Neural transplantation of human MSC and NT2 cells in the twitcher mouse model

Croitoru-Lamoury, Juliana; Williams, Kathleen; Lamoury, F.; Veas, Laura A.; Ajami, Bahareh; Taylor, R. M.; Brew, Bruce J.

doi:10.1080/14653240600879152

Cited by 27 publications

(17 citation statements)

References 71 publications

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“…Furthermore, they release a broad spectrum of signaling molecules including hepatocyte growth factor (HGF) [129], prostaglandin E2, TGF-β, indoleamine 2,3-dioxygenase (IDO), nitric oxide and IL-10 [130][131][132][133][134]. Transplantation of syngeneic MSCs into animal models of EAE result in significant functional recovery [135][136][137][138], in part by modulating immunological responses [139] and inducing T-cell anergy [138].…”

Section: Mesenchymal Stem Cellsmentioning

confidence: 99%

Cellular Approaches for Stimulating CNS Remyelination

Miller

Bai

2007

Regen. Med.

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Myelination is critical for the normal functioning of the vertebrate nervous system. In the CNS, myelin is produced by oligodendrocytes, and the loss of oligodendrocytes and myelin results in severe functional impairment. Although spontaneous remyelination occurs in chronic demyelinating diseases such as multiple sclerosis, the repair process eventually fails, often resulting in long-term disability. Two distinct general approaches can be considered to promote myelin repair. In one the target is stimulation of the endogenous myelin repair process through delivery of growth factors, and in the second the target is augmentation of the repair process through the delivery of exogenous cells with myelination potential. In both cases, effective treatment of diseases such as multiple sclerosis requires modulation of the immune system, since demyelination is associated with specific immunological activation. Recent studies have shown that some populations of stem cells, including mesenchymal stem cells, have the capacity of promoting endogenous myelin repair and modulating the immune response, prompting an assessment of their use as therapy in demyelinating diseases such as MS. Other types of demyelinating disorders, such as the leukodystrophies, may require multiple repair strategies including both replacement of dysfunctional cells and delivery or supplementation of growth factors, immune modulators or metabolic enzymes. Here we discuss the use of stem cells for the treatment of demyelinating diseases. While the current number of stem cell-based clinical trials for demyelinating diseases is limited, this is likely to increase significantly in the next few years, and a clear understanding of the applicability, limitations and underlying mechanisms mediating stem cell repair is critical.Demyelination, a characteristic of multiple sclerosis (MS), is also an important component of the pathology of a variety of other insults and injuries to the CNS. For example, extensive demyelination accompanies trauma to the brain or spinal cord, as well as stroke. More recently, demyelination has been linked to functional CNS deterioration associated with Alzheimer's disease [1], normal aging [2] and psychiatric disorders such as schizophrenia [3], suggesting that the development of therapeutic approaches to enhance remyelination may have widespread applications in the nervous system.The demyelination that develops in MS is probably a consequence of inflammation and an autoimmune attack on the cells of the CNS that involves three distinct mechanisms:• Direct immunological insults;• Excitotoxic insults and compromise of CNS cell metabolism Immunological insults may be a direct attack on neurons and axons by T cells and antibodies, or an indirect damaging of neurons and axons by inflammatory mediators from the innate immune system, cytokine-mediated neurotoxicity and inflammation-related toxic factors such as nitric oxide. Excitotoxic demyelination may result from release of neurotransmitters such as glutamate, inducing an influx of calc...

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Section: Mesenchymal Stem Cellsmentioning

confidence: 99%

Cellular Approaches for Stimulating CNS Remyelination

Miller

Bai

2007

Regen. Med.

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“…These clinical trials aimed to explore the therapeutic potential of hMSCs with regard to their immune-modulatory properties, tissue regenerative capacity, graft enhancement, tissue protection, and repair capabilities. Similarly, hMSCs have been applied in vivo for their efficacy in a variety of human disease models in immune-competent mice including skin and spinal cord repair [7], Huntington's disease, [8], other demyelinating diseases [9], and graft-versus-host disease [10]. …”

Section: Introductionmentioning

confidence: 99%

Dynamic Imaging of Marrow-Resident Granulocytes Interacting with Human Mesenchymal Stem Cells upon Systemic Lipopolysaccharide Challenge

Myers

Barkauskas

Huang

2013

Stem Cells International

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Human mesenchymal stem cells (hMSCs) have gained intense research interest due to their immune-modulatory, tissue differentiating, and homing properties to sites of inflammation. Despite evidence demonstrating the biodistribution of infused hMSCs in target organs using static fluorescence imaging or whole-body imaging techniques, surprisingly little is known about how hMSCs behave dynamically within host tissues on a single-cell level in vivo. Here, we infused fluorescently labeled clinical-grade hMSCs into immune-competent mice in which neutrophils and monocytes express a second fluorescent marker under the lysozyme M (LysM) promoter. Using intravital two-photon microscopy (TPM), we were able for the first time to capture dynamic interactions between hMSCs and LysM+ granulocytes in the calvarium bone marrow of recipient mice during systemic LPS challenge in real time. Interestingly, many of the infused hMSCs remained intact despite repeated cellular contacts with host neutrophils. However, we were able to observe the destruction and subsequent phagocytosis of some hMSCs by surrounding granulocytes. Thus, our imaging platform provides opportunities to gain insight into the biology and therapeutic mechanisms of hMSCs in vivo at a single-cell level within live hosts.

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“…), thus making them a promising therapeutic candidate for restoration of damaged tissue [40, 41]. In addition to being accessible for harvesting in clinical settings and easily expanded in culture, BMSCs are known to express GALC, modulate immune reactions in vitro , and do not elicit an immunological response in vivo [40, 42–44]. In light of these findings, IP injections of stem cells were administered to twitcher mouse pups in order to target the inflammation in the peripheral nervous system.…”

Section: Discussionmentioning

confidence: 99%

High-throughput screening of stem cell therapy for globoid cell leukodystrophy using automated neurophenotyping of twitcher mice

Scruggs

Bowles

Zhang

et al. 2013

Behavioural Brain Research

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Globoid cell leukodystrophy (Krabbe’s disease) is an autosomal recessive neurodegenerative disorder that results from the deficiency of galactosylceramidase, a lysosomal enzyme involved in active myelination. Due to the progressive, lethal nature of this disease and the limited treatment options available, multiple laboratories are currently exploring novel therapies using the mouse model of globoid cell leukodystrophy. In order to establish a protocol for motor function assessment of the twitcher mouse, this study tested the capability of an automated system to detect phenotypic differences across mouse genotypes and/or treatment groups. The sensitivity of this system as a screening tool for the assessment of therapeutic interventions was determined by the administration of murine bone marrow-derived stem cells into twitcher mice via intraperitoneal injection. Animal behavior was analyzed using the Noldus EthoVision XT7 software. Novel biomarkers, including abnormal locomotion (e.g., velocity, moving duration, distance traveled, turn angle) and observed behaviors (e.g., rearing activity, number of defecation boli), were established for the twitcher mouse. These parameters were monitored across all mouse groups, and the automated system detected improved locomotion in the treated twitcher mice based on the correction of angular velocity, turn angle, moving duration, and exploratory behavior, such as thigmotaxis. Further supporting these findings, the treated mice showed improved lifespan, gait, wire hang ability, twitching severity and frequency, and sciatic nerve histopathology. Taken together, these data demonstrate the utility of computer-based neurophenotyping for motor function assessment of twitcher mice and support its utility for detecting the efficacy of stem cell-based therapy for neurodegenerative disorders.

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Neural transplantation of human MSC and NT2 cells in the twitcher mouse model

Cited by 27 publications

References 71 publications

Cellular Approaches for Stimulating CNS Remyelination

Cellular Approaches for Stimulating CNS Remyelination

Dynamic Imaging of Marrow-Resident Granulocytes Interacting with Human Mesenchymal Stem Cells upon Systemic Lipopolysaccharide Challenge

High-throughput screening of stem cell therapy for globoid cell leukodystrophy using automated neurophenotyping of twitcher mice

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