Adipogenic Differentiation of hMSCs is Mediated by Recruitment of IGF-1r Onto the Primary Cilium Associated With Cilia Elongation

Funded by Marie Curie Intra European Fellowship (GENOMICDIFF) Wellcome Trust 08471

Can Dynamic Compression in the Absence of Growth Factors Induce Chondrogenic Differentiation of Bone Marrow Derived MSCs Encapsulated in Agarose Hydrogels?

The objectives of this study were twofold; to determine if cartilage specific matrix synthesis by mesenchymal stem cells (MSCs) is regulated by the magnitude and/or duration of dynamic compression in the absence of growth factors, and to investigate if expanding MSCs in the presence of both fibroblast growth factor-2 (FGF-2) and transforming growth factor β-3 (TGF-β3) would influence their subsequent response to dynamic compression following encapsulation in agarose hydrogels. Porcine bone marrow derived MSCs were suspended in agarose and cast to produce cylinders (Ø5×3mm). Constructs were maintained in a chemically defined medium. Dynamic compression was applied at 1 Hz at strain amplitudes of 5%, 10% and 5% superimposed upon a 5% pre-strain for durations of 1, 3 and 12 hours. MSCs were also expanded in the presence of FGF-2 and TGF-β3. The biochemical constituents of constructs were analyzed. Under strain magnitudes of 5% and 10% and durations of 1 and 3 hours small increases in sGAG accumulation relative to unloaded controls were observed. However this was orders of magnitude lower than that induced by TGF-β3 stimulation. Expansion in FGF-2 and TGF-β3 did not positively modulate chondrogenesis of MSCs in either unloaded or loaded culture

Mechanical Stimulation: A Crucial Element of Organ-on-Chip Models

Organ-on-chip (OOC) systems recapitulate key biological processes and responses in vitro exhibited by cells, tissues, and organs in vivo. Accordingly, these models of both health and disease hold great promise for improving fundamental research, drug development, personalized medicine, and testing of pharmaceuticals, food substances, pollutants etc. Cells within the body are exposed to biomechanical stimuli, the nature of which is tissue specific and may change with disease or injury. These biomechanical stimuli regulate cell behavior and can amplify, annul, or even reverse the response to a given biochemical cue or drug candidate. As such, the application of an appropriate physiological or pathological biomechanical environment is essential for the successful recapitulation of in vivo behavior in OOC models. Here we review the current range of commercially available OOC platforms which incorporate active biomechanical stimulation. We highlight recent findings demonstrating the importance of including mechanical stimuli in models used for drug development and outline emerging factors which regulate the cellular response to the biomechanical environment. We explore the incorporation of mechanical stimuli in different organ models and identify areas where further research and development is required. Challenges associated with the integration of mechanics alongside other OOC requirements including scaling to increase throughput and diagnostic imaging are discussed. In summary, compelling evidence demonstrates that the incorporation of biomechanical stimuli in these OOC or microphysiological systems is key to fully replicating in vivo physiology in health and disease

Highlight on the dynamic organization of the nucleus

The last decade has seen rapid advances in our understanding of the proteins of the nuclear envelope, which have multiple roles including positioning the nucleus, maintaining its structural organization, and in events ranging from mitosis and meiosis to chromatin positioning and gene expression. Diverse new and stimulating results relating to nuclear organization and genome function from across kingdoms were presented in a session stream entitled “Dynamic Organization of the Nucleus” at this year's Society of Experimental Biology (SEB) meeting in Brighton, UK (July 2016). This was the first session stream run by the Nuclear Dynamics Special Interest Group, which was organized by David Evans, Katja Graumann (both Oxford Brookes University, UK) and Iris Meier (Ohio State University, USA). The session featured presentations on areas relating to nuclear organization across kingdoms including the nuclear envelope, chromatin organization, and genome function

Dynamic compression can inhibit chondrogenesis of mesenchymal stem cells

Funding was provided by Science Foundation Ireland (07-RFP-ENMF142) and Enterprise Ireland (PC/2006/384)

Cell-matrix interactions regulate mesenchymal stem cell response to hydrostatic pressure.

Both hydrostatic pressure (HP) and cell-matrix interactions have independently been shown to regulate the chondrogenic differentiation of mesenchymal stem cells (MSCs). The objective of this study was to test the hypothesis that the response of MSCs to hydrostatic pressure will depend on the biomaterial within which the cells are encapsulated. Bone-marrow-derived MSCs were seeded into either agarose or fibrin hydrogels and exposed to 10 MPa of cyclic HP (1 Hz, 4 h per day, 5 days per week for 3 weeks) in the presence of either 1 or 10 ng ml(-1) of TGF-β3. Agarose hydrogels were found to support a spherical cellular morphology, while MSCs seeded into fibrin hydrogels attached and spread, with clear stress fiber formation. Hydrogel contraction was also observed in MSC-fibrin constructs. While agarose hydrogels better supported chondrogenesis of MSCs, HP only enhanced sulfated glycosaminoglycan (sGAG) accumulation in fibrin hydrogels, which correlated with a reduction in fibrin contraction. HP also reduced alkaline phosphatase activity in the media for both agarose and fibrin constructs, suggesting that this stimulus plays a role in the maintenance of the chondrogenic phenotype. This study demonstrates that a complex relationship exists between cell-matrix interactions and hydrostatic pressure, which plays a key role in regulating the chondrogenic differentiation of MSCs

Biophysical Regulation of Chromatin Architecture Instills a Mechanical Memory in Mesenchymal Stem Cells

This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material.This work was supported by the National Institutes of Health (R01 AR056624, R01 EB02425, T32 AR007132, and P30 AR050950) and a Marie Curie Intra European Fellowship (GENOMICDIFF, grant No. 301509). Additional support was provided by a Montague Research Award from the Perelman School of Medicine and a University of Pennsylvania University Research Foundation Award