Abstract
Schwann cells (SCs) are promising candidates for cell therapy due to their ability to promote peripheral nerve regeneration. However, SC-based therapies are hindered by the lack of a clinically renewable source of SCs. In this study, using a well-defined non-genetic approach, umbilical cord blood mesenchymal stem cells (cbMSCs), a clinically applicable cell type, were phenotypically, epigenetically, and functionally converted into SC-like cells (SCLCs) that stimulated effective sprouting of neuritic processes from neuronal cells. To further enhance their therapeutic capability, the cbMSC-derived SCLCs were assembled into three-dimensional (3D) cell spheroids by using a methylcellulose hydrogel system. The cell–cell and cell–extracellular matrix interactions were well-preserved within the formed 3D SCLC spheroids, and marked increases in neurotrophic, proangiogenic and anti-apoptotic factors were detected compared with cells that were harvested using conventional trypsin-based methods, demonstrating the superior advantage of SCLCs assembled into 3D spheroids. Transplantation of 3D SCLC spheroids into crush-injured rat sciatic nerves effectively promoted the recovery of motor function and enhanced nerve structure regeneration. In summary, by simply assembling cells into a 3D-spheroid conformation, the therapeutic potential of SCLCs derived from clinically available cbMSCs for promoting nerve regeneration was enhanced significantly. Thus, these cells hold great potential for translation to clinical applications for treating peripheral nerve injury.
Highlights
Peripheral nerve injury, which is often caused by traumatic accidents and can lead to considerable long-term disability, is a worldwide clinical issue associated with significant socioeconomic burden (Hoke, 2006)
We evaluated the expression of Schwann cell (SC)-related markers by cord blood mesenchymal stem cells (MSCs) (cbMSCs) after induction
CbMSCs, a clinically applicable cell source, were converted into SC-like cells (SCLCs) followed by assembling into the 3D spheroid configuration for treating peripheral nerve injury
Summary
Peripheral nerve injury, which is often caused by traumatic accidents and can lead to considerable long-term disability, is a worldwide clinical issue associated with significant socioeconomic burden (Hoke, 2006). The clinical application of SC-based transplantation therapy has been hindered by the difficultly in harvesting a sufficient number and purity of functional SCs (Mazzara et al, 2017). To address this problem, various types of stem cells, including pluripotent stem cells (Kim et al, 2017), neural stem cells (Christopherson et al, 2009), mesenchymal stem cells (MSCs) (Xue et al, 2017), and adipose-derived stem cells (Tomita et al, 2013), have been investigated for their ability to transdifferentiate into SCs. To address this problem, various types of stem cells, including pluripotent stem cells (Kim et al, 2017), neural stem cells (Christopherson et al, 2009), mesenchymal stem cells (MSCs) (Xue et al, 2017), and adipose-derived stem cells (Tomita et al, 2013), have been investigated for their ability to transdifferentiate into SCs Among these cell types, umbilical cord blood MSCs (cbMSCs) represent a clinically feasible candidate because they can be harvested autologously and non-invasively, cryopreserved for a long period, thawed and cultivated for rapid proliferation (Sung et al, 2012). MSCs are known to possess efficient immunomodulatory activity and can engineer a proregenerative local microenvironment for accelerating tissue repair (Ballini et al, 2017, 2018; Spagnuolo et al, 2018), thereby further benefiting the regeneration of injured peripheral nerve
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