The Long-Term Efficacy Study of Multiple Allogeneic Canine Adipose Tissue-Derived Mesenchymal Stem Cells Transplantations Combined With Surgery in Four Dogs With Lumbosacral Spinal Cord Injury.

Severe lumbosacral pain, paraparesis or paraplegia, and urinary incontinence are common but frustrating problems in dogs with lumbosacral spinal cord injury (SCI). The surgical interventions including stabilization and decompression may not restore satisfying neurological functions in severe SCI. Adipose tissue-derived mesenchymal stem cells (Ad-MSCs) show benefits in immunomodulation, anti-inflammation, and promotion of axonal growth and remyelination, and also display efficacy in several diseases in veterinary medicine. In this report, four dogs presented with fracture of sacrum vertebrae or fracture of seventh lumbar and lumbosacral displacement after road traffic accidents. The clinical signs include lumbosacral pain (4/4), paraparesis (3/4), paraplegia (1/4), and urinary incontinence (4/4). All dogs were treated by surgical decompression with or without stabilization 1 to 7 weeks after trauma. Allogeneic canine Ad-MSCs (cAd-MSCs) were injected locally on nerve roots through the surgical region in all dogs. One dose of intravenous transplantation and 4 doses of local transplantation were also performed within 8 weeks after the surgery separately. All dogs showed significant neurological improvements with normal ambulatory ability (4/4) and urinary control (3/4) 3 months after the surgery and the first cAd-MSCs transplantation. No side effect was related to multiple cAd-MSCs transplantations during 6 months monitoring in all dogs. In conclusion, multiple cAd-MSCs transplantations could be a recommended treatment combined with surgery in dogs with lumbosacral SCI.

Human Wharton's Jelly Mesenchymal Stem Cell-Mediated Sciatic Nerve Recovery Is Associated with the Upregulation of Regulatory T Cells.

The acceleration of peripheral nerve regeneration is crucial for functional nerve recovery. Our previous study demonstrated that human Wharton's jelly-derived mesenchymal stem cells (hWJ-MSC) promote sciatic nerve recovery and regeneration via the direct upregulation and release of neurotrophic factors. However, the immunomodulatory role of hWJ-MSC in sciatic nerve recovery remains unclear. The effects of hWJ-MSC on innate immunity, represented by macrophages, natural killer cells, and dendritic cells, as well as on adaptive immunity, represented by CD4+ T, CD8+ T, B, and regulatory T cells (Tregs), were examined using flow cytometry. Interestingly, a significantly increased level of Tregs was detected in blood, lymph nodes (LNs), and nerve-infiltrating cells on POD7, 15, 21, and 35. Anti-inflammatory cytokines, such as IL-4 and IL-10, were significantly upregulated in the LNs and nerves of hWJ-MSC-treated mice. Treg depletion neutralized the improved effects of hWJ-MSC on sciatic nerve recovery. In contrast, Treg administration promoted the functional recovery of five-toe spread and gait stance. hWJ-MSC also expressed high levels of the anti-inflammatory cytokines TGF-ß and IL-35. This study indicated that hWJ-MSC induce Treg development to modulate the balance between pro- and anti-inflammation at the injured sciatic nerve by secreting higher levels of anti-inflammatory cytokines.

Topical Application of Human Wharton's Jelly Mesenchymal Stem Cells Accelerates Mouse Sciatic Nerve Recovery and is Associated with Upregulated Neurotrophic Factor Expression.

Peripheral nerve regeneration following injury is often slow and impaired, which results in weakened and denervated muscle with subsequent atrophy. Human Wharton's jelly mesenchymal stem cells (hWJ-MSC) have potential regenerative properties which, however, remain unknown in mouse nerve recovery. This study investigated the effect of the topical application of hWJ-MSC onto repairing transected sciatic nerves in a mouse model. Human adipocyte-derived stem cells (hADSC) were used as a positive control. The sciatic nerve of BALB/c mice was transected at a fixed point and repaired under the microscope using 10-0 sutures. hWJ-MSC and hADSC were applied to the site of repair and mice were followed up for 1 year. The hWJ-MSC group had significantly better functional recovery of five-toe spread and gait angles compared with the negative control and hADSC groups. hWJ-MSC improved sciatic nerve regeneration in a dose-dependent fashion. The hWJ-MSC group had a better quality of regenerated nerve with an increased number of myelinated axons throughout. hWJ-MSC appear to be safe in mice after 1 year of follow-up. hWJ-MSC also expressed higher levels of neurotrophic factor-3, brain-derived neurotrophic factor, and glial-derived neurotrophic factor than hADSC. hWJ-MSC may promote better nerve recovery than hADSC because of this upregulation of neurotrophic factors.