are considered a new potential therapeutic modality for this disease3,4,5. Apart from their high proliferation and differentiation potential, embryonic MSCs (EMSCs) have been shown to exhibit superior immunoregulatory properties, and therefore, outperform bone marrow MSCs in the treatment of experimental allergic encephalomyelitis (EAE), a common model of MS6,7,8. However, the application of EMSCs is limited by ethical concerns. In recent years, placenta-derived MSCs (PMSCs) have emerged as an attractive alternate source of MSCs for their lack of ethical issues, non-invasive access, and abundant yield9. In a recent study, transplanted PMSCs were shown to reduce disease severity and improve survival in a mouse EAE model, presumably through the release of the anti-inflammatory protein tumor necrosis factor alpha (TNF-α)-stimulated gene/protein 6 (TSG-6)10. Increased blood–brain barrier (BBB) permeability and infiltration of inflammatory cells into the CNS lead to demyelination and neuronal dysfunction in EAE11. In MSC treatment of EAE, inflammatory factors such as nuclear factor kappa-light chain-enhancer of activated B cells (NF-κB), tumor necrosis factor alpha (TNF-α), and cyclooxygenase 2 (COX-2) in the inflamed CNS microenvironment can negatively impact the survival of grafted cells12. Thus, blocking inflammatory cell infiltration should protect not only the neurons within the CNS of transplant recipients but also the transplanted MSCs themselves. Angiopoietin-1 (Ang-1), an endothelial growth factor, is well documented to promote and maintain vascular maturation, homeostasis, and integrity13. It has been shown to inhibit inflammation-induced blood vessel leakage and inflammatory cell infiltration in a rat model of EAE14. C16 is a synthetic peptide that selectively binds the αvβ3 and αvβ1 integrins expressed on endothelial cells, and this binding has been shown to inhibit inflammatory cell transmigration by blocking leukocyte–endothelial interaction15. Furthermore, C16 and Ang-1 have been reported to work synergistically to mitigate vascular leakage and inflammation and protect against demyelination and axonal loss in rats with EAE14. In the present study, we examined the effects of intravenous C16 and Ang-1 on the efficacy of PMSC transplantation for treating EAE in a rat model. The neurological functions, CNS infiltration of inflammatory cells, perivascular edema, white matter demyelination, axonal loss, neuronal apoptosis, and reactive astrogliosis were evaluated. The homing of transplanted PMSCs to the CNS as well as the expression of the neurotrophic proteins brain-derived neurotrophic factor (BDNF), growth-associated protein 43 (GAP-43), p75 neurotrophin receptor (p75NTR) and the neuronal-glial lineage markers neurofilament protein 200 (NF-200) and myelin basic protein (MBP) in the engrafted PMSCs were examined. Results Intravenous C16 and Ang-1 enhanced the efficacy of PMSC therapy for preventing neurological dysfunctions in rats with EAE Neurological dysfunctions in rats with EAE started 1 week pos (...truncated)


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Ke-wei Tian, Yuan-yuan Zhang, Hong Jiang, Shu Han. Intravenous C16 and angiopoietin-1 improve the efficacy of placenta-derived mesenchymal stem cell therapy for EAE, Scientific Reports, 2018, Issue: 8, DOI: 10.1038/s41598-018-22867-9