Engineered neurogenesis in naïve adult rat cortex by Ngn2-mediated neuronal reprogramming of resident oligodendrocyte progenitor cells.

Adult tissue stem cells contribute to tissue homeostasis and repair but the long-lived neurons in the human adult cerebral cortex are not replaced, despite evidence for a limited regenerative response. However, the adult cortex contains a population of proliferating oligodendrocyte progenitor cells (OPCs). We examined the capacity of rat cortical OPCs to be re-specified to a neuronal lineage both in vitro and in vivo. Expressing the developmental transcription factor Neurogenin2 (Ngn2) in OPCs isolated from adult rat cortex resulted in their expression of early neuronal lineage markers and genes while downregulating expression of OPC markers and genes. Ngn2 induced progression through a neuronal lineage to express mature neuronal markers and functional activity as glutamatergic neurons. In vivo retroviral gene delivery of Ngn2 to naive adult rat cortex ensured restricted targeting to proliferating OPCs. Ngn2 expression in OPCs resulted in their lineage re-specification and transition through an immature neuronal morphology into mature pyramidal cortical neurons with spiny dendrites, axons, synaptic contacts, and subtype specification matching local cytoarchitecture. Lineage re-specification of rat cortical OPCs occurred without prior injury, demonstrating these glial progenitor cells need not be put into a reactive state to achieve lineage reprogramming. These results show it may be feasible to precisely engineer additional neurons directly in adult cerebral cortex for experimental study or potentially for therapeutic use to modify dysfunctional or damaged circuitry.

Induced Neurons for Disease Modeling and Repair: A Focus on Non-fibroblastic Cell Sources in Direct Reprogramming.

Direct cellular reprogramming exhibits distinct advantages over reprogramming from an induced pluripotent stem cell intermediate. These include a reduced risk of tumorigenesis and the likely preservation of epigenetic data. In vitro direct reprogramming approaches primarily aim to model the pathophysiological development of neurological disease and identify therapeutic targets, while in vivo direct reprogramming aims to develop treatments for various neurological disorders, including cerebral injury and cancer. In both approaches, there is progress toward developing increased control of subtype-specific production of induced neurons. A majority of research primarily utilizes fibroblasts as the donor cells. However, there are a variety of other somatic cell types that have demonstrated the potential for reprogramming into induced neurons. This review highlights studies that utilize non-fibroblastic cell sources for reprogramming, such as astrocytes, olfactory ensheathing cells, peripheral blood cells, Müller glia, and more. We will examine benefits and obstructions for translation into therapeutics or disease modeling, as well as efficiency of the conversion. A summary of donor cells, induced neuron types, and methods of induction is also provided.

GLP-1 nanomedicine alleviates gut inflammation.

The gut hormone, glucagon like peptide-1 (GLP-1) exerts anti-inflammatory effects. However, its clinical use is limited by its short half-life. Previously, we have shown that GLP-1 as a nanomedicine (GLP-1 in sterically stabilized phospholipid micelles, GLP-1-SSM) has increased in vivo stability. The current study was aimed at testing the efficacy of this GLP-1 nanomedicine in alleviating colonic inflammation and associated diarrhea in dextran sodium sulfate (DSS) induced mouse colitis model. Our results show that GLP-1-SSM treatment markedly alleviated the colitis phenotype by reducing the expression of pro-inflammatory cytokine IL-1ß, increasing goblet cells and preserving intestinal epithelial architecture in colitis model. Further, GLP-1-SSM alleviated diarrhea (as assessed by luminal fluid) by increasing protein expression of intestinal chloride transporter DRA (down regulated in adenoma). Our results indicate that GLP-1 nanomedicine may act as a novel therapeutic tool in alleviating gut inflammation and associated diarrhea in inflammatory bowel disease (IBD).

Curcumin in VIP-targeted sterically stabilized phospholipid nanomicelles: a novel therapeutic approach for breast cancer and breast cancer stem cells.

Breast cancer is a leading cause of cancer deaths among women in the US, with 40 % chance of relapse after treatment. Recent studies outline the role of cancer stem cells (CSCs) in tumor initiation, propagation, and regeneration of cancer. Moreover, it has been established that breast CSCs reside in a quiescent state that makes them more resistant to conventional cancer therapies than bulk cancer cells resulting in tumor relapse. In this study, we establish that CSCs are associated with the overexpression of vasoactive intestinal peptide (VIP) receptors which can be used to actively target these cells. We investigated the potential of using a novel curcumin nanomedicine (C-SSM) surface conjugated with VIP to target and hinder breast cancer with CSCs. Here, we formulated, characterized, and evaluated the feasibility of C-SSM nanomedicine in vitro. We investigated the cytotoxicity of C-SSM on breast cancer cells and CSCs by tumorsphere formation assay. Our results suggest that curcumin can be encapsulated in SSM up to 200 µg/ml with 1 mM lipid concentration. C-SSM nanomedicine is easy to prepare and maintains its original physicochemical properties after lyophilization, with an IC50 that is significantly improved from that of free curcumin (14.2±1.2 vs. 26.1±3.0 µM). Furthermore, C-SSM-VIP resulted in up to 20 % inhibition of tumorsphere formation at a dose of 5 µM. To this end, our findings demonstrate the feasibility of employing our actively targeted nanomedicine as a potential therapy for CSCs-enriched breast cancer.