Nanotransfection-based vasculogenic cell reprogramming drives functional recovery in a mouse model of ischemic stroke.

Ischemic stroke causes vascular and neuronal tissue deficiencies that could lead to substantial functional impairment and/or death. Although progenitor-based vasculogenic cell therapies have shown promise as a potential rescue strategy following ischemic stroke, current approaches face major hurdles. Here, we used fibroblasts nanotransfected with Etv2, Foxc2, and Fli1 (EFF) to drive reprogramming-based vasculogenesis, intracranially, as a potential therapy for ischemic stroke. Perfusion analyses suggest that intracranial delivery of EFF-nanotransfected fibroblasts led to a dose-dependent increase in perfusion 14 days after injection. MRI and behavioral tests revealed ~70% infarct resolution and up to ~90% motor recovery for mice treated with EFF-nanotransfected fibroblasts. Immunohistological analysis confirmed increases in vascularity and neuronal cellularity, as well as reduced glial scar formation in response to treatment with EFF-nanotransfected fibroblasts. Together, our results suggest that vasculogenic cell therapies based on nanotransfection-driven (i.e., nonviral) cellular reprogramming represent a promising strategy for the treatment of ischemic stroke.

A comprehensive regional analysis of genome-wide expression profiles for major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) is a global health challenge. In recent years, a large number of genome-wide expression studies (GWES) have been carried out to identify the transcriptomic profiles for MDD. The objective of this work was to carry out a comprehensive meta-analysis of available GWES for MDD. METHODS: GWES for MDD with available raw data were searched in NCBI GEO, Array Express and Stanley databases. Raw GWES data were preprocessed and normalized and meta-analytical procedures were carried out with the Network Analyst program. 743 samples from 24 primary studies were included in our meta-analyses for blood (Blo), amygdala (Amy), cerebellum (Cer), anterior cingulate cortex (ACC) and prefrontal cortex (PFC) regions. A functional enrichment analysis was carried out. RESULTS: We identified 35, 793, 231, 668 and 252 differentially expressed (DE) genes for Blo, Amy, Cer, ACC and PFC regions. A region-dependent significant enrichment for several functional categories, such as gene ontologies, signaling pathways and topographic parameters, was identified. There was convergence with other available genome-wide studies, such as GWAS, DNA methylation analyses and miRNA expression studies. LIMITATIONS: Raw data were not available for several primary studies that have been published previously. CONCLUSIONS: This is the largest meta-analysis for GWES in MDD. The examination of convergence of genome-wide evidence and of the functional enrichment analysis provides a global overview of potential neural signaling mechanisms dysregulated in MDD. Our comprehensive analysis of several brain regions identified lists of DE genes for MDD that are interesting candidates for further studies.

Functional genomics of candidate genes derived from genome-wide association studies for five common neurological diseases.

AIM: Recent genome-wide association studies (GWAS) are identifying novel candidate genes for several neurological diseases (NDs). However, a global functional analysis of those genes derived from GWAS for NDs is missing. We explored the genomic and functional features of novel candidate genes for five common NDs: Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, stroke and migraine. MATERIALS AND METHODS: A functional enrichment analysis was performed for GWAS-derived genes, for categories such as Kyoto Encyclopedia of Genes and Genomes pathways, gene expression, InterPro domains, transcription factor binding sites, gene ontology (GO) terms and microRNA (miRNA) targets. An analysis of protein-protein interactions was carried out. RESULTS: Six hundred and forty-two unique single nucleotide polymorphisms (SNPs) were identified for the five NDs and 2.3% of them were non-synonymous SNPs. There were no common SNPs for all five NDs and eight genes were associated with more than one ND. The enrichment analysis showed significant values for several GO categories, such as cell-cell adhesion and location in neurites and for expression in prefrontal cortex. An analysis of protein-protein interactions showed the evidence of a large component. Fifty-one of these GWAS-derived genes are known to be potentially druggable and twelve are known to harbor mutations for neuropsychiatric disorders. CONCLUSIONS: Our results suggest that there is little overlap between the genes identified in GWAS for the five common NDs. Identification of functional categories in the GWAS-derived candidate genes for common NDs could lead to a better understanding of their functional consequences and could be useful for the future discovery of additional genetic risk factors for those diseases.

Hand2 inhibits kidney specification while promoting vein formation within the posterior mesoderm.

Proper organogenesis depends upon defining the precise dimensions of organ progenitor territories. Kidney progenitors originate within the intermediate mesoderm (IM), but the pathways that set the boundaries of the IM are poorly understood. Here, we show that the bHLH transcription factor Hand2 limits the size of the embryonic kidney by restricting IM dimensions. The IM is expanded in zebrafish hand2 mutants and is diminished when hand2 is overexpressed. Within the posterior mesoderm, hand2 is expressed laterally adjacent to the IM. Venous progenitors arise between these two territories, and hand2 promotes venous development while inhibiting IM formation at this interface. Furthermore, hand2 and the co-expressed zinc-finger transcription factor osr1 have functionally antagonistic influences on kidney development. Together, our data suggest that hand2 functions in opposition to osr1 to balance the formation of kidney and vein progenitors by regulating cell fate decisions at the lateral boundary of the IM.