BDNF-Hypersecreting Human Mesenchymal Stem Cells Promote Functional Recovery, Axonal Sprouting, and Protection of Corticospinal Neurons after Spinal Cord Injury

Abstract

Transplantation of mesenchymal stem cells (MSCs) derived from bone marrow has been shown to improve functional outcome in spinal cord injury (SCI). We transplanted MSCs derived from human bone marrow (hMSCs) to study their potential therapeutic effect in SCI in the rat. In addition to hMSCs, we used gene-modified hMSCs to secrete brain-derived neurotrophic factor (BDNF-hMSCs). After a dorsal transection lesion was induced at T9, cells were microinjected on each side of the transection site. Fluorogold (FG) was injected into the epicenter of the lesion cavity to identify transected corticospinal tract (CST) neurons. At 5 weeks after transplantation, the animals were perfused. Locomotor recovery improvement was observed for the BDNF-hMSC group, but not in the hMSC group. Structurally there was increased sprouting of injured corticospinal tract and serotonergic projections after hMSC and BDNF-hMSC transplantation. Moreover, an increased number of serotonergic fibers was observed in spinal gray matter including the ventral horn at and below the level of the lesion, indicating increased innervation in the terminal regions of a descending projection important for locomotion. Stereological quantification was performed on the brains to determine neuronal density in primary motor (M1) cortex. The number of FG backfilled cells demonstrated an increased cell survival of CST neurons in M1 cortex in both the hMSC and BDNF-hMSC groups at 5 weeks, but the increase for the BDNF-hMSC group was greater. These results indicate that transplantation of hMSCs hypersecreting BDNF results in structural changes in brain and spinal cord, which are associated with improved functional outcome in acute SCI.

Transplantation of Mesenchymal Stem Cells Promotes an Alternative Pathway of Macrophage Activation and Functional Recovery after Spinal Cord Injury

“…In our study, transplanted MSC migrated to the neighborhood of the injured spinal cord, but did not differentiate into glial or neuronal elements. Current thinking is that the potential beneficial effects of MSC in SCI are not related to neuronal or glial differentiation of MSC, but rather from their secretion of growth factors and/or cytokines (Sasaki et al, 2009), which can provide neuroprotection (Chen et al, 2002;Parr et al, 2007), induction of axonal sprouting (Shen et al, 2006), neovascularization (Onda et al, 2008), and immunomodulation (Ohtaki et al, 2008;Bai et al, 2009). MSC may also promote axonal regeneration or encourage functional plasticity by establishing an environment that supports axonal growth, for example, by abrogating the inhibitory influence of the chondroitin sulfated proteoglycans (CSPG), and/or myelin debris present in the injury site and glial scar (Wright et al, 2011).…”

Localized Delivery of Brain-Derived Neurotrophic Factor-Expressing Mesenchymal Stem Cells Enhances Functional Recovery following Cervical Spinal Cord Injury

“…1,14,31,46,72 Furthermore, BDNF treatment can directly modulate synaptic efficacy in the adult rat. 73,74 Some of the beneficial effects of MSCs are mediated by release of neurotrophic factors 33,34 and, therefore, may be independent of cellular incorporation and differentiation.…”

“…Advantages of using MSCs include their endogenous release of neurotrophic factors, [30][31][32][33][34][35] and that they can be engineered to release higher levels of trophic factors such as BDNF. 31,[36][37][38][39] We hypothesized that localized delivery of BDNF-expressing MSCs (BDNF-MSCs) will promote functional recovery of rhythmic diaphragm activity after SH. Localized delivery was attained using intraspinal injections of adult rat MSCs engineered to produce releasable BDNF by retroviral treatment.…”

Stem Cells: New Hope For Spinal Cord Injury

“…The regenerative potential of iPSCs was confirmed in a rodent model of SCI (14,15); nevertheless, optimized growth and differentiation protocols and reliable safety assays should be established prior to the clinical application of iPSCs. nerve growth factor (NGF), vascular endothelial growth factor (VEGF), and hepatocyte growth factor (HGF) (22,23).…”