Walid Zaher

Skeletal (stromal) stem cells: An update on intracellular signaling pathways controlling osteoblast differentiation

Skeletal (marrow stromal) stem cells (BMSCs) are a group of multipotent cells that reside in the bone marrow stroma and can differentiate into osteoblasts, chondrocytes and adipocytes. Studying signaling pathways that regulate BMSC differentiation into osteoblastic cells is a strategy for identifying druggable targets for enhancing bone formation. This review will discuss the functions and the molecular mechanisms of action on osteoblast differentiation and bone formation; of a number of recently identified regulatory molecules: the non-canonical Notch signaling molecule Delta-like 1/preadipocyte factor 1 (Dlk1/Pref-1), the Wnt co-receptor Lrp5 and intracellular kinases. This article is part of a Special Issue entitled: Stem Cells and Bone.

Human stromal (mesenchymal) stem cells: basic biology and current clinical use for tissue regeneration.

Human stromal (mesenchymal) stem cells (hMSC) represent a group of non-hematopoietic stem cells present in the bone marrow stroma and the stroma of other organs including subcutaneous adipose tissue, placenta, and muscles. They exhibit the characteristics of somatic stem cells of self-renewal and multi-lineage differentiation into mesoderm-type of cells, e.g., to osteoblasts, adipocytes, chondrocytes and possibly other cell types including hepatocytes and astrocytes. Due to their ease of culture and multipotentiality, hMSC are increasingly employed as a source for cells suitable for a number of clinical applications, e.g., non-healing bone fractures and defects and also non-skeletal degenerative diseases like heart failure. Currently, the numbers of clinical trials that employ MSC are increasing. However, several biological and biotechnological challenges need to be overcome to benefit from the full potential of hMSC. In this current review, we present some of the most important and recent advances in understanding of the biology of hMSC and their current and potential use in therapy.

An update of human mesenchymal stem cell biology and their clinical uses

Abstract In the past decade, an increasing urge to develop new and novel methods for the treatment of degenerative diseases where there is currently no effective therapy has lead to the emerging of the cell therapy or cellular therapeutics approach for the management of those conditions where organ functions are restored through transplantation of healthy and functional cells. Stem cells, because of their nature, are currently considered among the most suitable cell types for cell therapy. There are an increasing number of studies that have tested the stromal stem cell functionality both in vitro and in vivo. Consequently, stromal (mesenchymal) stem cells (MSCs) are being introduced into many clinical trials due to their ease of isolation and efficacy in treating a number of disease conditions in animal preclinical disease models. The aim of this review is to revise MSC biology, their potential translation in therapy, and the challenges facing their adaptation in clinical practice.

Perforation of the inferior alveolar nerve by the maxillary artery: An anatomical study

The infratemporal fossa is a clinically important anatomical area for the delivery of local anaesthetic agents in dentistry and maxillofacial surgery. We studied the infratemporal fossas in white cadavers, and in particular the topographical relations of the inferior alveolar nerve and the maxillary artery. In 3 of the 50 fossas dissected the maxillary artery passed through the inferior alveolar nerve, splitting it into superficial and deep divisions. Entrapment of the maxillary artery may cause numbness or headache and may interfere with injection of local anaesthetics into the infratemporal fossa.

Adult stromal (skeletal, mesenchymal) stem cells: advances towards clinical applications

Mesenchymal Stem Cells (MSC) are non-hematopoietic adult stromal cells that reside in a perivascular niche in close association with pericytes and endothelial cells and possess self-renewal and multi-lineage differentiation capacity. The origin, unique properties, and therapeutic benefits of MSC are under intensive investigation worldwide. Several challenges with regard to the proper source of clinical-grade MSC and the efficacy of MSC-based treatment strategies need to be addressed before MSC can be routinely used in the clinic. Here, we discuss three areas that can potentially facilitate the translation of MSC into clinic: Generation of MSC-like cells from human pluripotent stem cells, strategies to enhance homing of MSC to injured tissues, and targeting of MSC in vivo.

Inhibitory Effects of Toll-Like Receptor 4, NLRP3 Inflammasome, and Interleukin-1β on White Adipocyte Browning

Adipose tissue expansion is accompanied by infiltration and accumulation of pro-inflammatory macrophages, which links obesity to pathologic conditions such as type 2 diabetes. However, little is known regarding the role of pro-inflammatory adipose tissue remodeling in the thermogenic activation of brown/beige fat. Here, we investigated the effect of pattern recognition receptors (PRR) activation in macrophages, especially the toll-like receptor 4 (TLR4) and Nod-like receptor 3 (NLRP3), on white adipocyte browning. We report that TLR4 activation by lipopolysaccharide repressed white adipocyte browning in response to β3-adrenergic receptor activation and caused ROS production and mitochondrial dysfunction, while genetic deletion of TLR4 protected mitochondrial function and thermogenesis. In addition, activation of NLRP3 inflammasome in macrophages attenuated UCP1 induction and mitochondrial respiration in cultures of primary adipocytes, while the absence of NLRP3 protected UCP1 in adipocytes. The effect of NLRP3 inflammasome activation on browning was mediated by IL-1β signaling, as blocking IL-1 receptor in adipocytes protected thermogenesis. We also report that IL-1β interferes with thermogenesis via oxidative stress stimulation and mitochondrial dysfunction as we observed a statistically significant increase in ROS production, decrease in SOD enzyme activity, and increase in mitochondrial depolarization in adipocytes treated with IL-1β. Collectively, we demonstrated that inflammatory response to obesity, such as TLR4 and NLRP3 inflammasome activation as well as IL-1β secretion, attenuates β3-adrenoreceptor-induced beige adipocyte formation via oxidative stress and mitochondrial dysfunction. Our findings provide insights into targeting innate inflammatory system for enhancement of the adaptive thermogenesis against obesity.

Skeletal Stem Cells for Bone and Cartilage Tissue Regeneration

There is an increasing interest in using stem cells in treatment of degenerative diseases such as Parkinson’s disease, liver failure, leukemia, diabetes, osteoarthritis (OA), and osteoporosis, for which there is no curative therapy. In this context, skeletal tissue regeneration is being addressed for a number of common clinical conditions including repair of non-healing fractures and bone defects through transplantation of skeletal stem cells (also known as stromal or adult or mesenchymal stem cells, MSCs) either alone or with osteoinductive/osteoconductive scaffolds. In the present Chapter, we will present biological characteristics of MSCs and will give an update regarding their use in skeletal tissue regeneration in preclinical animal models and in clinical trials.

Human Stromal Stem Cell Therapy Using Gene-Modified Cells

There is an increasing demand to develop novel approaches for the treatment of a large number of chronic degenerative diseases affecting primarily the aging population and where there is currently no effective therapy, e.g., Parkinson’s disease, liver failure, diabetes, osteoarthritis, and osteoporosis. An emerging therapeutic approach for the management of these conditions is cell therapy or cellular therapeutics where organ functions are restored through transplanting healthy, functional cells. Stem cells, because of their nature, are currently considered the most suitable cells for cell therapy. As mentioned in other chapters in this book, gene therapy aims at modifying specific characteristics of target cells with possible therapeutic effects. Thus, combining gene therapy with stem cell therapy provides an additional useful dimension to the use of stem cells for treatment. Stromal (mesenchymal) stem cells are being introduced into clinical trials due to their ease of isolation and efficacy in treating a number of disease conditions in animal preclinical disease models. Also, there are an increasing number of studies that have tested the genetically modified mesenchymal stem cells (MSC) functionality in vivo. The aim of this chapter is to review the potential use of gene-modified stem cells, in particular gene-modified MSC, in therapy and the challenges facing their use in clinical practice.