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1.
Chem Commun (Camb) ; 55(9): 1259-1262, 2019 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-30632548

RESUMO

A significant barrier to harnessing the power of cell-surface glycosaminoglycans (GAGs) to modulate glial cell-line-derived neurotrophic factor (GDNF) signaling is the difficulty in accessing key GAG structures involved. Here, we report tailored GDNF signaling using synthetic polyproline-based GAG mimetics (PGMs). PGMs deliver the much needed proactive programmability for GDNF recognition and effectively modulate GDNF-mediated neuronal processes in a cellular context.

2.
Chem Commun (Camb) ; 51(18): 3793-6, 2015 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-25648913

RESUMO

The secondary structure of the coiled coil peptides was regulated by altering the azido content at the hydrophobic core. These peptides were further investigated to form higher-order assemblies presumably via azido-mediated interactions.


Assuntos
Azidas/química , Peptídeos/química , Dicroísmo Circular , Interações Hidrofóbicas e Hidrofílicas , Microscopia Eletrônica de Transmissão , Estrutura Secundária de Proteína
3.
Chem Sci ; 6(1): 450-456, 2015 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-28694940

RESUMO

The challenges inherent in the synthesis of large glycosaminoglycan (GAG) polysaccharides have made chemically accessible multivalent glycoligands a valuable tool in the field of GAG mimetics. However, the difficulty of positioning sulfated sugar motifs at desired sites has hindered efforts to precisely tailor their biofunctions. Here, we achieved precise orientation of sulfated disaccharide motifs by taking advantage of a structurally well-defined polyproline scaffold, and describe systematic explorations into the importance of the spatial arrangement of sulfated sugars along the scaffold backbone in designing multivalent glycoligands. Our protein binding studies demonstrate that the specific conformational display of pendant sugars is central to direct their multivalent interactions with NGF. By employing computational modeling and cellular studies, we have further applied this approach to engineer NGF-mediated signaling by regulating the NGF/TrkA complexation process, leading to enhanced neuronal differentiation and neurite outgrowth of PC12 cells. Our findings offer a promising strategy for the pinpoint engineering of GAG-mediated biological processes and a novel method of designing new therapeutic agents that are highly specific to GAG-associated disease.

4.
Biomaterials ; 35(9): 2607-16, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24388815

RESUMO

Cell-cell and cell-matrix interactions are important events in directing stem cell chondrogenesis, which can be promoted in matrix microenvironments presenting appropriate ligands. In this study, interfacial polyelectrolyte complexation (IPC) based hydrogels were employed, wherein the unique formation of submicron size fibers facilitated spatial orientation of ligands within such hydrogels. The influence of aligned, collagen type I (Col I) presentation in IPC hydrogel on chondrogenic differentiation of human mesenchymal stem cells (MSC) was investigated. Early morphological dynamics, onset of N-cadherin/ß-catenin mediated chondrogenic induction and differentiation were compared between MSCs encapsulated in IPC-Col I and IPC-control (without Col I) hydrogels, and a conventional Col I hydrogel. MSCs in IPC-Col I hydrogel aligned and packed uniformly, resulting in enhanced cell-cell interactions and cellular condensation, facilitating superior chondrogenesis and the generation of mature hyaline neocartilage, with notable downregulation of fibrocartilaginous marker. Inhibition study using function blocking ß1-integrin antibodies reversed the aforementioned outcomes, indicating the importance of coupling integrin mediated cell-matrix interactions and N-cadherin/ß-catenin mediated downstream signaling events. This study demonstrated the significance of oriented ligand presentation for MSC chondrogenesis, and the importance of facilitating an orderly sequence of differentiation events, initiated by proximal interactions between MSCs and the extracellular matrix for robust neocartilage formation.


Assuntos
Comunicação Celular/efeitos dos fármacos , Condrogênese/efeitos dos fármacos , Eletrólitos/farmacologia , Matriz Extracelular/metabolismo , Hidrogéis/farmacologia , Células-Tronco Mesenquimais/citologia , Engenharia Tecidual/métodos , Animais , Linhagem da Célula/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Colágeno Tipo I/farmacologia , Matriz Extracelular/efeitos dos fármacos , Humanos , Integrina beta1/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Ratos , Alicerces Teciduais/química
5.
Nat Commun ; 4: 2353, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23955534

RESUMO

The in vivo efficacy of engineered tissue constructs depends largely on their integration with the host vasculature. Prevascularisation has been noted to facilitate integration of the constructs via anastomosis of preformed microvascular networks. Here we report a technique to fabricate aligned, spatially defined prevascularised tissue constructs with endothelial vessels by assembling individually tailored cell-laden polyelectrolyte hydrogel fibres. Stable, aligned endothelial vessels form in vitro within these constructs in 24 h, and these vessels anastomose with the host circulation in a mouse subcutaneous model. We create vascularised adipose and hepatic tissues by co-patterning the respective cell types with the preformed endothelial vessels. Our study indicates that the formation of aligned endothelial vessels in a hydrogel is an efficient prevascularisation approach in the engineering of tissue constructs.


Assuntos
Tecido Adiposo/irrigação sanguínea , Endotélio Vascular/metabolismo , Hidrogel de Polietilenoglicol-Dimetacrilato/metabolismo , Fígado/irrigação sanguínea , Engenharia Tecidual/métodos , Animais , Sobrevivência Celular , Células Endoteliais , Células Hep G2 , Humanos , Hidrogel de Polietilenoglicol-Dimetacrilato/química , Camundongos , Camundongos SCID , Neovascularização Fisiológica
6.
Adv Healthc Mater ; 1(1): 101-5, 2012 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-23184693

RESUMO

In multi-interfacial polyelectrolyte complexation (MIPC), fusion of nascent fibers from multiple interfaces brings the interfaces to a point from which a composite fiber is drawn. MIPC applied to two, three, and four polyelectrolyte complex interfaces leads to various patterned multicomponent fibers. Cells encapsulated in these fibers exhibit migration, aggregation and spreading in relation to the initial cell or matrix pattern.


Assuntos
Materiais Biocompatíveis/química , Técnicas de Cultura de Células/métodos , Eletrólitos/química , Engenharia Tecidual/métodos , Células 3T3 , Animais , Sobrevivência Celular , Teste de Materiais , Camundongos
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