Search

Stem cell transplantation therapies are currently under investigation for central nervous system disorders. Although preclinical models show benefit, clinical translation is somewhat limited by the absence of reliable noninvasive methods to confirm targeting and monitor transplanted cells in vivo. Here, we assess a novel magnetic resonance imaging (MRI) contrast agent derived from magnetotactic bacteria, magneto‐endosymbionts (MEs), as a translatable methodology for in vivo tracking of stem cells after intracranial transplantation. We show that ME labeling provides robust MRI contrast without impairment of cell viability or other important therapeutic features. Labeled cells were visualized immediately post‐transplantation and over time by serial MRI in nonhuman primate and mouse brain. Postmortem tissue analysis confirmed on‐target grft location, and linear correlations were observed between MRI signal, cell engraftment, and tissue ME levels, suggesting that MEs may be useful for determining graft survival or rejection. Overall, these findings indicate that MEs are an effective tool for in vivo tracking and monitoring of cell transplantation therapies with potential relevance to many cellular therapy applications. Translation of cell therapies for central nervous system disorders is often limited by an inability to noninvasively identify and track transplanted cells in vivo. McGinley et al report a novel MRI contrast agent based on magnetotactic bacteria that enables visualization and long‐term tracking of cell grafts in nonhuman primate and murine brain.

ABSTRACTDNA methylation is an epigenetic mechanism important for the regulation of gene expression, which plays a vital role in the interaction between genetic and environmental factors. Aberrant epigenetic changes are implicated in the pathogenesis of diabetes and diabetic complications, but the role of DNA methylation in diabetic peripheral neuropathy (DPN) is not well understood. Therefore, our aim in this study was to explore the role of DNA methylation in the progression of DPN in type 2 diabetes. We compared genome-wide DNA methylation profiles of human sural nerve biopsies from subjects with stable or improving nerve fibre counts to biopsies from subjects with progressive loss of nerve fibres. Nerve fibre counts were determined by comparing myelinated nerve fibre densities between an initial and repeat biopsy separated by 52 weeks. Subjects with significant nerve regeneration (regenerators) and subjects with significant nerve degeneration (degenerators) represent the two extreme DPN phenotypes. Using reduced representation bisulfite sequencing, we identified 3,460 differentially methylated CpG dinucleotides between the two groups. The genes associated with differentially methylated CpGs were highly enriched in biological processes that have previously been implicated in DPN such as nervous system development, neuron development, and axon guidance, as well as glycerophospholipid metabolism and mitogen-activated protein kinase (MAPK) signalling. These findings are the first to provide a comprehensive analysis of DNA methylation profiling in human sural nerves of subjects with DPN and suggest that epigenetic regulation has an important role in the progression of this prevalent diabetic complication.

Alzheimer's disease (AD) is the most prevalent age‐related neurodegenerative disorder and a leading cause of dementia. Current treatment fails to modify underlying disease pathologies and very little progress has been made to develop effective drug treatments. Cellular therapies impact disease by multiple mechanisms, providing increased efficacy compared with traditional single‐target approaches. In amyotrophic lateral sclerosis, we have shown that transplanted spinal neural stem cells (NSCs) integrate into the spinal cord, form synapses with the host, improve inflammation, and reduce disease‐associated pathologies. Our current goal is to develop a similar “best in class” cellular therapy for AD. Here, we characterize a novel human cortex‐derived NSC line modified to express insulin‐like growth factor‐I (IGF‐I), HK532‐IGF‐I. Because IGF‐I promotes neurogenesis and synaptogenesis in vivo, this enhanced NSC line offers additional environmental enrichment, enhanced neuroprotection, and a multifaceted approach to treating complex AD pathologies. We show that autocrine IGF‐I production does not impact the cell secretome or normal cellular functions, including proliferation, migration, or maintenance of progenitor status. However, HK532‐IGF‐I cells preferentially differentiate into gamma‐aminobutyric acid‐ergic neurons, a subtype dysregulated in AD; produce increased vascular endothelial growth factor levels; and display an increased neuroprotective capacity in vitro. We also demonstrate that HK532‐IGF‐I cells survive peri‐hippocampal transplantation in a murine AD model and exhibit long‐term persistence in targeted brain areas. In conclusion, we believe that harnessing the benefits of cellular and IGF‐I therapies together will provide the optimal therapeutic benefit to patients, and our findings support further preclinical development of HK532‐IGF‐I cells into a disease‐modifying intervention for AD. There is no cure for Alzheimer's disease (AD) and no means of prevention. Current drug treatments temporarily slow dementia symptoms but ultimately fail to alter disease course. Given the prevalence of AD and an increasingly aging population, alternative therapeutic strategies are necessary. Cellular therapies impact disease by multiple mechanisms, providing increased efficacy compared with traditional, single‐target drug discovery approaches. This study describes a novel enhanced human stem cell line that produces increased amounts of growth factors beneficial to the disease environment. Findings support further development into a potentially safe and clinically translatable cellular therapy for patients with AD. A human cortex‐derived neural stem cell (NSC) line modified to express insulin‐like growth factor‐I (IGF‐I), HK532‐IGF‐I, is characterized in this report. The cell line is under study as a cellular therapy for Alzheimer's disease (AD). HK532‐IGF‐I cells preferentially differentiated into gamma‐aminobutyric acid‐ergic neurons, a subtype dysregulated in AD; produced increased vascular endothelial growth factor levels; and displayed an increased neuroprotective capacity in vitro. HK532‐IGF‐I cells survived peri‐hippocampal transplantation in a murine AD model and exhibited long‐term persistence in targeted brain areas.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder resulting in motor neuron (MN) loss. There are currently no effective therapies; however, cellular therapies using neural progenitor cells protect MNs and attenuate disease progression in G93A‐SOD1 ALS rats. Recently, we completed a phase I clinical trial examining intraspinal human spinal stem cell (HSSC) transplantation in ALS patients which demonstrated our approach was safe and feasible, supporting the phase II trial currently in progress. In parallel, efforts focused on understanding the mechanisms underlying the preclinical benefit of HSSCs in vitro and in animal models of ALS led us to investigate how insulin‐like growth factor‐I (IGF‐I) production contributes to cellular therapy neuroprotection. IGF‐I is a potent growth factor with proven efficacy in preclinical ALS studies, and we contend that autocrine IGF‐I production may enhance the salutary effects of HSSCs. By comparing the biological properties of HSSCs to HSSCs expressing sixfold higher levels of IGF‐I, we demonstrate that IGF‐I production augments the production of glial‐derived neurotrophic factor and accelerates neurite outgrowth without adversely affecting HSSC proliferation or terminal differentiation. Furthermore, we demonstrate that increased IGF‐I induces more potent MN protection from excitotoxicity via both indirect and direct mechanisms, as demonstrated using hanging inserts with primary MNs or by culturing with organotypic spinal cord slices, respectively. These findings support our theory that combining autocrine growth factor production with HSSC transplantation may offer a novel means to achieve additive neuroprotection in ALS. StemCells2015;33:1480–1489