Publications by authors named "Nikolai Rakhilin"

19 Publications

  • Page 1 of 1

Intravital imaging of mouse embryos.

Science 2020 04;368(6487):181-186

Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, USA.

Embryonic development is a complex process that is unamenable to direct observation. In this study, we implanted a window to the mouse uterus to visualize the developing embryo from embryonic day 9.5 to birth. This removable intravital window allowed manipulation and high-resolution imaging. In live mouse embryos, we observed transient neurotransmission and early vascularization of neural crest cell (NCC)-derived perivascular cells in the brain, autophagy in the retina, viral gene delivery, and chemical diffusion through the placenta. We combined the imaging window with in utero electroporation to label and track cell division and movement within embryos and observed that clusters of mouse NCC-derived cells expanded in interspecies chimeras, whereas adjacent human donor NCC-derived cells shrank. This technique can be combined with various tissue manipulation and microscopy methods to study the processes of development at unprecedented spatiotemporal resolution.
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http://dx.doi.org/10.1126/science.aba0210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646360PMC
April 2020

An intravital window to image the colon in real time.

Nat Commun 2019 12 11;10(1):5647. Epub 2019 Dec 11.

Department of Biomedical Engineering, Duke University, Durham, NC, 27710, USA.

Intravital microscopy is a powerful technique to observe dynamic processes with single-cell resolution in live animals. No intravital window has been developed for imaging the colon due to its anatomic location and motility, although the colon is a key organ where the majority of microbiota reside and common diseases such as inflammatory bowel disease, functional gastrointestinal disorders, and colon cancer occur. Here we describe an intravital murine colonic window with a stabilizing ferromagnetic scaffold for chronic imaging, minimizing motion artifacts while maximizing long-term survival by preventing colonic obstruction. Using this setup, we image fluorescently-labeled stem cells, bacteria, and immune cells in live animal colons. Furthermore, we image nerve activity via calcium imaging in real time to demonstrate that electrical sacral nerve stimulation can activate colonic enteric neurons. The simple implantable apparatus enables visualization of live processes in the colon, which will open the window to a broad range of studies.
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http://dx.doi.org/10.1038/s41467-019-13699-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906443PMC
December 2019

Author Correction: Intestinal crypts recover rapidly from focal damage with coordinated motion of stem cells that is impaired by aging.

Sci Rep 2019 Sep 30;9(1):13992. Epub 2019 Sep 30.

Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, 14853, USA.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
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http://dx.doi.org/10.1038/s41598-019-43805-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6768855PMC
September 2019

SENP3-mediated host defense response contains HBV replication and restores protein synthesis.

PLoS One 2019 14;14(1):e0209179. Epub 2019 Jan 14.

Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, North Carolina, United States of America.

Certain organs are capable of containing the replication of various types of viruses. In the liver, infection of Hepatitis B virus (HBV), the etiological factor of Hepatitis B and hepatocellular carcinoma (HCC), often remains asymptomatic and leads to a chronic carrier state. Here we investigated how hepatocytes contain HBV replication and promote their own survival by orchestrating a translational defense mechanism via the stress-sensitive SUMO-2/3-specific peptidase SENP3. We found that SENP3 expression level decreased in HBV-infected hepatocytes in various models including HepG2-NTCP cell lines and a humanized mouse model. Downregulation of SENP3 reduced HBV replication and boosted host protein translation. We also discovered that IQGAP2, a Ras GTPase-activating-like protein, is a key substrate for SENP3-mediated de-SUMOylation. Downregulation of SENP3 in HBV infected cells facilitated IQGAP2 SUMOylation and degradation, which leads to suppression of HBV gene expression and restoration of global translation of host genes via modulation of AKT phosphorylation. Thus, The SENP3-IQGAP2 de-SUMOylation axis is a host defense mechanism of hepatocytes that restores host protein translation and suppresses HBV gene expression.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0209179PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331149PMC
September 2019

is a microRNA safeguard for -induced inflammatory colon oncogenesis.

Elife 2018 12 13;7. Epub 2018 Dec 13.

Center for Genomics and Computational Biology, Duke University, Durham, United States.

Inflammation often induces regeneration to repair the tissue damage. However, chronic inflammation can transform temporary hyperplasia into a fertile ground for tumorigenesis. Here, we demonstrate that the microRNA acts as a central safeguard to protect the inflammatory stem cell niche and reparative regeneration. Although playing little role in regular homeostasis, deficiency leads to colon tumorigenesis after infection. targets both immune and epithelial cells to restrain inflammation-induced stem cell proliferation. targets Interleukin six receptor (IL-6R) and Interleukin 23 receptor (IL-23R) to suppress T helper 17 (Th17) cell differentiation and expansion, targets chemokine CCL22 to hinder Th17 cell recruitment to the colon epithelium, and targets an orphan receptor Interleukin 17 receptor D (IL-17RD) to inhibit IL-17-induced stem cell proliferation. Our study highlights the importance of microRNAs in protecting the stem cell niche during inflammation despite their lack of function in regular tissue homeostasis.
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http://dx.doi.org/10.7554/eLife.39479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314783PMC
December 2018

Microbiota of Inflammatory Bowel Disease Models.

Annu Int Conf IEEE Eng Med Biol Soc 2018 Jul;2018:2374-2377

Gut microbiome plays an important role in inflammatory bowel disease (IBD), a group of intestinal chronic inflammation conditions that affect a large population. The animal models of IBD have long been established on basis of pathological features, but their ability to recapitulate patient gut microbiota is unknown. We investigated and compared the composition and biodiversity of bacterial population in the fecal samples from rat models of the two IBD subtypes, and compared them with patient samples. Our analyses revealed that inflammation reduces overall microbiome diversity and increased variation between individuals. We identified specific microbial signatures associated with the two IBD subtypes that were consistent between the animal models and human IBD patients, suggesting that the animal models can partially recapitulate the microbiota in human diseases. Furthermore, metagenome prediction analysis suggested microbial functions that were likely altered by host-microbiota interactions in IBD models.
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http://dx.doi.org/10.1109/EMBC.2018.8512848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6709594PMC
July 2018

Intestinal crypts recover rapidly from focal damage with coordinated motion of stem cells that is impaired by aging.

Sci Rep 2018 Jul 20;8(1):10989. Epub 2018 Jul 20.

Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, 14853, USA.

Despite the continuous renewal and turnover of the small intestinal epithelium, the intestinal crypt maintains a 'soccer ball-like', alternating pattern of stem and Paneth cells at the base of the crypt. To study the robustness of the alternating pattern, we used intravital two-photon microscopy in mice with fluorescently-labeled Lgr5+ intestinal stem cells and precisely perturbed the mosaic pattern with femtosecond laser ablation. Ablation of one to three cells initiated rapid motion of crypt cells that restored the alternation in the pattern within about two hours with only the rearrangement of pre-existing cells, without any cell division. Crypt cells then performed a coordinated dilation of the crypt lumen, which resulted in peristalsis-like motion that forced damaged cells out of the crypt. Crypt cell motion was reduced with inhibition of the ROCK pathway and attenuated with old age, and both resulted in incomplete pattern recovery. This suggests that in addition to proliferation and self-renewal, motility of stem cells is critical for maintaining homeostasis. Reduction of this newly-identified behavior of stem cells could contribute to disease and age-related changes.
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http://dx.doi.org/10.1038/s41598-018-29230-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6054609PMC
July 2018

Aldolase B-Mediated Fructose Metabolism Drives Metabolic Reprogramming of Colon Cancer Liver Metastasis.

Cell Metab 2018 Jun 26;27(6):1249-1262.e4. Epub 2018 Apr 26.

Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA. Electronic address:

Cancer metastasis accounts for the majority of cancer-related deaths and remains a clinical challenge. Metastatic cancer cells generally resemble cells of the primary cancer, but they may be influenced by the milieu of the organs they colonize. Here, we show that colorectal cancer cells undergo metabolic reprogramming after they metastasize and colonize the liver, a key metabolic organ. In particular, via GATA6, metastatic cells in the liver upregulate the enzyme aldolase B (ALDOB), which enhances fructose metabolism and provides fuel for major pathways of central carbon metabolism during tumor cell proliferation. Targeting ALDOB or reducing dietary fructose significantly reduces liver metastatic growth but has little effect on the primary tumor. Our findings suggest that metastatic cells can take advantage of reprogrammed metabolism in their new microenvironment, especially in a metabolically active organ such as the liver. Manipulation of involved pathways may affect the course of metastatic growth.
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http://dx.doi.org/10.1016/j.cmet.2018.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5990465PMC
June 2018

Matrix metalloproteinase inhibitors enhance the efficacy of frontline drugs against Mycobacterium tuberculosis.

PLoS Pathog 2018 04 26;14(4):e1006974. Epub 2018 Apr 26.

Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY, United States of America.

Mycobacterium tuberculosis (Mtb) remains a grave threat to world health with emerging drug resistant strains. One prominent feature of Mtb infection is the extensive reprogramming of host tissue at the site of infection. Here we report that inhibition of matrix metalloproteinase (MMP) activity by a panel of small molecule inhibitors enhances the in vivo potency of the frontline TB drugs isoniazid (INH) and rifampicin (RIF). Inhibition of MMP activity leads to an increase in pericyte-covered blood vessel numbers and appears to stabilize the integrity of the infected lung tissue. In treated mice, we observe an increased delivery and/or retention of frontline TB drugs in the infected lungs, resulting in enhanced drug efficacy. These findings indicate that targeting Mtb-induced host tissue remodeling can increase therapeutic efficacy and could enhance the effectiveness of current drug regimens.
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http://dx.doi.org/10.1371/journal.ppat.1006974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5919409PMC
April 2018

The neuropeptide neuromedin U stimulates innate lymphoid cells and type 2 inflammation.

Nature 2017 09 6;549(7671):282-286. Epub 2017 Sep 6.

Jill Roberts Institute for Research in Inflammatory Bowel Disease, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, New York 10021, USA.

The type 2 cytokines interleukin (IL)-4, IL-5, IL-9 and IL-13 have important roles in stimulating innate and adaptive immune responses that are required for resistance to helminth infection, promotion of allergic inflammation, metabolic homeostasis and tissue repair. Group 2 innate lymphoid cells (ILC2s) produce type 2 cytokines, and although advances have been made in understanding the cytokine milieu that promotes ILC2 responses, how ILC2 responses are regulated by other stimuli remains poorly understood. Here we demonstrate that ILC2s in the mouse gastrointestinal tract co-localize with cholinergic neurons that express the neuropeptide neuromedin U (NMU). In contrast to other haematopoietic cells, ILC2s selectively express the NMU receptor 1 (NMUR1). In vitro stimulation of ILC2s with NMU induced rapid cell activation, proliferation, and secretion of the type 2 cytokines IL-5, IL-9 and IL-13 that was dependent on cell-intrinsic expression of NMUR1 and G protein. In vivo administration of NMU triggered potent type 2 cytokine responses characterized by ILC2 activation, proliferation and eosinophil recruitment that was associated with accelerated expulsion of the gastrointestinal nematode Nippostrongylus brasiliensis or induction of lung inflammation. Conversely, worm burden was higher in Nmur1 mice than in control mice. Furthermore, use of gene-deficient mice and adoptive cell transfer experiments revealed that ILC2s were necessary and sufficient to mount NMU-elicited type 2 cytokine responses. Together, these data indicate that the NMU-NMUR1 neuronal signalling circuit provides a selective mechanism through which the enteric nervous system and innate immune system integrate to promote rapid type 2 cytokine responses that can induce anti-microbial, inflammatory and tissue-protective type 2 responses at mucosal sites.
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http://dx.doi.org/10.1038/nature23676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6066372PMC
September 2017

A Notch positive feedback in the intestinal stem cell niche is essential for stem cell self-renewal.

Mol Syst Biol 2017 04 28;13(4):927. Epub 2017 Apr 28.

School of Electrical and Computer Engineering, Cornell University, Ithaca, NY, USA

The intestinal epithelium is the fastest regenerative tissue in the body, fueled by fast-cycling stem cells. The number and identity of these dividing and migrating stem cells are maintained by a mosaic pattern at the base of the crypt. How the underlying regulatory scheme manages this dynamic stem cell niche is not entirely clear. We stimulated intestinal organoids with Notch ligands and inhibitors and discovered that intestinal stem cells employ a positive feedback mechanism via direct Notch binding to the second intron of the Notch1 gene. Inactivation of the positive feedback by CRISPR/Cas9 mutation of the binding sequence alters the mosaic stem cell niche pattern and hinders regeneration in organoids. Dynamical system analysis and agent-based multiscale stochastic modeling suggest that the positive feedback enhances the robustness of Notch-mediated niche patterning. This study highlights the importance of feedback mechanisms in spatiotemporal control of the stem cell niche.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5408779PMC
http://dx.doi.org/10.15252/msb.20167324DOI Listing
April 2017

Adult enteric nervous system in health is maintained by a dynamic balance between neuronal apoptosis and neurogenesis.

Proc Natl Acad Sci U S A 2017 05 18;114(18):E3709-E3718. Epub 2017 Apr 18.

Center for Neurogastroenterology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205;

According to current dogma, there is little or no ongoing neurogenesis in the fully developed adult enteric nervous system. This lack of neurogenesis leaves unanswered the question of how enteric neuronal populations are maintained in adult guts, given previous reports of ongoing neuronal death. Here, we confirm that despite ongoing neuronal cell loss because of apoptosis in the myenteric ganglia of the adult small intestine, total myenteric neuronal numbers remain constant. This observed neuronal homeostasis is maintained by new neurons formed in vivo from dividing precursor cells that are located within myenteric ganglia and express both Nestin and p75NTR, but not the pan-glial marker Sox10. Mutation of the phosphatase and tensin homolog gene in this pool of adult precursors leads to an increase in enteric neuronal number, resulting in ganglioneuromatosis, modeling the corresponding disorder in humans. Taken together, our results show significant turnover and neurogenesis of adult enteric neurons and provide a paradigm for understanding the enteric nervous system in health and disease.
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http://dx.doi.org/10.1073/pnas.1619406114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5422809PMC
May 2017

Simultaneous optical and electrical in vivo analysis of the enteric nervous system.

Nat Commun 2016 06 7;7:11800. Epub 2016 Jun 7.

School of Electrical and Computer Engineering, Cornell University, Ithaca, New York 14853, USA.

The enteric nervous system (ENS) is a major division of the nervous system and vital to the gastrointestinal (GI) tract and its communication with the rest of the body. Unlike the brain and spinal cord, relatively little is known about the ENS in part because of the inability to directly monitor its activity in live animals. Here, we integrate a transparent graphene sensor with a customized abdominal window for simultaneous optical and electrical recording of the ENS in vivo. The implanted device captures ENS responses to neurotransmitters, drugs and optogenetic manipulation in real time.
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http://dx.doi.org/10.1038/ncomms11800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4899629PMC
June 2016

A real-time spike classification method based on dynamic time warping for extracellular enteric neural recording with large waveform variability.

J Neurosci Methods 2016 Mar 21;261:97-109. Epub 2015 Dec 21.

School of Electrical and Computer Engineering, Cornell University, Ithaca, NY 14853, USA.

Background: Computationally efficient spike recognition methods are required for real-time analysis of extracellular neural recordings. The enteric nervous system (ENS) is important to human health but less well-understood with few appropriate spike recognition algorithms due to large waveform variability.

New Method: Here we present a method based on dynamic time warping (DTW) with high tolerance to variability in time and magnitude. Adaptive temporal gridding for "fastDTW" in similarity calculation significantly reduces the computational cost. The automated threshold selection allows for real-time classification for extracellular recordings.

Results: Our method is first evaluated on synthesized data at different noise levels, improving both classification accuracy and computational complexity over the conventional cross-correlation based template-matching method (CCTM) and PCA+k-means clustering without time warping. Our method is then applied to analyze the mouse enteric neural recording with mechanical and chemical stimuli. Successful classification of biphasic and monophasic spikes is achieved even when the spike variability is larger than millisecond in width and millivolt in magnitude.

Comparison With Existing Method(s): In comparison with conventional template matching and clustering methods, the fastDTW method is computationally efficient with high tolerance to waveform variability.

Conclusions: We have developed an adaptive fastDTW algorithm for real-time spike classification of ENS recording with large waveform variability against colony motility, ambient changes and cellular heterogeneity.
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http://dx.doi.org/10.1016/j.jneumeth.2015.12.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4749467PMC
March 2016

Comprehensive models of human primary and metastatic colorectal tumors in immunodeficient and immunocompetent mice by chemokine targeting.

Nat Biotechnol 2015 Jun 25;33(6):656-60. Epub 2015 May 25.

Department of Medicine, Weill Cornell Medical College, New York, New York, USA.

Current orthotopic xenograft models of human colorectal cancer (CRC) require surgery and do not robustly form metastases in the liver, the most common site clinically. CCR9 traffics lymphocytes to intestine and colorectum. We engineered use of the chemokine receptor CCR9 in CRC cell lines and patient-derived cells to create primary gastrointestinal (GI) tumors in immunodeficient mice by tail-vein injection rather than surgery. The tumors metastasize inducibly and robustly to the liver. Metastases have higher DKK4 and NOTCH signaling levels and are more chemoresistant than paired subcutaneous xenografts. Using this approach, we generated 17 chemokine-targeted mouse models (CTMMs) that recapitulate the majority of common human somatic CRC mutations. We also show that primary tumors can be modeled in immunocompetent mice by microinjecting CCR9-expressing cancer cell lines into early-stage mouse blastocysts, which induces central immune tolerance. We expect that CTMMs will facilitate investigation of the biology of CRC metastasis and drug screening.
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http://dx.doi.org/10.1038/nbt.3239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4532544PMC
June 2015

miR-1269 promotes metastasis and forms a positive feedback loop with TGF-β.

Nat Commun 2015 Apr 15;6:6879. Epub 2015 Apr 15.

1] School of Electrical and Computer Engineering, Cornell University, Ithaca, New York 14853, USA [2] Department of Biomedical Engineering, Cornell University, Ithaca, New York 14853, USA [3] Department of Biological and Environmental Engineering, Cornell University, Ithaca, New York 14853, USA.

As patient survival drops precipitously from early-stage cancers to late-stage and metastatic cancers, microRNAs that promote relapse and metastasis can serve as prognostic and predictive markers as well as therapeutic targets for chemoprevention. Here we show that miR-1269a promotes colorectal cancer (CRC) metastasis and forms a positive feedback loop with TGF-β signalling. miR-1269a is upregulated in late-stage CRCs, and long-term monitoring of 100 stage II CRC patients revealed that miR-1269a expression in their surgically removed primary tumours is strongly associated with risk of CRC relapse and metastasis. Consistent with clinical observations, miR-1269a significantly increases the ability of CRC cells to invade and metastasize in vivo. TGF-β activates miR-1269 via Sox4, while miR-1269a enhances TGF-β signalling by targeting Smad7 and HOXD10, hence forming a positive feedback loop. Our findings suggest that miR-1269a is a potential marker to inform adjuvant chemotherapy decisions for CRC patients and a potential therapeutic target to deter metastasis.
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http://dx.doi.org/10.1038/ncomms7879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4399006PMC
April 2015

A metabolic signature of colon cancer initiating cells.

Annu Int Conf IEEE Eng Med Biol Soc 2014 ;2014:4759-62

Colon cancer initiating cells (CCICs) are more tumorigenic and metastatic than the majority of colorectal cancer (CRC) cells. CCICs have also been associated with stem cell-like properties. However, there is a lack of system-level understanding of what mechanisms distinguish CCICs from common CRC cells. We compared the transcriptomes of CD133+ CCICs and CD133- CRC cells from multiple sources, which identified a distinct metabolic signature for CD133(high) CCICs. High-resolution unbiased metabolomics was then performed to validate this CCIC metabolic signature. Specifically, levels of enzymes and metabolites involved in glycolysis, the citric acid (TCA) cycle, and cysteine and methionine metabolism are altered in CCICs. Analyses of the alterations further suggest an epigenetic link. This metabolic signature provides mechanistic insights into CCIC phenotypes and may serve as potential biomarkers and therapeutic targets for future CRC treatment.
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http://dx.doi.org/10.1109/EMBC.2014.6944688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4302416PMC
September 2015

A microRNA miR-34a-regulated bimodal switch targets Notch in colon cancer stem cells.

Cell Stem Cell 2013 May;12(5):602-15

School of Electrical and Computer Engineering, Cornell University, Ithaca, NY 14853, USA.

microRNAs regulate developmental cell-fate decisions, tissue homeostasis, and oncogenesis in distinct ways relative to proteins. Here, we show that the tumor suppressor microRNA miR-34a is a cell-fate determinant in early-stage dividing colon cancer stem cells (CCSCs). In pair-cell assays, miR-34a distributes at high levels in differentiating progeny, whereas low levels of miR-34a demarcate self-renewing CCSCs. Moreover, miR-34a loss of function and gain of function alter the balance between self-renewal versus differentiation both in vitro and in vivo. Mechanistically, miR-34a sequesters Notch1 mRNA to generate a sharp threshold response where a bimodal Notch signal specifies the choice between self-renewal and differentiation. In contrast, the canonical cell-fate determinant Numb regulates Notch levels in a continuously graded manner. Altogether, our findings highlight a unique microRNA-regulated mechanism that converts noisy input into a toggle switch for robust cell-fate decisions in CCSCs.
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http://dx.doi.org/10.1016/j.stem.2013.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646336PMC
May 2013

Tunable physiologic interactions of adhesion molecules for inflamed cell-selective drug delivery.

Biomaterials 2011 May;32(13):3487-98

Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA.

Dysregulated inflammation contributes to the pathogenesis of various diseases. Therapeutic efficacy of anti-inflammatory agents, however, falls short against resilient inflammatory responses, whereas long-term and high-dose systemic administration can cause adverse side effects. Site-directed drug delivery systems would thus render more effective and safer treatments by increasing local dosage and minimizing toxicity. Nonetheless, achieving clinically effective targeted delivery to inflammatory sites has been difficult due to diverse cellular players involved in immunity and endogenous targets being expressed at basal levels. Here we exploit a physiological molecular interaction between intercellular adhesion molecule (ICAM)-1 and lymphocyte function associated antigen (LFA)-1 to deliver a potent anti-inflammatory drug, celastrol, specifically and comprehensively to inflamed cells. We found that affinity and avidity adjusted inserted (I) domain, the major binding site of LFA-1, on liposome surface enhanced the specificity toward lipopolysaccharides (LPS)-treated or inflamed endothelial cells (HMEC-1) and monocytes (THP-1) via ICAM-1 overexpression, reflecting inherent affinity and avidity modulation of these molecules in physiology. Targeted delivery of celastrol protected cells from recurring LPS challenges, suppressing pro-inflammatory responses and inflammation-induced cell proliferation. Targeted delivery also blocked THP-1 adhesion to inflamed HMEC-1, forming barriers to immune cell accumulation and to aggravating inflammatory signals. Our results demonstrate affinity and avidity of targeting moieties on nanoparticles as important design parameters to ensure specificity and avoid toxicities. We anticipate that such tunable physiologic interactions could be used for designing effective drug carriers for in vivo applications and contribute to treating a range of immune and inflammatory diseases.
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http://dx.doi.org/10.1016/j.biomaterials.2011.01.046DOI Listing
May 2011