Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis

Pluchino, ﻿Stefano; Quattrini, Angelo; Brambilla, Elena; Gritti, Angela; Salani, Giuliana; Dina, Giorgia; Galli, Rossella; Carro, Ubaldo Del; Amadio, Stefano; Bergami, Alessandra; Furlan, Roberto; Comi, Giancarlo; Vescovi, Angelo L.; Martino, Gianvito

doi:10.1038/nature01552

Cited by 998 publications

(922 citation statements)

References 31 publications

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“…intravenously or intracerebroventricularly) NPCs Chu et al, 2003;Pluchino et al, 2003). NPCs injected systemically into healthy animals were in fact never found in the CNS, while exclusively accumulating (and persisting only for a short period) in peripheral organs (Pluchino et al, 2003). Specific homing of transplanted NPCs has been shown, so far, in experimental brain stroke (Chu et al, 2003;Lindvall and Kokaia, 2011), SCI (Takeuchi et al, 2007), epilepsy (Chu et al, 2004;Hattiangady et al, 2008), HD (Lee et al, 2006), and glioblastoma (Aboody et al, 2000;Ahmed et al, 2011).…”

Section: Homing and Extravasationmentioning

confidence: 99%

“…Tethering, rolling and firm adhesion of injected stem cells to activated endothelial cells and subsequent diapedesis into inflamed CNS areas are sequentially mediated by the constitutive expression of functional α and β integrins (Campos et al, 2004(Campos et al, , 2006Leone et al, 2005;Pluchino et al, 2003Pluchino et al, , 2005, cell adhesion molecules such as CD44 (Pluchino et al, 2003(Pluchino et al, , 2005 (Fig. 2), and chemokine receptors (e.g.…”

Section: Homing and Extravasationmentioning

confidence: 99%

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How stem cells speak with host immune cells in inflammatory brain diseases

Pluchino

Cossetti

2013

Glia

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107

108

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Advances in stem cell biology have raised great expectations that diseases and injuries of the central nervous system (CNS) may be ameliorated by the development of non-hematopoietic stem cell medicines. Yet, the application of adult stem cells as CNS therapeutics is challenging and the interpretation of some of the outcomes ambiguous. In fact, the initial idea that stem cell transplants work only via structural cell replacement has been challenged by the observation of consistent cellular signaling between the graft and the host. Cellular signaling is the foundation of coordinated actions and flexible responses, and arises via networks of exchanging and interacting molecules that transmit patterns of information between cells. Sustained stem cell graft-to-host communication leads to remarkable trophic effects on endogenous brain cells and beneficial modulatory actions on innate and adaptive immune responses in vivo, ultimately promoting the healing of the injured CNS. Among a number of adult stem cell types, mesenchymal stem cells (MSCs) and neural stem/precursor cells (NPCs) are being extensively investigated for their ability to signal to the immune system upon transplantation in experimental CNS diseases. Here, we focus on the main cellular signaling pathways that grafted MSCs and NPCs use to establish a therapeutically relevant cross talk with host immune cells, while examining the role of inflammation in regulating some of the bidirectionality of these communications. We propose that the identification of the players involved in stem cell signaling might contribute to the development of innovative, high clinical impact therapeutics for inflammatory CNS diseases.

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Section: Homing and Extravasationmentioning

confidence: 99%

Section: Homing and Extravasationmentioning

confidence: 99%

How stem cells speak with host immune cells in inflammatory brain diseases

Pluchino

Cossetti

2013

Glia

Self Cite

107

108

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“…Targeting the perivascular niche has been suggested mainly by the intravenous route of cell delivery from which the cells may cross the blood-brain-barrier [253,273,274]. The specific homing of NSCs to the brain was explained in part by the constitutive expression of a wide array of adhesion molecules (integrins, selectins, and so forth) and chemokine receptors by the transplanted cells [273,275].…”

Section: Route Of Cell Deliverymentioning

confidence: 99%

Cell Therapy for Multiple Sclerosis

Ben‐Hur

2011

Neurotherapeutics

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The spontaneous recovery observed in the early stages of multiple sclerosis (MS) is substituted with a later progressive course and failure of endogenous processes of repair and remyelination. Although this is the basic rationale for cell therapy, it is not clear yet to what degree the MS brain is amenable for repair and whether cell therapy has an advantage in comparison to other strategies to enhance endogenous remyelination. Central to the promise of stem cell therapy is the therapeutic plasticity, by which neural precursors can replace damaged oligodendrocytes and myelin, and also effectively attenuate the autoimmune process in a local, nonsystemic manner to protect brain cells from further injury, as well as facilitate the intrinsic capacity of the brain for recovery. These fundamental immunomodulatory and neurotrophic properties are shared by stem cells of different sources. By using different routes of delivery, cells may target both affected white matter tracts and the perivascular niche where the trafficking of immune cells occur. It is unclear yet whether the therapeutic properties of transplanted cells are maintained with the duration of time. The application of neural stem cell therapy (derived from fetal brain or from human embryonic stem cells) will be realized once their purification, mass generation, and safety are guaranteed. However, previous clinical experience with bone marrow stromal (mesenchymal) stem cells and the relative easy expansion of autologous cells have opened the way to their experimental application in MS. An initial clinical trial has established the probable safety of their intravenous and intrathecal delivery. Short-term follow-up observed immunomodulatory effects and clinical benefit justifying further clinical trials.

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“…LP is a minimally invasive method of cell delivery, and stem cells may be well suited for LP transplantation because of their responsiveness to signals from the injured CNS. 2,4,8 Also, cell transplantation via LP may be relevant for conditions such as multiple sclerosis with widely disseminated lesions making intramedullary transplantation impractical.…”

Section: Introductionmentioning

confidence: 99%

Intrathecal transplantation of stem cells by lumbar puncture for thoracic spinal cord injury in the rat

et al. 2011

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Study design: Experimental investigation of intrathecal transplantation of stem cells by lumbar puncture (LP) in a rat model that simulates human thoracic spinal cord injury (SCI). Objectives: To examine the distribution and phenotype of spinal cord-derived neural stem/progenitor cells (NSPCs) and bone marrow-derived mesenchymal stromal cells (BMSCs) following LP transplantation in SCI rats. Setting: Toronto Western Research Institute, Toronto, Ontario, Canada. Methods: NSPCs or BMSCs were transplanted via LP at level L3-5 1 week after compression SCI at T8. Rats were killed at 3, 17 and 27 days after LP transplantation and the relative distribution of cells at C4, T8 and L3-5 was quantitated. The phenotype of the NSPC and BMSC was assessed with immunocytochemistry in vitro and following LP transplantation. Results: By 4 weeks, more NSPC migrated to the lesion site relative to BMSC and uninjured animals. However, there was no preferential homing of either of these types of cells into the parenchyma of the injury site, and most of the transplanted cells remained in the intrathecal space. In vitro, spinal cord-derived NSPC proliferated and expressed nestin, but after LP transplantation, NSPC became post-mitotic and primarily expressed oligodendrocyte markers. In contrast, BMSC did not express any neural antigens in vivo. Conclusion: LP is a minimally invasive method of cell transplantation that produces wide dissemination of cells in the subarachnoid space of the spinal cord. This is the first study to report and quantify the phenotype and spatial distribution of LP transplanted NSPC and BMSC in the intact and injured spinal cord.

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Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis

Cited by 998 publications

References 31 publications

How stem cells speak with host immune cells in inflammatory brain diseases

How stem cells speak with host immune cells in inflammatory brain diseases

Cell Therapy for Multiple Sclerosis

Intrathecal transplantation of stem cells by lumbar puncture for thoracic spinal cord injury in the rat

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