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Oscillatory fluid flow induces the osteogenic lineage commitment of mesenchymal stem cells: The effect of shear stress magnitude, frequency, and duration
A potent regulator of bone anabolism is physical loading. However, it is currently unclear whether physical stimuli such as fluid shear within the marrow cavity is sufficient to directly drive the osteogenic lineage commitment of resident mesenchymal stem cells (MSC). Therefore, the objective of the study is to employ a systematic analysis of oscillatory fluid flow (OFF) parameters predicted to occur in vivo on early MSC osteogenic responses and late stage lineage commitment. MSCs were exposed to OFF of 1Pa, 2Pa and 5Pa magnitudes at frequencies of 0.5Hz, 1Hz and 2Hz for 1h, 2h and 4h of stimulation. Our findings demonstrate that OFF elicits a positive osteogenic response in MSCs in a shear stress magnitude, frequency, and duration dependent manner that is gene specific. Based on the mRNA expression of osteogenic markers Cox2, Runx2 and Opn after short-term fluid flow stimulation, we identified that a regime of 2Pa shear magnitude and 2Hz frequency induces the most robust and reliable upregulation in osteogenic gene expression. Furthermore, long-term mechanical stimulation utilising this regime, elicits a significant increase in collagen and mineral deposition when compared to static control demonstrating that mechanical stimuli predicted within the marrow is sufficient to directly drive osteogenesis.
Journal Article
TGFβ1 – induced recruitment of human bone mesenchymal stem cells is mediated by the primary cilium in a SMAD3-dependent manner
The recruitment of mesenchymal stem cells (MSCs) is a crucial process in the development, maintenance and repair of tissues throughout the body. Transforming growth factor-β1 (TGFβ1) is a potent chemokine essential for the recruitment of MSCs in bone, coupling the remodelling cycle. The primary cilium is a sensory organelle with important roles in bone and has been associated with cell migration and more recently TGFβ signalling. Dysregulation of TGFβ signalling or cilia has been linked to a number of skeletal pathologies. Therefore, this study aimed to determine the role of the primary cilium in TGFβ1 signalling and associated migration in human MSCs. In this study we demonstrate that low levels of TGFβ1 induce the recruitment of MSCs, which relies on proper formation of the cilium. Furthermore, we demonstrate that receptors and downstream signalling components in canonical TGFβ signalling localize to the cilium and that TGFβ1 signalling is associated with activation of SMAD3 at the ciliary base. These findings demonstrate a novel role for the primary cilium in the regulation of TGFβ signalling and subsequent migration of MSCs, and highlight the cilium as a target to manipulate this key pathway and enhance MSC recruitment for the treatment of skeletal diseases.
Journal Article
Human bone marrow stem/stromal cell osteogenesis is regulated via mechanically activated osteocyte‐derived extracellular vesicles
Bone formation or regeneration requires the recruitment, proliferation, and osteogenic differentiation of stem/stromal progenitor cells. A potent stimulus driving this process is mechanical loading. Osteocytes are mechanosensitive cells that play fundamental roles in coordinating loading‐induced bone formation via the secretion of paracrine factors. However, the exact mechanisms by which osteocytes relay mechanical signals to these progenitor cells are poorly understood. Therefore, this study aimed to demonstrate the potency of the mechanically stimulated osteocyte secretome in driving human bone marrow stem/stromal cell (hMSC) recruitment and differentiation, and characterize the secretome to identify potential factors regulating stem cell behavior and bone mechanobiology. We demonstrate that osteocytes subjected to fluid shear secrete a distinct collection of factors that significantly enhance hMSC recruitment and osteogenesis and demonstrate the key role of extracellular vesicles (EVs) in driving these effects. This demonstrates the pro‐osteogenic potential of osteocyte‐derived mechanically activated extracellular vesicles, which have great potential as a cell‐free therapy to enhance bone regeneration and repair in diseases such as osteoporosis. Bone formation/regeneration requires the recruitment and osteogenic differentiation of stem/stromal progenitor cells. A potent stimulus driving this process is mechanical loading. In his study, we demonstrate that osteocytes coordinate stem cell behavior in response to loading via modulation of their secretome that is delivered via extracellular vesicles (EVs). This therefore highlights mechanically activated EVs as potential therapies for bone regeneration.
Journal Article
العمالة الفلسطينية في إسرائيل ومشروع الدولة الفلسطينية، 1967-2007 = al-ʻImālah al-Filasṭīnīyah fī Isrāʼīl wa-mashrūʻ al-dawlah al-Filasṭīnīyah, 1967-2007
منذ أن احتلت إسرائيل الضفة الغربية وقطاع غزة سنة 1967، كان للعمالة الفلسطينية المهاجرة دور أساسي في ربط الاقتصاد الفلسطيني بإسرائيل. فقد استوعب هذا الاقتصاد أكثر من ثلث القوى العاملة المستخدمة، ورسم شكل التنمية الاقتصادية الفلسطينية وطبيعتها. لكن، منذ اتفاق أوسلو للسلام سنة 1993، ندرت تدفقات هجرة العمالة، وهو ما سبب انخفاضا في دخل الفرد الفلسطيني وأدى إلى تنبؤات فحواها أن عهد هذه الهجرة وصل إلى نهايته.
BOOK
TRPV4-mediates oscillatory fluid shear mechanotransduction in mesenchymal stem cells in part via the primary cilium
Skeletal homeostasis requires the continued replenishment of the bone forming osteoblast from a mesenchymal stem cell (MSC) population, a process that has been shown to be mechanically regulated. However, the mechanisms by which a biophysical stimulus can induce a change in biochemical signaling, mechanotransduction, is poorly understood. As a precursor to loading-induced bone formation, deciphering the molecular mechanisms of MSC osteogenesis is a critical step in developing novel anabolic therapies. Therefore, in this study we characterize the expression of the mechanosensitive calcium channel Transient Receptor Potential subfamily V member 4 (TRPV4) in MSCs and demonstrate that TRPV4 localizes to areas of high strain, specifically the primary cilium. We demonstrate that TRPV4 is required for MSC mechanotransduction, mediating oscillatory fluid shear induced calcium signaling and early osteogenic gene expression. Furthermore, we demonstrate that TRPV4 can be activated pharmacologically eliciting a response that mirrors that seen with mechanical stimulation. Lastly, we show that TRPV4 localization to the primary cilium is functionally significant, with MSCs with defective primary cilia exhibiting an inhibited osteogenic response to TRPV4 activation. Collectively, this data demonstrates a novel mechanism of stem cell mechanotransduction, which can be targeted therapeutically, and further highlights the critical role of the primary cilium in MSC biology.
Journal Article
Enhanced corrosion resistance and cytocompatibility of biomimetic hyaluronic acid functionalised silane coating on AZ31 Mg alloy for orthopaedic applications
This paper reports the corrosion resistant and cytocompatible properties of the hyaluronic acid-silane coating on AZ31 Mg alloy. In this study, the osteoinductive properties of high molecular weight hyaluronic acid (HA, 1–4 MDa) and the corrosion protection of silane coatings were incorporated as a composite coating on biodegradable AZ31 Mg alloy for orthopaedic applications. The multi-step fabrication of coatings first involved dip coating of a passivated AZ31 Mg alloy with a methyltriethoxysilane-tetraethoxysilane sol-gel to deposit a dense, cross-linked and corrosion resistant silane coating (AZ31-MT). The second step was to create an amine-functionalised surface by treating coated alloy with 3-aminopropyl-triethoxy silane (AZ31-MT-A) which facilitated the immobilisation of HA via EDC-NHS coupling reactions at two different concentrations i.e 1 mg.ml−1 (AZ31-MT-A-HA1) and 2 mg.ml−1 (AZ31-MT-A-HA2). These coatings were characterised by Fourier transform infrared spectroscopy, atomic force microscopy and static contact angle measurements which confirmed the successful assembly of the full coatings onto AZ31 Mg alloy. The influence of HA-silane coating on the corrosion of Mg alloy was investigated by electrical impedance spectroscopy and long-term immersion studies measurements in HEPES buffered DMEM. The results showed an enhanced corrosion resistance of HA functionalised silane coated AZ31 substrate over the uncoated equivalent alloy. Furthermore, the cytocompatibility of MC3T3-E1 osteoblasts was evaluated on HA-coated AZ31-MT-A substrates by live-dead staining, quantification of total cellular DNA content, scanning electron microscope and alkaline phosphatase activity. The results showed HA concentration-dependent improvement of osteoblast cellular response in terms of enhanced cell adhesion, proliferation and differentiation. These findings hold great promise in employing such biomimetic multifunctional coatings to improve the corrosion resistance and cytocompatibility of biodegradable Mg-based alloy for orthopaedic applications.
Journal Article