probing-roles-physical-forces-early-chick-embryonic

Probing the Roles of Physical Forces in Early Chick Embryonic Morphogenesis

Embryonic development is traditionally studied from the perspective of biomolecular genetics, but the fundamental importance of mechanics in morphogenesis ...

Dartmouth College

The capability to sense and respond to external mechanical stimuli at various timescales is essential to many physiological aspects in plants, including self-protection, intake of nutrients and reproduction. Remarkably, some plants have evolved the ability to react to mechanical stimuli within a few seconds despite a lack of muscles and nerves. The fast movements of plants in response to mechanical stimuli have long captured the curiosity of scientists and engineers, but the mechanisms behind these rapid thigmonastic movements are still not understood completely. In this article, we provide an overview of such thigmonastic movements in several representative plants, including Dionaea, Utricularia, Aldrovanda, Drosera and Mimosa. In addition, we review a series of studies that present biomimetic structures inspired by fast-moving plants. We hope that this article will shed light on the current status of research on the fast movements of plants and bioinspired structures and also promote interdisciplinary studies on both the fundamental mechanisms of plants' fast movements and biomimetic structures for engineering applications, such as artificial muscles, multi-stable structures and bioinspired robots. 

Fast nastic motion of plants and bioinspired structures.

Hepatectomy generally offers the best chance of long-term survival for patients with hepatocellular carcinoma (HCC). Many studies have shown that hepatectomy accelerates tumor metastasis, but the mechanism remains unclear.

Elevated MTSS1 expression associated with metastasis and poor prognosis of residual hepatitis B-related hepatocellular carcinoma.

Erratum to: Elevated MTSS1 expression associated with metastasis and poor prognosis of residual hepatitis B-related hepatocellular carcinoma.

Nanoparticles have shown promise as both drug delivery vehicles and direct antitumor systems, but they must be properly designed in order to maximize efficacy. Computational modeling is often used both to design new nanoparticles and to better understand existing ones. Modeled processes include the release of drugs at the tumor site and the physical interaction between the nanoparticle and cancer cells. In this article, we provide an overview of three different targeted drug delivery methods (passive targeting, active targeting and physical targeting), compare methods of action, advantages, limitations, and the current stage of research. For the most commonly used nanoparticle carriers, fabrication methods are also reviewed. This is followed by a review of computational simulations and models on nanoparticle-based drug delivery.

Design of Nanoparticle-Based Carriers for Targeted Drug Delivery.

Stem cell-based therapy remains one of the promising approaches for cardiac repair and regeneration. However, its applications are restricted by the limited efficacy of cardiac differentiation. To address this issue, we examined whether carbon nanotubes (CNTs) would provide an instructive extracellular microenvironment to facilitate cardiogenesis in brown adipose-derived stem cells (BASCs) and to elucidate the underlying signaling pathways. In this study, we systematically investigated a series of cellular responses of BASCs due to the incorporation of CNTs into collagen (CNT-Col) substrates that promoted cell adhesion, spreading, and growth. Moreover, we found that CNT-Col substrates remarkably improved the efficiency of BASCs cardiogenesis by using fluorescence staining and quantitative real-time reverse transcription-polymerase chain reaction. Critically, CNTs in the substrates accelerated the maturation of BASCs-derived cardiomyocytes. Furthermore, the underlying mechanism for promotion of BASCs cardiac differentiation by CNTs was determined by immunostaining, quantitative real-time reverse transcription-polymerase chain reaction, and Western blotting assay. It is notable that β1-integrin-dependent TGF-β1 signaling pathway modulates the facilitative effect of CNTs in cardiac differentiation of BASCs. Therefore, it is an efficient approach to regulate cardiac differentiation of BASCs by the incorporation of CNTs into the native matrix. Importantly, our findings can not only facilitate the mechanistic understanding of molecular events initiating cardiac differentiation in stem cells, but also offer a potentially safer source for cardiac regenerative medicine.

Carbon nanotube-based substrates promote cardiogenesis in brown adipose-derived stem cells via β1-integrin-dependent TGF-β1 signaling pathway.

Carbon nanotube (CNT)-based hydrogels have been shown to support cardiomyocyte growth and function. However, their role in cellular integrity among cardiomyocytes has not been studied in detail and the mechanisms underlying this process remain unclear. Here, single walled CNTs incorporated into gelatin with methacrylate anhydride (CNT/GelMA) hydrogels were utilized to construct cardiac tissues, which enhanced cardiomyocyte adhesion and maturation. Furthermore, through the use of immunohistochemical staining, transmission electron microscopy and intracellular calcium transient measurement, the incorporation of CNTs into the scaffolds was observed to markedly enhance the assembly and formation in the cardiac constructs. Importantly, we further explored the underlying mechanism behind these effects through the use of immunohistochemical staining and western blotting. The β1-integrin-mediated FAK and RhoA signaling pathways were found to be responsible for CNT-induced upregulation of electrical and mechanical junction proteins respectively. Together, our study provides new insights into the facilitative effects of CNTs on ID formation, which has important significance for improving the quality of engineered cardiac tissue and applying them to cardiac regenerative therapies.

Carbon nanotube-composite hydrogels promote intercalated disc assembly in engineered cardiac tissues through β1-integrin mediated FAK and RhoA pathway.

We employed both theoretical and computational models supported by experiments to study the multistable behavior of an edge-effect driven Si/Cr micro-claw. Our study showed that individual micro-claws demonstrate either monostability or bistability as the magnitude of the edge effect is varied.

Edge effect of strained bilayer nanofilms for tunable multistability and actuation.

Nanocrystalline diamond nanomembranes with thinning-reduced flexural rigidities can be shaped into various 3D mesostructures, such as tubes, jagged ribbons, nested tubes, helices, and nested rings. Microscale helical diamond architectures are formed by controlled debonding in agreement with finite-element simulation results. Rolled-up diamond tubular microcavities exhibit pronounced defect-related photoluminescence with whispering-gallery-mode resonance.

Deterministic Self-Rolling of Ultrathin Nanocrystalline Diamond Nanomembranes for 3D Tubular/Helical Architecture.

During early development, the tubular embryonic chick brain undergoes a combination of progressive ventral bending and rightward torsion, one of the earliest organ-level left-right asymmetry events in development. Existing evidence suggests that bending is caused by differential growth, but the mechanism for the predominantly rightward torsion of the embryonic brain tube remains poorly understood. Here, we show through a combination of  experiments, a physical model of the embryonic morphology and mechanics analysis that the vitelline membrane (VM) exerts an external load on the brain that drives torsion. Our theoretical analysis showed that the force is of the order of 10 micronewtons. We also designed an experiment to use fluid surface tension to replace the mechanical role of the VM, and the estimated magnitude of the force owing to surface tension was shown to be consistent with the above theoretical analysis. We further discovered that the asymmetry of the looping heart determines the chirality of the twisted brain via physical mechanisms, demonstrating the mechanical transfer of left-right asymmetry between organs. Our experiments also implied that brain flexure is a necessary condition for torsion. Our work clarifies the mechanical origin of torsion and the development of left-right asymmetry in the early embryonic brain.

How the embryonic chick brain twists.

In the normal lung, a dominant structural element is an elastic "line element" that originates in the central bronchi and inserts into the distal airspaces. Despite its structural importance, the process that leads to development of the cable line element is unknown. To investigate the morphologic events contributing to its development, we used optical clearing methods to examine the postnatal rat lung. An unexpected finding was numerous spheres, with a median diameter of 1-2 µm, within the primary septa of the rat lung. The spheres demonstrated green autofluorescence, selective fluorescent eosin staining, reactivity with carboxyfluorescein succinimidyl ester, and specific labeling with anti-tropoelastin monoclonal antibody-findings consistent with tropoelastin. The sphere number peaked on rat postnatal day 4 (P4) and were rare by P14. The disappearance of the spheres was coincident with the development of the cable line element in the rat lung. Transmission electron microscopy demonstrated no consistent association between parenchymal cells and sphere alignment. In contrast, the alignment of tropoelastin spheres appeared to be the direct result of interactions of scaffold proteins including collagen fibers and fibrillin microfibrils. We conclude that the spatial organization of the cable line element appears to be independent of tropoelastin deposition, but dependent on crosslinking to scaffold proteins within the primary septa. Anat Rec, 300:1670-1679, 2017. © 2017 Wiley Periodicals, Inc.

Extracellular Assembly of the Elastin Cable Line Element in the Developing Lung.

Cell culture has become an indispensable tool to help uncover fundamental biophysical and biomolecular mechanisms by which cells assemble into tissues and organs, how these tissues function, and how that function becomes disrupted in disease. Cell culture is now widely used in biomedical research, tissue engineering, regenerative medicine, and industrial practices. Although flat, two-dimensional (2D) cell culture has predominated, recent research has shifted toward culture using three-dimensional (3D) structures, and more realistic biochemical and biomechanical microenvironments. Nevertheless, in 3D cell culture, many challenges remain, including the tissue-tissue interface, the mechanical microenvironment, and the spatiotemporal distributions of oxygen, nutrients, and metabolic wastes. Here, we review 2D and 3D cell culture methods, discuss advantages and limitations of these techniques in modeling physiologically and pathologically relevant processes, and suggest directions for future research.

Modeling Physiological Events in 2D vs. 3D Cell Culture.

Compressed monodisperse emulsions in confined space exhibit highly ordered structures. The influence of the volume fraction and the confinement geometry on the organized structures is investigated and the mechanism by which structural transition occurs is studied. Based on the understanding of ordering behavior of compressed emulsions, a simple and high-throughput method to fabricate monodisperse polyhedral microgels using the emulsions as the template is developed. By controlling the geometry of the confined spaces, a variety of shapes such as hexagonal prism, Fejes Toth honeycomb prism, truncated octahedron, pyritohedron, and truncated hexagonal trapezohedron are implemented. Moreover, the edge sharpness of each shape is controllable by adjusting the drop volume fraction. This design principle can be readily extended to other shapes and materials, and therefore provides a useful means to create polyhedral microparticles for both fundamental study and practical applications.

Creation of Faceted Polyhedral Microgels from Compressed Emulsions.

Circular RNAs (circRNAs) represent a class of endogenous noncoding RNAs that have recently been recognized as important regulators of gene expression and pathological networks. However, their transcriptional activities and functional mechanisms in cancer remain largely unknown. Here, we present results from a global circRNA expression and functional analysis of patients with hepatocellular carcinoma (HCC). Using a circRNA microarray, we identified 226 differentially expressed circRNAs, of which 189 were significantly upregulated and 37 were downregulated. High expression of circRNA_100338, one of the upregulated circRNAs in HCC, is closely correlated with a low cumulative survival rate and metastatic progression in HCC patients with hepatitis B. Furthermore, our in silico and experimental analyses identified miR-141-3p as a direct target of circRNA_100338. Thus, circRNA_100338 functions as an endogenous sponge for miR-141-3p in HCC. In addition, we identified the crucial antagonistic roles of circRNA_100338 and miR-141-3p in the regulation of invasive potential in liver cancer cells. Overall, the differential expression of multiple circRNAs in HCC tissues and their clinical significance in hepatitis B-related HCC patients as revealed by our study suggests that circRNA_100338 is a potentially valuable biomarker for HCC diagnosis and target for HCC therapeutics.

Comprehensive circular RNA profiling reveals the regulatory role of the circRNA-100338/miR-141-3p pathway in hepatitis B-related hepatocellular carcinoma.

Trans-activating transcriptional activator (TAT), a cell-penetrating peptide, is extensively used for facilitating cellular uptake and nuclear targeting of drug delivery systems. However, the positively charged TAT peptide strongly interacts with serum components and undergoes substantial phagocytosis by the reticuloendothelial system, causing a short blood circulation in vivo. In this work, an acid-active tumor targeting nanoplatform DA-TAT-PECL is developed to inhibit the nonspecific interactions of TAT in the bloodstream. 2,3-dimethylmaleic anhydride (DA) is used to convert the TAT's amines to carboxylic acid; the resulting DA-TAT is conjugated to poly(ethylene glycol)-poly(ε-caprolactone) (PEG-PCL, PECL) to get DA-TAT-PECL. After self-assembly into polymeric micelles, they are capable of circulating in the physiological condition for a long time and promoting cell penetration upon accumulation at the tumor site and deshielding the DA group. Moreover, camptothecin (CPT) is used as the anticancer drug and modified into a dimer (CPT) -ss-Mal, in which two CPT molecules are connected by a reduction-labile maleimide thioether bond. The Förster resonance energy transfer signal between CPT and maleimide thioether bond is monitored to visualize the drug release process, and effective targeted delivery of antitumor drugs is demonstrated. This pH/reduction dual-responsive micelle system provides a new platform for high fidelity cancer therapy.

Dimeric Drug Polymeric Micelles with Acid-Active Tumor Targeting and FRET-Traceable Drug Release.

Increasing amounts of evidence indicate that Missing in metastasis B (MIM-B) promotes cancer metastasis. Here, we sought to better understand the mechanism through which MIM-B promotes tumor metastasis in hepatocellular carcinoma (HCC).

Article	Year
Fast nastic motion of plants and bioinspired structures. Journal of the Royal Society, Interface\| PubMed ID: 26354828	2015
Elevated MTSS1 expression associated with metastasis and poor prognosis of residual hepatitis B-related hepatocellular carcinoma. Journal of experimental & clinical cancer research : CR\| PubMed ID: 27230279	2016
Erratum to: Elevated MTSS1 expression associated with metastasis and poor prognosis of residual hepatitis B-related hepatocellular carcinoma. Journal of experimental & clinical cancer research : CR\| PubMed ID: 27342210	2016
Design of Nanoparticle-Based Carriers for Targeted Drug Delivery. Journal of nanomaterials\| PubMed ID: 27398083	2016
Carbon nanotube-based substrates promote cardiogenesis in brown adipose-derived stem cells via β1-integrin-dependent TGF-β1 signaling pathway. International journal of nanomedicine\| PubMed ID: 27660434	2016
Carbon nanotube-composite hydrogels promote intercalated disc assembly in engineered cardiac tissues through β1-integrin mediated FAK and RhoA pathway. Acta biomaterialia\| PubMed ID: 27769942	2017
Edge effect of strained bilayer nanofilms for tunable multistability and actuation. Nanoscale\| PubMed ID: 28067396	2017
Deterministic Self-Rolling of Ultrathin Nanocrystalline Diamond Nanomembranes for 3D Tubular/Helical Architecture. Advanced materials (Deerfield Beach, Fla.)\| PubMed ID: 28165163	2017
How the embryonic chick brain twists. Journal of the Royal Society, Interface\| PubMed ID: 28334695	2016
Extracellular Assembly of the Elastin Cable Line Element in the Developing Lung. Anatomical record (Hoboken, N.J. : 2007)\| PubMed ID: 28380679	2017
Modeling Physiological Events in 2D vs. 3D Cell Culture. Physiology (Bethesda, Md.)\| PubMed ID: 28615311	2017
Creation of Faceted Polyhedral Microgels from Compressed Emulsions. Small (Weinheim an der Bergstrasse, Germany)\| PubMed ID: 28650575	2017
Comprehensive circular RNA profiling reveals the regulatory role of the circRNA-100338/miR-141-3p pathway in hepatitis B-related hepatocellular carcinoma. Scientific reports\| PubMed ID: 28710406	2017
Dimeric Drug Polymeric Micelles with Acid-Active Tumor Targeting and FRET-Traceable Drug Release. Advanced materials (Deerfield Beach, Fla.)\| PubMed ID: 29210480	2018
Missing-in-metastasis B (MIM-B) combined with caveolin-1 promotes metastasis of hepatocellular carcinoma. Oncotarget\| PubMed ID: 29221140	2017

Zi Chen

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