Derivation of Neural Stem Cells from Human Adult Peripheral CD34+ Cells for an Autologous Model of Neuroinflammation

Wang, Tongguang; Choi, Elliot H.; Monaco, Maria Chiara; Campanac, Émilie; Medynets, Marie; Do, Thao; Rao, Prashant; Johnson, Kory R.; Elkahloun, Abdel G.; Geldern, Gloria von; Johnson, Tory P.; Subramaniam, Sriram; Hoffman, Dax A.; Major, Eugene O.; Nath, Avindra

doi:10.1371/journal.pone.0081720

Cited by 28 publications

(25 citation statements)

References 62 publications

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“…Unlike neurons, GFAP‐expressing reactive astrocytes are known to be a dynamic cell population 31 which persist for many years even in chronically inactive MS lesions 32 . Further confounding the situation, CD‐34‐positive autologous hematopoietic stem cells used as part of the IAHSCT itself are capable of differentiation into GFAP‐expressing reactive astrocytes 33 . We postulate that while peripheral levels of NfL represent the loss of finite pool of neuronal axons, levels of GFAP more likely reflect the turnover of reactive astrocytes carrying out a spectrum of roles in MS lesions.…”

Section: Discussionmentioning

confidence: 99%

Neurotoxicity after hematopoietic stem cell transplant in multiple sclerosis

Thebault

Lee

Bose

et al. 2020

Ann Clin Transl Neurol

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Objective: Accelerated brain volume loss has been noted following immunoablative autologous hematopoietic stem cell transplantation (IAHSCT) for multiple sclerosis. As with other MS treatments, this is often interpreted as 'pseudoatrophy', related to reduced inflammation. Treatment-related neurotoxicity may be contributory. We sought objective evidence of post-IAHSCT toxicity by quantifying levels of Neurofilament Light Chain (sNfL) and Glial Fibrillary Acidic Protein (sGFAP) before and after treatment as markers of neuroaxonal and glial cell damage. Methods: Sera were collected from 22 MS patients pre-and post-IAHSCT at 3, 6, 9, and 12 months along with 28 noninflammatory controls. sNfL and sGFAP quantification was performed using the SiMoA single-molecule assay. Results: Pre-IAHSCT levels of sNfL and sGFAP were elevated in MS patients compared with controls (geometric mean sNfL 21.8 vs. 6.4 pg/mL, sGFAP 107.4 vs. 50.7 pg/mL, P = 0.0001 for both). Three months after IAHSCT, levels of sNfL and sGFAP increased from baseline by 32.1% and 74.8%, respectively (P = 0.0029 and 0.0004). sNfL increases correlated with total busulfan dose (P = 0.034), EDSS score worsening at 6 months (P = 0.041), and MRI grey matter volume loss at 6 months (P = 0.0023). Subsequent NfL levels reduced to less than baseline (12-month geometric mean 11.3 pg/mL P = 0.0001) but were still higher than controls (P = 0.0001). sGFAP levels reduced more slowly but at 12 months were approaching baseline levels (130.7 pg/mL). Interpretation: There is direct evidence of transient CNS toxicity immediately after IAHSCT which may be chemotherapy mediated and contributes to transient increases in MRI atrophy.

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Section: Discussionmentioning

confidence: 99%

Neurotoxicity after hematopoietic stem cell transplant in multiple sclerosis

Thebault

Lee

Bose

et al. 2020

Ann Clin Transl Neurol

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“…Human neural progenitor cells were derived, cultured, and differentiated as previously described (35) after approval by the Office of Human Subjects Research and Protection at the NIH. Cells were fixed with 4% (w/v) paraformaldehyde and immunostained with rabbit anti–leiomodin-1 (1:100) for 16 hours at 4°C and goat anti-rabbit Alexa Fluor 488 (Life Technologies, 1:400) for 2 hours at RT.…”

Section: Methodsmentioning

confidence: 99%

“…Cells were fixed with 4% (w/v) paraformaldehyde and immunostained with rabbit anti–leiomodin-1 (1:100) for 16 hours at 4°C and goat anti-rabbit Alexa Fluor 488 (Life Technologies, 1:400) for 2 hours at RT. Vybrant Dil cell-labeling solution (Invitrogen) was used to visualize the plasma membrane, and DAPI (1 μg/ml; Roche Diagnostics) was used for nuclear staining (35). A Nikon Eclipse Ti total internal reflection fluorescence (TIRF) microscope equipped with a 488/561/405/647 LU4A Lasers System and an Andor iXon3 electron-multiplying charge-coupled device camera by using an Apo TIRF (100× objective; numerical aperture, 1.49) was used for imaging with acquisition (NIS-Elements Advanced Research) and processing (ImageJ) to obtain the composite RGB images.…”

Section: Methodsmentioning

confidence: 99%

Nodding syndrome may be an autoimmune reaction to the parasitic worm Onchocerca volvulus

et al. 2017

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Nodding syndrome is an epileptic disorder of unknown etiology that occurs in children in East Africa. There is an epidemiological association with Onchocerca volvulus, the parasitic worm that causes onchocerciasis (river blindness), but there is limited evidence that the parasite itself is neuroinvasive. We hypothesized that nodding syndrome may be an autoimmune-mediated disease. Using protein chip methodology, we detected autoantibodies to leiomodin-1 more abundantly in patients with nodding syndrome compared to unaffected controls from the same village. Leiomodin-1 autoantibodies were found in both the sera and cerebrospinal fluid of patients with nodding syndrome. Leiomodin-1 was found to be expressed in mature and developing human neurons in vitro and was localized in mouse brain to the CA3 region of the hippocampus, Purkinje cells in the cerebellum, and cortical neurons, structures that also appear to be affected in patients with nodding syndrome. Antibodies targeting leiomodin-1 were neurotoxic in vitro, and leiomodin-1 antibodies purified from patients with nodding syndrome were cross-reactive with O. volvulus antigens. This study provides initial evidence supporting the hypothesis that nodding syndrome is an autoimmune epileptic disorder caused by molecular mimicry with O. volvulus antigens and suggests that patients may benefit from immunomodulatory therapies.

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“…Pluripotent stem cells derived from human umbilical cord blood have similar potential of neuronal differentiation as neural stem cells derived from foetus [34][35][36][93][94][95][96][97][98][99]. Neurons derived from these hUCBSCs have expression of different early and mature neuronal markers namely, nestin, musashi-1, nectin, neuronal nuclei (NeuN), post-synaptic density protein 95 (PSD95), synaptophysin (SYP), β-III tubulin (TUJ-1), growth-associated protein 43 (GAP43), various forms of neurofilaments (NF), neurotrophic growth factors and neuron-specific receptors N-methyl-D-aspartate (NMDA) and γ-aminobutyric acid (GABA) [34-36, 38, 53, 86, 94, 100-107].…”

Section: Human Umbilical Cord Blood Stem Cells Easily Differentiates mentioning

confidence: 99%

An Overview on Human Umbilical Cord Blood Stem Cell-Based Alternative In Vitro Models for Developmental Neurotoxicity Assessment

Singh

Kashyap

2015

Mol Neurobiol

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The developing brain is found highly vulnerable towards the exposure of different environmental chemicals/drugs, even at concentrations, those are generally considered safe in mature brain. The brain development is a very complex phenomenon which involves several processes running in parallel such as cell proliferation, migration, differentiation, maturation and synaptogenesis. If any step of these cellular processes hampered due to exposure of any xenobiotic/drug, there is almost no chance of recovery which could finally result in a life-long disability. Therefore, the developmental neurotoxicity (DNT) assessment of newly discovered drugs/molecules is a very serious concern among the neurologists. Animal-based DNT models have their own limitations such as ethical concerns and lower sensitivity with less predictive values in humans. Furthermore, non-availability of human foetal brain tissues/cells makes job more difficult to understand about mechanisms involve in DNT in human beings. Although, the use of cell culture have been proven as a powerful tool for DNT assessment, but many in vitro models are currently utilizing genetically unstable cell lines. The interpretation of data generated using such terminally differentiated cells is hard to extrapolate with in vivo situations. However, human umbilical cord blood stem cells (hUCBSCs) have been proposed as an excellent tool for alternative DNT testing because neuronal development from undifferentiated state could exactly mimic the original pattern of neuronal development in foetus when hUCBSCs differentiated into neuronal cells. Additionally, less ethical concern, easy availability and high plasticity make them an attractive source for establishing in vitro model of DNT assessment. In this review, we are focusing towards recent advancements on hUCBSCs-based in vitro model to understand DNTs.

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Derivation of Neural Stem Cells from Human Adult Peripheral CD34+ Cells for an Autologous Model of Neuroinflammation

Cited by 28 publications

References 62 publications

Neurotoxicity after hematopoietic stem cell transplant in multiple sclerosis

Neurotoxicity after hematopoietic stem cell transplant in multiple sclerosis

Nodding syndrome may be an autoimmune reaction to the parasitic worm Onchocerca volvulus

An Overview on Human Umbilical Cord Blood Stem Cell-Based Alternative In Vitro Models for Developmental Neurotoxicity Assessment

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