Additive Effects of Sonic Hedgehog and Nell-1 Signaling in Osteogenic Versus Adipogenic Differentiation of Human Adipose-Derived Stromal Cells

Section of Orthodontics, Dental and Craniofacial Research Institute, School of Dentistry, University of California, Los Angeles, California, USA.
Stem cells and development (Impact Factor: 3.73). 02/2012; 21(12):2170-8. DOI: 10.1089/scd.2011.0461
Source: PubMed


A theoretical inverse relationship exists between osteogenic (bone forming) and adipogenic (fat forming) mesenchymal stem cell (MSC) differentiation. This inverse relationship in theory partially underlies the clinical entity of osteoporosis, in which marrow MSCs have a preference for adipose differentiation that increases with age. Two pro-osteogenic cytokines have been recently studied that each also possesses antiadipogenic properties: Sonic Hedgehog (SHH) and NELL-1 proteins. In the present study, we assayed the potential additive effects of the biologically active N-terminus of SHH (SHH-N) and NELL-1 protein on osteogenic and adipogenic differentiation of human primary adipose-derived stromal cell (hASCs). We observed that both recombinant SHH-N and NELL-1 protein significantly enhanced osteogenic differentiation and reduced adipose differentiation across all markers examined (alkaline phosphatase, Alizarin red and Oil red O staining, and osteogenic gene expression). Moreover, SHH-N and NELL-1 directed signaling produced additive effects on the pro-osteogenic and antiadipogenic differentiation of hASCs. NELL-1 treatment increased Hedgehog signaling pathway expression; coapplication of the Smoothened antagonist Cyclopamine reversed the pro-osteogenic effect of NELL-1. In summary, Hedgehog and Nell-1 signaling exert additive effects on the pro-osteogenic and antiadipogenic differentiation of ASCs. These studies suggest that the combination cytokines SHH-N+NELL-1 may represent a viable future technique for inducing the osteogenic differentiation of MSCs.

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    • "A commonly studied method of promoting osteogenic differentiation is to manipulate signaling pathways important in skeletal development, such as Wnt [28], Hedgehog [29–31], BMP (Bone Morphogenic Protein) [32–34], and the emerging anti-inflammatory molecule NELL-1 [30, 35–37]. A transition away from an interest in BMP2 may be expected due to an increasing side effect profile including postoperative inflammation [35, 38] and osteoclast activation [39–41]. "
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    ABSTRACT: The development of tissue engineering and regeneration constitutes a new platform for translational medical research. Effective therapies for bone engineering typically employ the coordinated manipulation of cells, biologically active signaling molecules, and biomimetic, biodegradable scaffolds. Bone tissue engineering has become increasingly dependent on the merging of innovations from each of these fields, as they continue to evolve independently. This foreword will highlight some of the most recent advances in bone tissue engineering and regeneration, emphasizing the interconnected fields of stem cell biology, cell signaling biology, and biomaterial research. These include, for example, novel methods for mesenchymal stem cell purification, new methods of Wnt signaling pathway manipulation, and cutting edge computer assisted nanoscale design of bone scaffold materials. In the following special issue, we sought to incorporate these diverse areas of emphasis in order to reflect current trends in the field.
    Full-text · Article · Apr 2014
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    • "The commitment and differentiation of MSC towards an adipogenic or osteogenic cell fate depend on a variety of signaling and transcription factors. A large body of experimental evidence suggests that an inverse correlation exists between adipogenesis and osteogenesis (Figure 2) [29, 30]. The evidence for an inverse relationship is primarily based on in vitro studies in which culture supplements upregulate osteogenic differentiation with associated downregulation of adipogenic differentiation, or vice versa [31–34]. "
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    ABSTRACT: Mesenchymal stem cells (MSC) are multipotent cells, functioning as precursors to a variety of cell types including adipocytes, osteoblasts, and chondrocytes. Between osteogenic and adipogenic lineage commitment and differentiation, a theoretical inverse relationship exists, such that differentiation towards an osteoblast phenotype occurs at the expense of an adipocytic phenotype. This balance is regulated by numerous, intersecting signaling pathways that converge on the regulation of two main transcription factors: peroxisome proliferator-activated receptor- γ (PPAR γ ) and Runt-related transcription factor 2 (Runx2). These two transcription factors, PPAR γ and Runx2, are generally regarded as the master regulators of adipogenesis and osteogenesis. This review will summarize signaling pathways that govern MSC fate towards osteogenic or adipocytic differentiation. A number of signaling pathways follow the inverse balance between osteogenic and adipogenic differentiation and are generally proosteogenic/antiadipogenic stimuli. These include β -catenin dependent Wnt signaling, Hedgehog signaling, and NELL-1 signaling. However, other signaling pathways exhibit more context-dependent effects on adipogenic and osteogenic differentiation. These include bone morphogenic protein (BMP) signaling and insulin growth factor (IGF) signaling, which display both proosteogenic and proadipogenic effects. In summary, understanding those factors that govern osteogenic versus adipogenic MSC differentiation has significant implications in diverse areas of human health, from obesity to osteoporosis to regenerative medicine.
    Full-text · Article · Dec 2013
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    • "Recently, Zhang et al. [77] studied the osteogenic differentiation of ASCs in presence of VEGF, BMP-6, or VEGF plus BMP-6, showing that the combination of VEGF and BMP-6 significantly enhance the expression of osteospecific genes like Dlx5 and osterix and suggesting a cross-talk between VEGF and BMP-6 signaling pathways during the osteogenic differentiation of ASCs. Also, two pro-osteogenic cytokine, Sonic Hedgehog (SHH) and Nell-1, have been studied by James et al. [76], revealing the additive effects of SHH and NELL-1 on the osteogenic differentiation of ASCs. "
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    ABSTRACT: Adipose tissue represents a hot topic in regenerative medicine because of the tissue source abundance, the relatively easy retrieval, and the inherent biological properties of mesenchymal stem cells residing in its stroma. Adipose-derived mesenchymal stem cells (ASCs) are indeed multipotent somatic stem cells exhibiting growth kinetics and plasticity, proved to induce efficient tissue regeneration in several biomedical applications. A defined consensus for their isolation, classification, and characterization has been very recently achieved. In particular, bone tissue reconstruction and regeneration based on ASCs has emerged as a promising approach to restore structure and function of bone compromised by injury or disease. ASCs have been used in combination with osteoinductive biomaterial and/or osteogenic molecules, in either static or dynamic culture systems, to improve bone regeneration in several animal models. To date, few clinical trials on ASC-based bone reconstruction have been concluded and proved effective. The aim of this review is to dissect the state of the art on ASC use in bone regenerative applications in the attempt to provide a comprehensive coverage of the topics, from the basic laboratory to recent clinical applications.
    Full-text · Article · Nov 2013
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