Research reportReactivation of denervated Schwann cells by neurons induced from bone marrow-derived mesenchymal stem cells
Introduction
Peripheral nerve injury (PNI) is a significant source of long-term morbidity, disability and economic burden (Jones et al., 2016). The peripheral nervous system (PNS) differs from the central nervous system in that it shows a certain capacity for axonal regeneration, though spontaneous regeneration is always incomplete and often has poor outcomes (Du et al., 2017). In recent decades, cell-based therapy, including embryonic (Cui et al., 2008) and mesenchymal stem cells (Pan et al., 2017; Zheng et al., 2017a), as well as Schwann cells (SCs) (Levi et al., 2016) have been proven promising for promoting neuroregeneration. Moreover, our group and others have introduced neurons induced from stem cells as an effective strategy for promoting peripheral nerve regeneration (PNR) (Lin et al., 2009; Kurimoto et al., 2016; Ullah et al., 2017; Zhang et al., 2017).
Previous studies have demonstrated that grafted neurons can survive in peripheral nerves, express neuronal marker, and even form neuromuscular junctions and delay muscle atrophy after PNI (MacDonald et al., 2003; Lin et al., 2009; Gu et al., 2010). However, the mechanisms underlying neural transplantation therapy for PNR after injury are still not fully understood. Furthermore, the evolution and role of native denervated SCs in neural transplantation therapy were often neglected and thus are still unknown. SCs play a significant role in PNR; they switch into acute denervated SCs post-injury and then proliferate quickly, form the Bungnerās bands, and promote nerve regeneration. All of these functions for promoting regeneration of acute denervated SCs depends on axon-SCs interactions (Corfas et al., 2004). Based on the axon-SCs interactions, we hypothesized that transplantation of neurons could form axon-SCs interactions to reactivate denervated SCs and promote PNR.
In the present study, we co-cultured denervated SCs with NI-BMSCs that were induced from bone marrow-derived mesenchymal stem cells (BMSCs) by our own methods (Zhang and Alexanian, 2014; Zheng et al., 2017b) and then examined the proliferation of denervated SCs and the expression of neurotrophic factors and adhesion molecules from these cells in vitro. NI-BMSCs were transplanted into the distal stump in a sciatic nerve injury model, the survival of the grafted NI-BMSCs; the morphology, arrangement and quantity of native denervated SCs were examined, myelination, axonal regeneration and sciatic nerve functional recovery were also determinated. Our data indicated that transplanted NI-BMSCs reactivated denervated SCs and promoted sciatic nerve regeneration.
Section snippets
Animals and sciatic nerve injury model
Male Sprague-Dawley (SD) rats and transgenic green fluorescent protein (GFP) SD rats were purchased from the Animal Center of the Second Military Medical University (Shanghai, China). All animal experiments were approved by the Animal Care and Use Committee of the Second Military Medical University (permit number SYXK-2002-042).
Forty-eight adult male SD rats, weighing 180ā220āÆg, were randomly divided into 4 groups of 12 rats each: normal group (Normal, without injury), phosphate-buffered saline
Characteristics of SCs
After 48āÆh incubation, cells began to grow from the nerve segments, and many cells climbed out after 5āÆdays, forming a classical parallel swirling alignment of dendritic processes (Fig. 1AāD). After purification by cytarabine and passed to the fourth generation, SCs were growing homogeneously and displayed a long bipolar or tripolar elongated shape with a small oval-shaped nucleus (Fig. 1EāF).
To further explore the characteristics of the cells which had grown from nerve segments, S100Ī² which
Discussion
In this study, we demonstrated that NI-BMSCs triggered the proliferation of denervated SCs as well as the expression and secretion of neurotrophic factors and neural adhesion molecules in vitro. We also found that grafted NI-BMSCs accelerated the proliferation of native denervated SCs, enhanced myelination and axonal regeneration, and promoted regeneration of sciatic nerves in rats. And compared to BMSCs, NI-BMSCs had more effective promotion for sciatic nerves regeneration.
Conclusion
In current study, NI-BMSCs were co-cultured with denervated SCs in vitro and transplanted in a rat sciatic nerve injury model. It was demonstrated that co-culturing SCs with NI-BMSCs accelerated the proliferation of denervated SCs and promoted the expression and secretion of neurotrophic factors and neural adhesion molecules in vitro. In addition, it was also revealed that NI-BMSCs reactivated native denervated SCs, facilitated their proliferation as well as enhancing myelination, axonal
Conflict of interests
The authors declare no conflict of interests.
Acknowledgement
This work was supported by the Funds of the National Natural Science Foundation of China (81271396).
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Authors equally contributed.