Abstract
Growth factors such as transforming growth factor beta1 (TGF-β1), have critical roles in the regulation of the chondrogenic differentiation of mesenchymal stem cells (MSCs), which promote cartilage repair. However, the clinical applications of the traditional growth factors are limited by their high cost, functional heterogeneity and unpredictable effects, such as cyst formation. It may be advantageous for cartilage regeneration to identify a low-cost substitute with greater chondral specificity and easy accessibility. As a neuropeptide, nerve growth factor (NGF) was involved in cartilage metabolism and NGF is hypothesized to mediate the chondrogenic differentiation of MSCs. We isolated NGF from Chinese cobra venom using a three-step procedure that we had improved upon from previous studies, and investigated the chondrogenic potential of NGF on bone marrow MSCs (BMSCs) both in vitro and in vivo. The results showed that NGF greatly upregulated the expression of cartilage-specific markers. When applied to cartilage repair for 4, 8 and 12 weeks, NGF-treated BMSCs have greater therapeutic effect than untreated BMSCs. Although inferior to TGF-β1 regarding its chondrogenic potential, NGF showed considerably lower expression of collagen type I, which is a fibrocartilage marker, and RUNX2, which is critical for terminal chondrocyte differentiation than TGF-β1, indicating its chondral specificity. Interestingly, NGF rarely induced BMSCs to differentiate into a neuronal phenotype, which may be due to the presence of other chondrogenic supplements. Furthermore, the underlying mechanism revealed that NGF-mediated chondrogenesis may be associated with the activation of PI3K/AKT and MAPK/ERK signaling pathways via the specific receptor of NGF, TrkA. In addition, NGF is easily accessed because of the abundance and low price of cobra venom, as well as the simplified methods for separation and purification. This study was the first to demonstrate the chondrogenic potential of NGF, which may provide a reference for cartilage regeneration in the clinic.
Highlights
Adult human mesenchymal stem cells (MSCs) attracted the most attention for cartilage tissue engineering studies, because of their high proliferation rate, easy availability and capacity to differentiate into multiple cell types.[1]
The fraction containing peak 2, which displayed Nerve growth factor (NGF) bioactivity was collected, which was analyzed with high-performance liquid chromatography (HPLC) on a TSK-G2000-SW to purify and test the purity of NGF (Figure 1d)
The results indicated that NGF predominantly induced the stem cells into chondrocytes instead of the neuronal phenotype in an environment favoring chondrogenesis
Summary
Adult human mesenchymal stem cells (MSCs) attracted the most attention for cartilage tissue engineering studies, because of their high proliferation rate, easy availability and capacity to differentiate into multiple cell types.[1]. Growth factors have critical roles of inducers that regulate the chondrogenic differentiation of MSCs. traditional growth factors such as TGF-β1 fall short in meeting the needs of clinical applications because they are limited by their high cost, rapid degradation and ready loss of activity. The crucial effects of sensory and sympathetic neurotransmitters on proper limb formation during embryonic skeletal growth have been well documented.[7] This is confirmed by the detection of neuropeptide containing nerve fibers in the interior of the cartilage and periosteum.[8] Clinical observations suggest that nerve fibers are important for the regulation of skeletal metabolism.[9] Patients with neurological disorders exhibit skeletal pathophysiology.[7,10] Nel-like molecule-1 (Nell-1), a growth factor that is strongly expressed in neural tissue, was shown to promote chondrocyte proliferation, ECM deposition[11,12] and regulate chondrogenic differentiation.[13]. Received 24.11.16; revised 29.3.17; accepted 06.4.17; Edited by D Aberdam receptor (p75NTR), were expressed in chondrocytes or chondrocyte-like cells in hyaline, fibrous and elastic cartilaginous tissues.[21,22,23] In most cases, NGF exerts its biological action by triggering its specific receptor, TrkA, which activated the major cytosolic/endosomal pathways, including MAPK, ERK and PI3K/AKT.[24,25,26] These signaling pathways are
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