Guest editorial: special issue on bone tissue engineering

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Synergistic growth factor microenvironments

Growth factors (GF) are remarkably powerful signalling molecules that orchestrate developmental biology. GFs are currently used in medjcal applications with limited success but it is clear that if their potential can be harnessed for biomedicine then they could underpin the discipline of regenerative medicine. However, while we understand that biology uses cell-secreted growth factors tethered to the ECM, biologists typically employ GFs in soluble format at high concentrations. When used in vivo, this causes off-target, unwanted effects, which severely limits their use. There is a vast amount of literature dealing with material systems that control the delivery of GFs. However, it was soon observed that GFs could be more effectively presented bound to surfaces from a solid-phase state rather than in soluble form, recapitulating the way the extracellular matrix (ECM) binds GFs. In parallel, evidence was found that within the ECM, GFs can actually work in cooperation with integrins and that this produced ehnaced GF signalling due to the crosstalk between both receptors. Recently this knowledge was used to engineer microenvironments that target simultaneous integrin and GF receptor engagement seeking to maximise GF effects in vitro (e.g. in terms of stem cell differentiation) but also tissue repair in vivo (e.g. bone regeneration and wound healing). This feature article introduces the concept of synergistic GF/integrin signalling and then introduces GF delivery systems that were key in the development of more advanced synergistic growth factor microenvironments

Designing stem cell niches for differentiation and self-renewal

Mesenchymal stem cells, characterized by their ability to differentiate into skeletal tissues and self-renew, hold great promise for both regenerative medicine and novel therapeutic discovery. However, their regenerative capacity is retained only when in contact with their specialized microenvironment, termed the stem cell niche. Niches provide structural and functional cues that are both biochemical and biophysical, stem cells integrate this complex array of signals with intrinsic regulatory networks to meet physiological demands. Although, some of these regulatory mechanisms remain poorly understood or difficult to harness with traditional culture systems. Biomaterial strategies are being developed that aim to recapitulate stem cell niches, by engineering microenvironments with physiological-like niche properties that aim to elucidate stem cell-regulatory mechanisms, and to harness their regenerative capacity in vitro. In the future, engineered niches will prove important tools for both regenerative medicine and therapeutic discoveries

Dietary Uncoupling of Gut Microbiota and Energy Harvesting from Obesity and Glucose Tolerance in Mice

The authors gratefully acknowledge Doctoral Training Partnership funding from the BBSRC (M.J.D.) and funding from the Scottish Government (P.J.M., A.W.R., and A.W.W.). We also thank the Centre for Genome-Enabled Biology and Medicine for help with next-generation sequencing and Karen Garden and the Rowett’s Analytical Services for SCFA analysis. SUPPLEMENTAL INFORMATION Supplemental Information includes four figures and two tables and can be found with this article online at https://doi.org/10.1016/j.celrep.2017.10.056.Peer reviewedPublisher PD

Current approaches for modulation of the nanoscale interface in the regulation of cell behavior

Regulation of cell behavior in response to nanoscale features has been the focus of much research in recent years and the successful generation of nanoscale features capable of mimicking the natural nanoscale interface has been of great interest in the field of biomaterials research. In this review, we discuss relevant nanofabrication techniques and how they are combined with bioengineering applications to mimic the natural extracellular matrix (ECM) and create valuable nanoscale interfaces

Cellular response to low adhesion nanotopographies

This review focuses on how cells respond to low-adhesion nanotopographies. In order to do this, fabrication techniques, how cells may locate nanofeatures through the use of filopodia and possible mechanotransductive mechanisms are discussed. From this, examples of low-adhesion topographies and sizes and arrangements that may lead to low-adhesion are discussed. Finally, it is hypothesized as to how specifically low-adhesion materials may fit into the outlined mechanotransductive mechanisms

Genomic analysis of the role of transcription factor C/EBPδ in the regulation of cell behaviour on nanometric grooves

C/EBPδ is a tumour suppressor transcription factor that induces gene expression involved in suppressing cell migration. Here we investigate whether C/EBPδ-dependent gene expression also affects cell responses to nanometric topology. We found that ablation of the C/EBPδ gene in mouse embryonal fibroblasts (MEFs) decreased cell size, adhesion and cytoskeleton spreading on 240 nm and 540 nm nanometric grooves. ChIP-SEQ and cDNA microarray analyses demonstrated that many binding sites for C/EBPδ, and the closely related C/EBPβ, exist throughout the mouse genome and control the upregulation or downregulation of many adjacent genes. We also identified a group of C/EBPδ-dependent, trans-regulated genes, whose promoters contained no C/EBPδ binding sites and yet their activity was regulated in a C/EBPδ-dependent manner. These genes include signalling molecules (e.g. SOCS3), cytoskeletal components (Tubb2, Krt16 and Krt20) and cytoskeletal regulators (ArhGEF33 and Rnd3) and are possibly regulated by cis-regulated diffusible mediators, such as IL6. Of particular note, SOCS3 was shown to be absolutely required for efficient cell spreading and contact guidance on 240 nm and 540 nm nanometric grooves. C/EBPδ is therefore involved in the complex regulation of multiple genes, including cytoskeletal components and signalling mediators, which influence the nature of cell interactions with nanometric topology

Investigation of the limits of nanoscale filopodial interactions

Mesenchymal stem cells are sensitive to changes in feature height, order and spacing. We had previously noted that there was an inverse relationship between osteoinductive potential and feature height on 15-, 55- and 90 nm-high titania nanopillars, with 15 nm-high pillars being the most effective substrate at inducing osteogenesis of human mesenchymal stem cells. The osteoinductive effect was somewhat diminished by decreasing the feature height to 8 nm, however, which suggested that there was a cut-off point, potentially associated with a change in cell–nanofeature interactions. To investigate this further, in this study, a scanning electron microscopy/three-dimensional scanning electron microscopy approach was used to examine the interactions between mesenchymal stem cells and the 8 and 15 nm nanopillared surfaces. As expected, the cells adopted a predominantly filopodial mode of interaction with the 15 nm-high pillars. Interestingly, fine nanoscale membrane projections, which we have termed ‘nanopodia,’ were also employed by the cells on the 8 nm pillars, and it seems that this is analogous to the cells ‘clinging on with their fingertips’ to this scale of features

Magnetically levitated mesenchymal stem cell spheroids cultured with a collagen gel maintain phenotype and quiescence

Multicellular spheroids are an established system for three-dimensional cell culture. Spheroids are typically generated using hanging drop or non-adherent culture; however, an emerging technique is to use magnetic levitation. Herein, mesenchymal stem cell spheroids were generated using magnetic nanoparticles and subsequently cultured within a type I collagen gel, with a view towards developing a bone marrow niche environment. Cells were loaded with magnetic nanoparticles, and suspended beneath an external magnet, inducing self-assembly of multicellular spheroids. Cells in spheroids were viable and compared to corresponding monolayer controls, maintained stem cell phenotype and were quiescent. Interestingly, core spheroid necrosis was not observed, even with increasing spheroid size, in contrast to other commonly used spheroid systems. This mesenchymal stem cell spheroid culture presents a potential platform for modelling in vitro bone marrow stem cell niches, elucidating interactions between cells, as well as a useful model for drug delivery studies

Mesenchymal stem cell fate : applying biomaterials for control of stem cell behavior

The materials pipeline for biomaterials and tissue engineering applications is under continuous development. Specifically, there is great interest in the use of designed materials in the stem cell arena as materials can be used to manipulate the cells providing control of behaviour. This is important as the ability to 'engineer' complexity and subsequent in vitro growth of tissues and organs is a key objective for tissue engineers. This review will describe the nature of the materials strategies, both static and dynamic, and their influence specifically on mesenchymal stem cell fate