Selective Delivery to Vascular Addresses: In Vivo Applications of Cell-Type-Specific Cell-Penetrating Peptides

2006 ◽  
pp. 435-444
Keyword(s):  
Cell Penetrating Peptides ◽  
Specific Cell ◽  
Cell Type ◽  
Cell Penetrating ◽  
Cell Type Specific ◽  
Selective Delivery

scholarly journals Novel Lung Targeting Cell Penetrating Peptides as Vectors for Delivery of Therapeutics

2021 ◽  
Author(s):  
Maliha Zahid ◽  
Kayla McCandless ◽  
Sanjay Mishra ◽  
Jeffrey Stiltner ◽  
Kyle Feldman ◽  
...  
Keyword(s):  
Amino Acid ◽  
Lung Tissue ◽  
Cell Penetrating Peptides ◽  
Mouse Lung ◽  
Specific Cell ◽  
Lung Targeting ◽  
Biodistribution Studies ◽  
Cell Penetrating

Abstract Cell penetrating peptides are unique, 5-30 amino acid long peptides that are able to breach cell membrane barriers and carry cargoes intracellularly in a functional form. Our prior work identified a synthetic, non-naturally occurring 12-amino acid long peptide that we termed cardiac targeting peptide (CTP: APWHLSSQYSRT) due to its ability to transduce cardiomyocytes in vivo. Studies looking into its mechanism of transduction identified two lung targeting peptides (LTPs), S7A (APWHLSAQYSRT) and R11A (APWHLSSQYSAT). These peptides robustly transduced human bronchial epithelial cell lines in vitro and mouse lung tissue in vivo. This uptake occurred independently of clathrin mediated endocytosis. Biodistribution studies of R11A showed peak uptake at 15 minutes with uptake in liver but not kidneys, indicating primarily a hepatobiliary mode of excretion. Cyclic version of both peptides was ~100-fold more efficient in permeating cells than their linear counterparts. As proof of principle, we conjugated anti-spike and anti-envelope SARS-CoV-2 siRNAs to cyclized R11A and demonstrate anti-viral efficacy in vitro. Our work presented here identifies two novel lung-specific cell penetrating peptides that could potentially deliver myriad therapeutic cargoes to lung tissue.

scholarly journals Cell Type-Specific Survey of Epigenetic Modifications by Tandem Chromatin Immunoprecipitation Sequencing

2017 ◽  
Author(s):  
Mari Mito ◽  
Mitsutaka Kadota ◽  
Kaori Tanaka ◽  
Yasuhide Furuta ◽  
Kuniya Abe ◽  
...  
Keyword(s):  
Chromatin Immunoprecipitation ◽  
Cortical Neurons ◽  
Expression Profiles ◽  
Cell Types ◽  
Epigenetic Modifications ◽  
Specific Cell ◽  
Cell Type ◽  
Chromatin Immunoprecipitation Sequencing ◽  
Cell Type Specific

AbstractBackgroundThe nervous system of higher eukaryotes is composed of numerous types of neurons and glia that together orchestrate complex neuronal responses. However, this complex pool of cells typically poses analytical challenges in investigating gene expression profiles and their epigenetic basis for specific cell types. Here, we developed a novel method that enables cell type-specific analyses of epigenetic modifications using tandem chromatin immunoprecipitation sequencing (tChIP-Seq).ResultsFLAG-tagged histone H2B, a constitutive chromatin component, was first expressed in Camk2a-positive pyramidal cortical neurons and used to purify chromatin in a cell type-specific manner. Subsequent chromatin immunoprecipitation using antibodies against H3K4me3—an active promoter mark—allowed us to survey neuron-specific coding and non-coding transcripts. Indeed, tChIP-Seq identified hundreds of genes associated with neuronal functions and genes with unknown functions expressed in cortical neurons.ConclusionstChIP-Seq thus provides a versatile approach to investigating the epigenetic modifications of particular cell types in vivo.

Cell-Type Specific and Cytoplasmic Targeting of PEGylated Carbon Nanotube-Based Nanoassemblies

2008 ◽  
Vol 8 (5) ◽  
pp. 2259-2269 ◽  
Author(s):  
Matthew H. Cato ◽  
Federica D'Annibale ◽  
David M. Mills ◽  
Fabio Cerignoli ◽  
Marcia I. Dawson ◽  
...  
Keyword(s):  
Carbon Nanotubes ◽  
Average Length ◽  
Cell Receptor ◽  
Specific Cell ◽  
Cell Type ◽  
Cytoplasmic Delivery ◽  
Cell Type Specific ◽  
Walled Carbon Nanotubes

In this paper we report the fabrication of a multivalent, cell-type specific and cytoplasmic delivery system based on single-walled carbon nanotubes. The latter were functionalized through adsorption of phospholipids terminated by biotinylated PEG chains functionalized with fluorochrome-coupled neutravidin, and subsequently with antibodies (anti-CD3ε and anti-CD28) for T cell receptor post-signaling endocytosis and a synthetic fusogenic polymer for disruption of lysosomal compartments. The biomimetic nanoassemblies were composed by PEGylated individual/very small bundles of carbon nanotubes having an average length and a standard deviation of 176 nm and 77 nm, respectively. The nanoassemblies were stably dispersed under physiological conditions, visible by conventional optical and confocal microscopy and specifically targeted to T cells both in vitro and in living animals. The addition of a fusogenic polymer to the nanoassemblies did not affect the cellular uptake and allowed the release into the cytosol of the targeted cells both in vitro and in the animals. The present manuscript is the first report about the cytoplasmic delivery of carbon nanotubes in a specific cell type in intact animals and paves the way for their use as in vivo intracellular delivery systems.

ITag-RNA Allows in Vivo Cell-Type Specific Transcriptional Characterization and Tracking of Circulating Transcripts

2018 ◽  
Author(s):  
J. Darr ◽  
M. Lassi ◽  
R. Gerlini ◽  
F. Scheid ◽  
M. Hrabě de Angelis ◽  
...  
Keyword(s):  
Cell Type ◽  
Cell Type Specific

scholarly journals Shisa6 mediates cell-type specific regulation of depression in the nucleus accumbens

2021 ◽  
Author(s):  
Hee-Dae Kim ◽  
Jing Wei ◽  
Tanessa Call ◽  
Nicole Teru Quintus ◽  
Alexander J. Summers ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Current Treatment ◽  
Specific Cell ◽  
Excitatory Synapses ◽  
Cell Type ◽  
Cell Type Specific ◽  
Specific Regulation ◽  
Circuit Function

AbstractDepression is the leading cause of disability and produces enormous health and economic burdens. Current treatment approaches for depression are largely ineffective and leave more than 50% of patients symptomatic, mainly because of non-selective and broad action of antidepressants. Thus, there is an urgent need to design and develop novel therapeutics to treat depression. Given the heterogeneity and complexity of the brain, identification of molecular mechanisms within specific cell-types responsible for producing depression-like behaviors will advance development of therapies. In the reward circuitry, the nucleus accumbens (NAc) is a key brain region of depression pathophysiology, possibly based on differential activity of D1- or D2- medium spiny neurons (MSNs). Here we report a circuit- and cell-type specific molecular target for depression, Shisa6, recently defined as an AMPAR component, which is increased only in D1-MSNs in the NAc of susceptible mice. Using the Ribotag approach, we dissected the transcriptional profile of D1- and D2-MSNs by RNA sequencing following a mouse model of depression, chronic social defeat stress (CSDS). Bioinformatic analyses identified cell-type specific genes that may contribute to the pathogenesis of depression, including Shisa6. We found selective optogenetic activation of the ventral tegmental area (VTA) to NAc circuit increases Shisa6 expression in D1-MSNs. Shisa6 is specifically located in excitatory synapses of D1-MSNs and increases excitability of neurons, which promotes anxiety- and depression-like behaviors in mice. Cell-type and circuit-specific action of Shisa6, which directly modulates excitatory synapses that convey aversive information, identifies the protein as a potential rapid-antidepressant target for aberrant circuit function in depression.

scholarly journals Engineered ionizable lipid nanoparticles for targeted delivery of RNA therapeutics into different types of cells in the liver

2021 ◽  
Vol 7 (9) ◽  
pp. eabf4398
Author(s):  
M. Kim ◽  
M. Jeong ◽  
S. Hur ◽  
Y. Cho ◽  
J. Park ◽  
...  
Keyword(s):  
Cellular Uptake ◽  
Targeted Delivery ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipid Nanoparticles ◽  
Liver Sinusoidal Endothelial Cells ◽  
Main Challenge ◽  
Cell Type Specific ◽  
Selective Delivery

Ionizable lipid nanoparticles (LNPs) have been widely used for in vivo delivery of RNA therapeutics into the liver. However, a main challenge remains to develop LNP formulations for selective delivery of RNA into certain types of liver cells, such as hepatocytes and liver sinusoidal endothelial cells (LSECs). Here, we report the engineered LNPs for the targeted delivery of RNA into hepatocytes and LSECs. The effects of particle size and polyethylene glycol–lipid content in the LNPs were evaluated for the hepatocyte-specific delivery of mRNA by ApoE-mediated cellular uptake through low-density lipoprotein receptors. Targeted delivery of RNA to LSECs was further investigated using active ligands. Incorporation of mannose allowed the selective delivery of RNA to LSECs, while minimizing the unwanted cellular uptake by hepatocytes. These results demonstrate that engineered LNPs have great potential for the cell type–specific delivery of RNA into the liver and other tissues.

Differential pial and penetrating arterial responses examined by optogenetic activation of astrocytes and neurons

2021 ◽  
pp. 0271678X2110103
Author(s):  
Nao Hatakeyama ◽  
Miyuki Unekawa ◽  
Juri Murata ◽  
Yutaka Tomita ◽  
Norihiro Suzuki ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Acetylcholine Receptors ◽  
Step Function ◽  
Muscarinic Acetylcholine Receptors ◽  
Cell Type ◽  
Function Type ◽  
Neuron Activation ◽  
Cell Type Specific ◽  
Arterial Responses

A variety of brain cells participates in neurovascular coupling by transmitting and modulating vasoactive signals. The present study aimed to probe cell type-dependent cerebrovascular (i.e., pial and penetrating arterial) responses with optogenetics in the cortex of anesthetized mice. Two lines of the transgenic mice expressing a step function type of light-gated cation channel (channelrhodopsine-2; ChR2) in either cortical neurons (muscarinic acetylcholine receptors) or astrocytes (Mlc1-positive) were used in the experiments. Photo-activation of ChR2-expressing astrocytes resulted in a widespread increase in cerebral blood flow (CBF), extending to the nonstimulated periphery. In contrast, photo-activation of ChR2-expressing neurons led to a relatively localized increase in CBF. The differences in the spatial extent of the CBF responses are potentially explained by differences in the involvement of the vascular compartments. In vivo imaging of the cerebrovascular responses revealed that ChR2-expressing astrocyte activation led to the dilation of both pial and penetrating arteries, whereas ChR2-expressing neuron activation predominantly caused dilation of the penetrating arterioles. Pharmacological studies showed that cell type-specific signaling mechanisms participate in the optogenetically induced cerebrovascular responses. In conclusion, pial and penetrating arterial vasodilation were differentially evoked by ChR2-expressing astrocytes and neurons.

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