Macrophage centripetal migration drives spontaneous healing process after spinal cord injury

Kobayakawa, Kazu; Ohkawa, Yasuyuki; Yoshizaki, Shingo; Tamaru, Tetsuya; Saito, Takeyuki; Kijima, Ken; Yokota, Kazuya; Hara, Michiya; Kubota, Kensuke; Matsumoto, Yoshihiro; Harimaya, Katsumi; Ozato, Keiko; Masuda, Takahiro; Tsuda, Makoto; Tamura, Tomohide; Inoue, Kazuhide; Edgerton, V. Reggie; Iwamoto, Yukihide; Nakashima, Yasuharu; Okada, Seiji

doi:10.1126/sciadv.aav5086

Cited by 68 publications

(50 citation statements)

References 67 publications

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“…M2 macrophages may also enhance the polarization of reactive astrocytes after SCI (Sonn et al, 2019). Inhibition of the centripetal migration of macrophages impairs the migration of astrocytes and glial scar formation, resulting in exacerbated neuronal loss and decreased functional recovery (Kobayakawa et al, 2019). However, excessive macrophage activity also contributes to damaging cascade reactions, secondary damage and axonal dieback (Evans et al, 2014).…”

Section: Macrophagesmentioning

confidence: 99%

Dissecting the Dual Role of the Glial Scar and Scar-Forming Astrocytes in Spinal Cord Injury

Yang

Dai

Chen

et al. 2020

Front. Cell. Neurosci.

134

161

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Recovery from spinal cord injury (SCI) remains an unsolved problem. As a major component of the SCI lesion, the glial scar is primarily composed of scar-forming astrocytes and plays a crucial role in spinal cord regeneration. In recent years, it has become increasingly accepted that the glial scar plays a dual role in SCI recovery. However, the underlying mechanisms of this dual role are complex and need further clarification. This dual role also makes it difficult to manipulate the glial scar for therapeutic purposes. Here, we briefly discuss glial scar formation and some representative components associated with scar-forming astrocytes. Then, we analyze the dual role of the glial scar in a dynamic perspective with special attention to scar-forming astrocytes to explore the underlying mechanisms of this dual role. Finally, taking the dual role of the glial scar into account, we provide several pieces of advice on novel therapeutic strategies targeting the glial scar and scar-forming astrocytes.

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Section: Macrophagesmentioning

confidence: 99%

Dissecting the Dual Role of the Glial Scar and Scar-Forming Astrocytes in Spinal Cord Injury

Yang

Dai

Chen

et al. 2020

Front. Cell. Neurosci.

134

161

View full text Add to dashboard Cite

show abstract

“…Both the CNS cells in the neurovascular unit and blood-borne peripheral cells constantly modulate the BSCB and influence its breakdown and repair after SCI [ 11 ], however, a significant amount of research in the past few years has focused on the effects of astrocytes and pericytes on BSCB homeostasis, yet the role of macrophages/microglia in the BSCB has been seldom defined. Current data indicate that a large number of peripheral macrophages will enter the injured spinal cord and trigger a cascade of responses after SCI [ 12 ]. It was showed that macrophages have two polarization states including “classically-activated”, proinflammatory, cytotoxic M1 phenotype and “alternatively-activated”, anti-inflammatory, pro-repair M2 phenotype [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Exosomal miR-155 from M1-polarized macrophages promotes EndoMT and impairs mitochondrial function via activating NF-κB signaling pathway in vascular endothelial cells after traumatic spinal cord injury

Tang

Rong

et al. 2021

Redox Biology

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Pathologically, blood-spinal-cord-barrier (BSCB) disruption after spinal cord injury (SCI) leads to infiltration of numerous peripheral macrophages into injured areas and accumulation around newborn vessels. Among the leaked macrophages, M1-polarized macrophages are dominant and play a crucial role throughout the whole SCI process. The aim of our study was to investigate the effects of M1-polarized bone marrow-derived macrophages (M1-BMDMs) on vascular endothelial cells and their underlying mechanism. Microvascular endothelial cell line bEnd.3 cells were treated with conditioned medium or exosomes derived from M1-BMDMs, followed by evaluations of endothelial-to-mesenchymal transition (EndoMT) and mitochondrial function. After administration, we found conditioned medium or exosomes from M1-BMDMs significantly promoted EndoMT of vascular endothelial cells in vitro and in vivo , which aggravated BSCB disruption after SCI. In addition, significant dysfunction of mitochondria and accumulation of reactive oxygen species (ROS) were also detected. Furthermore, bioinformatics analysis demonstrated that miR-155 is upregulated in both M1-polarized macrophages and microglia. Experimentally, exosomal transfer of miR-155 participated in M1-BMDMs-induced EndoMT and mitochondrial ROS generation in bEnd.3 cells, and subsequently activated the NF-κB signaling pathway by targeting downstream suppressor of cytokine signaling 6 (SOCS6), and suppressing SOCS6-mediated p65 ubiquitination and degradation. Finally, a series of rescue assay further verified that exosomal miR155/SOCS6/p65 axis regulated the EndoMT process and mitochondrial function in vascular endothelial cells. In summary, our work revealed a potential mechanism describing the communications between macrophages and vascular endothelial cells after SCI which could benefit for future research and aid in the development of potential therapies for SCI.

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“…In spite of their therapeutic potential, there are some obvious disadvantages associated to the use of MSCs in the treatment of SCI. Specifically, the survival rate of the transplanted stem cells is very low due to severe inflammatory responses or other factors in the injured microenvironment [ 10 – 12 ]. Additionally, the scar-forming gliosis prevents the integration, differentiation, and axon outgrowth of grafted stem cells in the lesion area [ 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

Exosomes derived from human placental mesenchymal stem cells enhanced the recovery of spinal cord injury by activating endogenous neurogenesis

et al. 2021

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Background Spinal cord injury (SCI) is a debilitating medical condition that can result in the irreversible loss of sensorimotor function. Current therapies fail to provide an effective recovery being crucial to develop more effective approaches. Mesenchymal stem cell (MSC) exosomes have been shown to be able to facilitate axonal growth and act as mediators to regulate neurogenesis and neuroprotection, holding great therapeutic potential in SCI conditions. This study aimed to assess the potential of human placental MSC (hpMSC)-derived exosomes on the functional recovery and reactivation of endogenous neurogenesis in an experimental animal model of SCI and to explore the possible mechanisms involved. Methods The hpMSC-derived exosomes were extracted and transplanted in an experimental animal model of SCI with complete transection of the thoracic segment. Functional recovery, the expression of neural stem/progenitor cell markers and the occurrence of neurogenesis, was assessed 60 days after the treatment. In vitro, neural stem cells (NSCs) were incubated with the isolated exosomes for 24 h, and the phosphorylation levels of mitogen-activated protein kinase kinase (MEK), extracellular signal-regulated kinases (ERK), and cAMP response element binding (CREB) proteins were assessed by western blot. Results Exosomes were successfully isolated and purified from hpMSCs. Intravenous injections of these purified exosomes significantly improved the locomotor activity and bladder dysfunction of SCI animals. Further study of the exosomes’ therapeutic action revealed that hpMSC-derived exosomes promoted the activation of proliferating endogenous neural stem/progenitor cells as denoted by the significant increase of spinal SOX2+GFAP+, PAX6+Nestin+, and SOX1+KI67+ cells. Moreover, animals treated with exosomes exhibited a significative higher neurogenesis, as indicated by the higher percentage of DCX+MAP 2+ neurons. In vitro, hpMSC-derived exosomes promoted the proliferation of NSCs and the increase of the phosphorylated levels of MEK, ERK, and CREB. Conclusions This study provides evidence that the use of hpMSC-derived exosomes may constitute a promising therapeutic strategy for the treatment of SCI.

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Macrophage centripetal migration drives spontaneous healing process after spinal cord injury

Cited by 68 publications

References 67 publications

Dissecting the Dual Role of the Glial Scar and Scar-Forming Astrocytes in Spinal Cord Injury

Dissecting the Dual Role of the Glial Scar and Scar-Forming Astrocytes in Spinal Cord Injury

Exosomal miR-155 from M1-polarized macrophages promotes EndoMT and impairs mitochondrial function via activating NF-κB signaling pathway in vascular endothelial cells after traumatic spinal cord injury

Exosomes derived from human placental mesenchymal stem cells enhanced the recovery of spinal cord injury by activating endogenous neurogenesis

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