Recovery of paralyzed limb motor function in canine with complete spinal cord injury following implantation of MSC-derived neural network tissue

Abstract

We have reported previously that bone marrow mesenchymal stem cell (MSC)-derived neural network scaffold not only survived in the injury/graft site of spinal cord but also served as a "neuronal relay" that was capable of improving the limb motor function in a complete spinal cord injury (SCI) rat model. It remained to be explored whether such a strategy was effective for repairing the large spinal cord tissue loss as well as restoring motor function in larger animals. We have therefore extended in this study to construct a canine MSC-derived neural network tissue in vitro with the aim to evaluate its efficacy in treating adult beagle dog subjected to a complete transection of the spinal cord. The results showed that after co-culturing with neurotropin-3 overexpressing Schwann cells in a gelatin sponge scaffold for 14 days, TrkC overexpressing MSCs differentiated into neuron-like cells. In the latter, some cells appeared to make contacts with each other through synapse-like structures with trans-synaptic electrical activities. Remarkably, the SCI canines receiving the transplantation of the MSC-derived neural network tissue demonstrated a gradual restoration of paralyzed limb motor function, along with improved electrophysiological presentation when compared with the control group. Magnetic resonance imaging and diffusion tensor imaging showed that the canines receiving the MSC-derived neural network tissue exhibited robust nerve tract regeneration in the injury/graft site. Histological analysis showed that some of the MSC-derived neuron-like cells had survived in the injury/graft site up to 6.5 months. Implantation of MSC-derived neural network tissue significantly improved the microenvironment of the injury/graft site. It is noteworthy that a variable number of them had integrated with the regenerating corticospinal tract nerve fibers and 5-HT nerve fibers through formation of synapse-like contacts. The results suggest that the transplanted MSC-derived neural network tissue may serve as a structural and functional "neuronal relay" to restore the paralyzed limb motor function in the canine with complete SCI.

Epidural Fat-Derived Mesenchymal Stem Cell: First Report of Epidural Fat-Derived Mesenchymal Stem Cell

“…Many experimental studies using MSC have been conducted [15-17]; however, they are mostly induced from subcutaneous fat tissue owing to the ease in harvesting and availability, or other originated stem cells. Second, EF-MSC may also affect peridural adhesion or scarring by MSC-induced anti-inflammatory properties [10,16,18,19]. Postsurgical epidural scarring or adhesions are considered significant issues for clinical impairments, such as the post-laminectomy syndrome [1,6] that may be caused by the removal of the EF tissue during spine surgery.…”

Stem Cells in Veterinary Medicine—Current State and Treatment Options

“…One possibility is a tissue engineering approach. In one study, constructed canine MSC-derived neural network tissue was transplanted into the spinal cord and resulted in the gradual restoration of paralyzed limb motor function (243). More studies and further developments are therefore needed to establish whether cell therapy and tissue engineering approaches are beneficial for spinal cord injuries, especially in patients with spontaneous injuries where the progress of the disease is often very different from the experimentally induced pathologies.…”

The cell repair research of spinal cord injury: a review of cell transplantation to treat spinal cord injury

“…Mesenchymal stem cells (MSCs) are the most widely used stem cells in pluripotent adult stem cells, and mostly exist in bone marrow, fat and pericarpal tissues (such as cord blood, amniotic membrane, placenta, etc.). MSCs can secrete a variety of growth factors, cytokines and neurotrophic factors, which improve the spinal cord microenvironment [16], regulate immune response, support hematopoiesis, inhibit excessive inflammatory response, promote angiogenesis and tissue repair, anti-scarring tissue proliferation, anti-apoptosis, anti-inflammatory, and promote endogenous stem/progenitor cell proliferation and axonal growth [17,18].…”

“…Neuropathic pain (NP) is a chronic debilitating disease caused by neurodegeneration after SCI, and about 59% of SCI patients may experience such chronic pain [16]. Although there are a variety of drugs used in the treatment of SCI-NP, their medical effect is not optimistic, and the side effects are inevitable [44,45].…”