Bone Marrow Stromal Cells Rescue Ischemic Brain by Trophic Effects and Phenotypic Change Toward Neural Cells

Abstract

Background. Transplantation of bone marrow stromal cells (BMSCs) may contribute to functional recovery after stroke. This study was designed to clarify their mechanisms, trophic effects of neurotrophic factors, and neural differentiation. Methods. Mouse neurons exposed to glutamate were cocultured with mouse BMSCs. Either neutralizing antibodies against brain-derived neurotrophic factor (BDNF) or nerve growth factor (NGF) or Trk inhibitor K252a was added to explore the mechanism of their protective effects. Fluorescence in situ hybridization (FISH) was used to assess BDNF or NGF mRNA expression in BMSCs. The mice were subjected to permanent focal ischemia, and 7 days later, either BMSCs or the vehicle was stereotactically transplanted into the ipsilateral striatum. The mouse brains were processed for FISH and immunostaining 2 or 4 weeks after transplantation. Results. BMSCs significantly ameliorated glutamate-induced neuronal death. Treatment with anti-BDNF antibody significantly reduced their protective effects. FISH analysis showed that the majority of BMSCs expressed BDNF and NGF mRNA in vitro. BMSC transplantation significantly improved the survival of neurons in peri-infarct areas. FISH analysis revealed that approximately half of BMSCs expressed BDNF and NGF mRNA 2 weeks after transplantation; however, the percentage of BDNF and NGF mRNA-positive cells decreased thereafter. Instead, the percentage of microtubule-associated protein 2-positive BMSCs gradually increased during 4 weeks after transplantation. Conclusions. These findings strongly suggest that BDNF may be a key factor underlying the trophic effects of BMSCs. BMSCs might exhibit the trophic effect in the early stage of cell therapy and the phenotypic change toward neural cells thereafter.

Human ciliary neurotrophic factor–overexpressing stable bone marrow stromal cells in the treatment of a rat model of traumatic spinal cord injury

“…There is compelling evidence that supports the idea that BMSCs can secrete a variety of neurotrophic factors per se; hence, the better results in the recovery of the CB group in comparison with the not-receivingetransplanted cell groups can be attributed to this phenomenon. In fact, it is well accepted that BMSCs can secrete glial cellederived neurotrophic factor, brain-derived neurotrophic factor, nerve growth factor and so forth [17,18]. Although neurotrophic therapy is a promising approach to tilt the balance toward treatment of CNS trauma, albeit at optimum secretion levels, it appears that combined therapy is a more realistic approach to overcome all barricades.…”

Stem cell therapy for abrogating stroke-induced neuroinflammation and relevant secondary cell death mechanisms

“…BM-MSCs may promote functional improvements in part due to the secretion of neurotrophic factors, which in turn stimulate endogenous cerebral repair processes. The active neurotrophic factors secreted by BM-MSCs include: hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), basic fibroblast growth factor (bFGF, FGF-2), and insulin growth factor-1 (IGF-1) (Eckert et al, 2013, Chen et al, 2015, Shichinohe et al, 2015). BM-MSCs also promote endogenous neurogenesis by encouraging the recruitment of primary stem cells from the subventricular zone (SVZ) and subgranular zone (SGZ) to site of injury and diminishing the rate of apoptotic insult in the penumbral zone of the principal lesion (Li et al, 2016).…”

Enhancing endogenous capacity to repair a stroke-damaged brain: An evolving field for stroke research

“…For example, when HUCB cell conditioned media was analyzed by ELISA, the cells secreted intercellular adhesion molecule-1 (ICAM-1), Selectins (E and L), and IL-8, VEGF, vascular cell adhesion molecule (VCAM), stromal derived factor 1b (SDF-1b), and IL-6 (Chen et al, 2010). They also express both nerve growth factor (NGF) and its receptor TrkA (Bracci-Laudiero et al, 2003; Shichinohe et al, 2015), brain derived neurotrophic factor (BDNF) and neurotrophin 4/5 (NT4/5) (Fan et al, 2005; Shichinohe et al, 2015), pentraxin 3 and thrombospondin 1 (Park et al, 2015a). …”