Intravenous infusion of mesenchymal stem cells promotes functional recovery in a model of chronic spinal cord injury

Morita, Tomohiro; Sasaki, Masanori; Kataoka‐Sasaki, Yuko; Nakazaki, Masahito; Nagahama, Hiroshi; Oka, Shinichi; Oshigiri, Tsutomu; Takebayashi, Toru; Yamashita, Toshihiko; Kocsis, Jeffery D.; Honmou, Osamu

doi:10.1016/j.neuroscience.2016.08.037

Cited by 105 publications

(81 citation statements)

References 52 publications

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“…This finding has been previously and consistently observed: intravenously administered MSCs were not detected at lesion sites of SCI, whereas they showed beneficial effects on functional recovery [42,65]. However, in immunosuppressed rats, intravenously applied MSCs migrated to the lesion sites of SCI [69] or cerebral ischemia injury [70], although no engrafted MSCs were detected at lesion sites 3 weeks post administration [71]. These results suggest that the differentiation ability and direct cell-tocell contact are not the primary mechanisms that mediate the therapeutic functions of MSCs in injury repair.…”

Section: Discussionsupporting

confidence: 84%

Mesenchymal Stem Cell-Derived Exosomes Reduce A1 Astrocytes via Downregulation of Phosphorylated NFκB P65 Subunit in Spinal Cord Injury

Wang

Pei

Liang

et al. 2018

Cell Physiol Biochem

154

119

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Background/Aims: Neurotoxic A1 astrocytes are induced by inflammation after spinal cord injury (SCI), and the inflammation-related Nuclear Factor Kappa B (NFκB) pathway may be related to A1-astrocyte activation. Mesenchymal stem cell (MSC) transplantation is a promising therapy for SCI, where transplanted MSCs exhibit anti-inflammatory effects by downregulating proinflammatory factors, such as Tumor Necrosis Factor (TNF)-α and NFκB. MSC-exosomes (MSC-exo) reportedly mimic the beneficial effects of MSCs. Therefore, in this study, we investigated whether MSCs and MSC-exo exert inhibitory effects on A1 astrocytes and are beneficial for recovery after SCI. Methods: The effects of MSC and MSC-exo on SCIinduced A1 astrocytes, and the potential mechanisms were investigated in vitro and in vivo using immunofluorescence and western blot. In addition, we assessed the histopathology, levels of proinflammatory cytokines and locomotor function to verify the effects of MSC and MSC-exo on SCI rats. Results: MSC or MSC-exo co-culture reduced the proportion of SCIinduced A1 astrocytes. Intravenously-injected MSC or MSC-exo after SCI significantly reduced the proportion of A1 astrocytes, the percentage of p65 positive nuclei in astrocytes, and the percentage of TUNEL-positive cells in the ventral horn. Additionally, we observed decreased lesion area and expression of TNFα, Interleukin (IL)-1α and IL-1β, elevated expression of Myelin Basic Protein (MBP), Synaptophysin (Syn) and Neuronal Nuclei (NeuN), and improved Basso, Beattie & Bresnahan (BBB) scores and inclined-plane-test angle. In vitro assay showed that MSC and MSC-exo reduced SCI-induced A1 astrocytes, probably via inhibiting the nuclear translocation of the NFκB p65. Conclusion: MSC and MSC-exo reduce SCI-induced A1 astrocytes, probably via inhibiting nuclear translocation of NFκB p65, and exert antiinflammatory and neuroprotective effects following SCI, with the therapeutic effect of MSCexo comparable with that of MSCs when applied intravenously.

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Section: Discussionsupporting

confidence: 84%

Mesenchymal Stem Cell-Derived Exosomes Reduce A1 Astrocytes via Downregulation of Phosphorylated NFκB P65 Subunit in Spinal Cord Injury

Wang

Pei

Liang

et al. 2018

Cell Physiol Biochem

154

119

View full text Add to dashboard Cite

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“…The function of stem cell transplantation approach for SCI might be different depending on the different time phases [16]. For chronic SCI, MSCs were transplanted 8–10 weeks after the induction of SCI and an improved functional recovery and neural regeneration was verified [78, 79]. The systemic infusion of MSCs resulted in functional improvement, which is associated with structural changes, including stabilization of the blood-spinal cord barrier (BSCB), axonal sprouting/regeneration, and remyelination.…”

Section: Function Of Msc Transplantation After Scimentioning

confidence: 99%

Roles of Mesenchymal Stem Cells in Spinal Cord Injury

Zhang

2017

Stem Cells International

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Spinal cord injury (SCI) represents one of the most complicated and heterogeneous pathological processes of central nervous system (CNS) impairments, which is still beyond functional regeneration. Transplantation of mesenchymal stem cells (MSCs) has been shown to promote the repair of the injured spinal cord tissues in animal models, and therefore, there is much interest in the clinical use of these cells. However, many questions which are essential to improve the therapy effects remain unanswered. For instance, the functional roles and related molecular regulatory mechanisms of MSCs in vivo are not yet completely determined. It is important for transplanted cells to migrate into the injured tissue, to survive and undergo neural differentiation, or to play neural protection roles by various mechanisms after SCI. In this review, we will focus on some of the recent knowledge about the biological behavior and function of MSCs in SCI. Meanwhile, we highlight the function of biomaterials to direct the behavior of MSCs based on our series of work on silk fibroin biomaterials and attempt to emphasize combinational strategies such as tissue engineering for functional improvement of SCI.

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“…Different procedures have been reported, including intravenous, intramedullary and intradural transplantations [38,[58][59][60] . Following systemic and parenchymal transplantation, the limited number and viability of stem cells in situ and pulmonary passage impede the effectiveness of this technique [61,62] .…”

Section: Discussionmentioning

confidence: 99%

Multichannel polymer scaffold seeded with activated Schwann cells and bone mesenchymal stem cells improves axonal regeneration and functional recovery after rat spinal cord injury

Yang

Zhang

et al. 2017

Acta Pharmacol Sin

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The adult mammalian CNS has a limited capacity to regenerate after traumatic injury. In this study, a combinatorial strategy to promote axonal regeneration and functional recovery after spinal cord injury (SCI) was evaluated in adult rats. The rats were subjected to a complete transection in the thoracic spinal cord, and multichannel scaffolds seeded with activated Schwann cells (ASCs) and/or rat bone marrow-derived mesenchymal stem cells (MSCs) were acutely grafted into the 3-mm-wide transection gap. At 4 weeks posttransplantation and thereafter, the rats receiving scaffolds seeded with ASCs and MSCs exhibited significant recovery of nerve function as shown by the Basso, Beattie and Bresnahan (BBB) score and electrophysiological test results. Immunohistochemical analyses at 4 and 8 weeks after transplantation revealed that the implanted MSCs at the lesion/graft site survived and differentiated into neuron-like cells and co-localized with host neurons. Robust bundles of regenerated fibers were identified in the lesion/graft site in the ASC and MSC co-transplantation rats, and neurofilament 200 (NF) staining confirmed that these fibers were axons. Furthermore, myelin basic protein (MBP)-positive myelin sheaths were also identified at the lesion/graft site and confirmed via electron microscopy. In addition to expressing mature neuronal markers, sparse MSC-derived neuron-like cells expressed choline acetyltransferase (ChAT) at the injury site of the ASC and MSC co-transplantation rats. These findings suggest that co-transplantation of ASCs and MSCs in a multichannel polymer scaffold may represent a novel combinatorial strategy for the treatment of spinal cord injury.

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Intravenous infusion of mesenchymal stem cells promotes functional recovery in a model of chronic spinal cord injury

Cited by 105 publications

References 52 publications

Mesenchymal Stem Cell-Derived Exosomes Reduce A1 Astrocytes via Downregulation of Phosphorylated NFκB P65 Subunit in Spinal Cord Injury

Mesenchymal Stem Cell-Derived Exosomes Reduce A1 Astrocytes via Downregulation of Phosphorylated NFκB P65 Subunit in Spinal Cord Injury

Roles of Mesenchymal Stem Cells in Spinal Cord Injury

Multichannel polymer scaffold seeded with activated Schwann cells and bone mesenchymal stem cells improves axonal regeneration and functional recovery after rat spinal cord injury

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