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The Wnt signaling pathway is a key regulator of cell proliferation and differentiation^[1]. Wnt1 mainly promotes neural stem cell proliferation, also helps to the differentiation of various types of neurons^[2]. Wnt3a mainly promotes the differentiation of neural stem cells^[3], and Wnt5a (a non-classical Wnt) promotes neuron polarity and axonal growth^[4]. Sommer^[5] believed that the Wnt signaling pathway have many different roles on neural stem cells during neural tissue development. However, Wnt signaling molecules for promoting the neuron-like differentiation of in vitro cultured bone marrow mesenchymal stem cells (BMSCs) has not been reported. This study aims to differentiate the in vitro cultured BMSCs into neuron-like cells by using different combinations of cell factors and Wnt signaling molecules, so as to search Wnt signaling molecules that promote differentiation.

Central nervous system degenerative disease or injury may seriously affect the quality of life in patients, and cell transplantation therapy may be one of the most effective treatments. Experiments show that, BMSCs can express neurons and glial cells phenotype-specific proteins under certain conditions, then differentiate into neurons and glial cells^[7]. However, the approaches through which the BMSCs transformation into neurons is still unclear. At present, scholars believe that Wnt signaling pathway is a key regulatory link of neural stem cell proliferation and differentiation, it is involved in gene expression regulation, cell adhesion and migration, as well as cell polarization^[8]. Immunohistochemical results showed that, Nestin and NSE positive rate was higher in Wnt3a group, RT-PCR results also suggested the expression of nerve-related differentiation markers, indicating a clear improvement of Wnt3a for BMSCs differentiation into neuron-like cells. But how to initialize the mechanism underlying BMSCs differentiate into neuron-like cells remains unclear. Studies have observed that Wnt3a may encourage the expression of β-catenin^[9], and Wnt/β-catenin pathway is highly conserved during evolution, the main molecular components and the related regulatory mechanism of this pathway have been basically clarified^[10]. In recent years, many studies show that, Wnt signaling pathway plays an important role in neural development, it is involved in neural stem cell proliferation and differentiation process^[11], also determines the volume and size of brain tissue^[12]. Over-expressed and activated Wnt/β-catenin in the forebrain may lead to an increment of cerebral cortical size, which is due to promoting neural progenitor cell proliferation and inhibiting neural stem cells differentiate into neurons^[13]. Gene knockout mice studies have shown that, Wnt signal pathway has an important role in the development of the nervous system in embryonic development^[14]. Wnt gene mutations lead to the loss or abnormality of midbrain, hippocampus, spinal cord, neural crest and other nerve tissues. Through Wnt3a expression, spinal cord motor neurons guide sensory neurons to connect with each other right, thus forming neural pathways that can control the muscles. The critical factor for sustained high expression of Wnt signaling pathway, β-catenin, makes a lot of nerve stem cells which should differentiate back to the cell cycle, the number of neural stem cells significantly increased, resulting in the expansion of fetal rat brain cortex surface area^[15]. bFGF, as a cytokine, also can promote BMSCs differentiate into neuron-like cells^[16], immunohistochemical experiments showed that Nestin expression was weakly positive, indicating a part of BMSCs transformed into neural stem cells. Other studies have indicated that bFGF and other cytokines can jointly promote the transformation of BMSCs into neuron-like cells. bFGF is involved in the regulation of proliferation and differentiation of neural stem cells, and bFGF also plays an important role in the process of neural stem cells differentiate into neurons^[17]. bFGF can not only promote neural stem cells mitosis, inhibit neural stem cells differentiation, help to maintain the stem cell state, but also participate in deciding the final differentiation of neural stem cells^[18]. bFGF interacted with other cytokines may play a different role. bFGF and Wnt signaling pathway have been proved to interact in different ways^[19]. Through different ways, bFGF can increase the the β-catenin in the in vitro cultured neural precursor cells, β-catenin signaling can be also directly or indirectly regulated into neuron gene expression, thus affecting the neural stem cell proliferation and differentiation. In this study, the combination of Wnt3a and bFGF showed that most of the BMSCs could differentiate into neural stem cells, while Wnt5a was not shown to promote differentiation of BMSCs, therefore Wnt3a is believed to promote neural differentiation, which may be related to Wnt3a promotes stem cell proliferation and bFGF promotes neural stem celldifferentiation. In addition, there may be synergies between the two.

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