Xiaodan Jiang

Adenoviral-mediated interleukin-18 expression in mesenchymal stem cells effectively suppresses the growth of glioma in rats.

Glioma is the most common primary intracranial malignant tumor. Despite advances in surgical techniques and adjuvant radio‐ and chemotherapies, the prognosis for patients with glioma remains poor. We have explored the effects of using genetically modified mesenchymal stem cells (MSCs) to treat malignant glioma in rats. Mesenchymal stem cells isolated from Sprague–Dawley rats can directly suppress the growth of C6 cells in vitro. MSCs transplanted intratumorally can also significantly inhibit the growth of glioma and prolong survival in C6 glioma‐bearing models. MSCs producing Interleukin‐18 infected by adenoviral vector inhibited glioma growth and prolonged the survival of glioma‐bearing rats. Transplantation of IL‐18 secreting MSCs was associated with enhanced T cell infiltration and long‐term anti‐tumor immunity. Thus, IL‐18 may be an effective adoptive immunotherapy for malignant glioma. When used in conjunction with MSCs as targeting vehicles in vivo, IL‐18 may offer a promising new treatment option for malignant glioma.

NT-3-secreting human umbilical cord mesenchymal stromal cell transplantation for the treatment of acute spinal cord injury in rats.

An animal model for clip spinal cord injury (SCI) was used to determine whether Neurotrophin-3 (NT-3) genetically modified human umbilical mesenchymal stem cells (NT-3-HUMSCs) could promote the morphologic and functional recovery of injured spinal cords. Using the Basso, Beattie, and Bresnahan scores and a grid test, the rats in the HUMSC-treated and NT-3-HUMSCs groups had significantly improved locomotor functional recovery more than the control group. In comparison, the NT-3-HUMSCs group achieved better functional recovery than the HUMSCs group at the end of 12 weeks after SCI. The functional recovery was accompanied by increased intensity of 5-HT fibers, increased volume of spared myelination, and decreased area of the cystic cavity in the NT-3-HUMSCs group compared with the HUMSCs group. Moreover, transplanted NT-3-HUMSCs survived and produced larger amounts of NT-3 than the HUMSCs in the host spinal cord. These results show that NT-3 enhanced the therapeutic effects of HUMSCs after clip injury of the spinal cord.

Beneficial effect of autologous transplantation of bone marrow stromal cells and endothelial progenitor cells on cerebral ischemia in rabbits

We tested the therapeutic effect of autologous transplanted bone marrow stromal cells (BMSCs) and endothelial progenitor cells (EPCs) on cerebral ischemia in rabbits. Rabbit permanent middle cerebral artery occlusion (MCAO) models were intravenously injected with ex vivo expanded autologous BMSCs (n = 8), EPCs (n = 8), or phosphate-buffered saline (n = 6). 14 days after the transplantation, both infusion groups witnessed a functional improvement, a decrease in the number of apoptotic cells and an increase in the microvessel density in the ischemic boundary area, as compared to vehicle-treated control group. The EPCs treated group also exhibited a diminished infarct area in comparison with the control group. Moreover, immunohistochemistry revealed that few transplanted BMSCs expressed markers for astrocytes (GFAP+) and neurons (NeuN+), and most of EPCs were capable of binding to UEA-1 lectin and were incorporated into capillaries. Our data suggest that both BMSCs and EPCs, despite differences in their action mechanism, can be functional cytoreagents for treatment of cerebral ischemia in rabbits.

Comparison of adult neurospheres derived from different origins for treatment of rat spinal cord injury

This study is designed to evaluate the therapeutic effects of three types of neurospheres (NSs) derived from brain, bone marrow and adipose tissue in a rat model of spinal contusive injury. As shown by BBB locomotor rating scale and grid test, the optimal therapeutic responses generated by subventricular zone-derived NSs (SVZ-NSs), and followed by adipose-derived (AD-NSs) and bone marrow-derived NSs (BM-NSs) after being grafted into the injured spinal cord. In three cell-treated groups, very few (<1%) grafted cells survived and these survived cells mainly differentiated into oligodendrocytes at week 12 after injury. Additionally, all the cell-treated groups, especially in the SVZ-treated group showed an increase in host oligodendrocytes than control group. Moreover, the level of selective neurotrophins (NTs) in the SVZ-NSs group were significantly higher than those in the BM-NSs and AD-NSs groups, and the level of NTs in the saline group was also significantly higher than sham group. Therefore, not cell replacement or infusion but neuroprotective action associated with endogenous oligodendrocytes and NTs that active by the grafted NSs may contribute to the functional recovery.

Combination of bone marrow stromal cell transplantation with mobilization by granulocyte-colony stimulating factor promotes functional recovery after spinal cord transection

PurposeSpinal cord injury (SCI) results in severe neurological deficit. However, the functional recovery following SCI is very poor due to the neural lost and limited axonal regeneration. To date, there was no effective treatment. Recent studies have shown that bone marrow stromal cells (BMSCs) transplantated into the central nervous system (CNS) can survive and differentiate into neuronal-like cells. Additionally, granulocyte colony-stimulating factor (G-CSF) can mobilize hematopoietic stem cells and inhibit neural cell apoptosis. Thus, we aimed to evaluate the combined effect of BMSC transplantation and G-CSF administration on rats with traverse spinal cord injury.MethodsBMSCs were cultured in vitro, labeled with Hoechst33342, and then transplanted into the lesion site with or without G-CSF administration (50xa0μg/kg/day) for 5 subsequent days. The groups included an untreated control, along with treatment by G-CSF alone, BMSCs alone, and G-CSFu2009+u2009BMSCs.ResultsIn this study, by the end of eighth week after SCI injury, the animals in group treated with G-CSFu2009+u2009BMSCs showed higher BBB scores than the other two groups. Morphometric assessment showed that the lesion areas in the rats of the G-CSFu2009+u2009BMSCs group were much smaller. Compared with the control, BMSC, and G-CSF groups, less expression of apoptosis cells and more neural-cell markers around the spinal cord injury were found in rats treated with G-CSFu2009+u2009BMSCs.ConclusionsThe animals with the combination treatment achieved a better functional and morphologic recovery, although partial. This synergistic effect between BMSCs and G-CSF may be attributed to extrinsic and endogenous neurogenesis in the traverse spinal cord injury.

Human umbilical vein-derived dopaminergic-like cell transplantation with nerve growth factor ameliorates motor dysfunction in a rat model of Parkinson's disease.

Mesenchymal stem cells are capable of differentiating into dopaminergic-like cells, but currently no report has been available to describe the induction of human umbilical vein mesenchymal stem cells (HUVMSCs) into dopaminergic-like cells. In this study, we induced HUVMSCs in vitro into neurospheres constituted by neural stem-like cells, and further into cells bearing strong morphological, phenotypic and functional resemblances with dopaminergic-like cells. These HUVMSC-derived dopaminergic-like cells, after grafting into the brain of a rat model of Parkinson’s disease (PD), showed a partial therapeutic effect in terms of the behavioral improvement. Nerve growth factor was reported to improve the local microenvironment of the grafted cells, and we therefore further tested the effect of dopaminergic-like cell grafting combined with nerve growth factor (NGF) administration at the site of cell transplantation. The results showed that NGF administration significantly promoted the survival of the grafted cells in the host brain and enhanced the content of dopaminergic in the local brain tissue. Behavioral test demonstrated a significant improvement of the motor function of the PD rats after dopaminergic-like cell grafting with NGF administration as compared with that of rats receiving the cell grafting only. These results suggest that transplantation of the dopaminergic-like cells combined with NGF administration may represent a new strategy of stem cell therapy for PD.

In vivo magnetic resonance tracking of Feridex-labeled bone marrow-derived neural stem cells after autologous transplantation in rhesus monkey.

Bone marrow stroma cells-derived neural stem cells (BMSCs-D-NSCs) transplantation is a promising strategy for the treatment of nervous system disorders. The development of a non-invasive method to follow the fate of BMSCs-D-NSCs in vivo is very important for the future application of this treatment. In this paper, we show for the first time, that BMSCs-D-NSCs from rhesus monkeys can be labeled in vitro with the superparamagnetic iron oxide (SPIO) contrast agent Feridex and Poly-L-lysine (PLL) without affecting morphology, cell cycle, telomerase activity, proliferation and differentiation ability of the labeled cells. Furthermore, when autografted into the striatum, these cells survived, differentiated and were incorporated into the brain, and could be reliably tracked using MRI, as confirmed by histological examination of the grafting sites with PKH(67) fluorescence. These results suggest that Feridex labeling of BMSCs-D-NSCs is feasible, efficient and safe for MRI tracing following autografting into the rhesus monkey nervous system.

Species-dependent neuropathology in transgenic SOD1 pigs

Mutations in the human copper/zinc superoxide dismutase 1 (hSOD1) gene cause familial amyotrophic lateral sclerosis (ALS). It remains unknown whether large animal models of ALS mimic more pathological events seen in ALS patients via novel mechanisms. Here, we report the generation of transgenic pigs expressing mutant G93A hSOD1 and showing hind limb motor defects, which are germline transmissible, and motor neuron degeneration in dose- and age-dependent manners. Importantly, in the early disease stage, mutant hSOD1 did not form cytoplasmic inclusions, but showed nuclear accumulation and ubiquitinated nuclear aggregates, as seen in some ALS patient brains, but not in transgenic ALS mouse models. Our findings revealed that SOD1 binds PCBP1, a nuclear poly(rC) binding protein, in pig brain, but not in mouse brain, suggesting that the SOD1-PCBP1 interaction accounts for nuclear SOD1 accumulation and that species-specific targets are key to ALS pathology in large mammals and in humans.

Effects of Differentiated Versus Undifferentiated Adipose Tissue-derived Stromal Cell Grafts on Functional Recovery After Spinal Cord Contusion

Controversies exist concerning the need for mesenchymal stromal cells (MSCs) to be transdifferentiated prior to their transplantation. In the present study, we compared the results of grafting into the rat contused spinal cord undifferentiated, adipose tissue-derived stromal cells (uADSCs) versus ADSCs induced by two different protocols to form differentiated nervous tissue. Using Basso, Beattie, and Bresnahan scores and grid tests, we found that three cell-treated groups, including uADSCs-treated, dADSCs induced by Protocol 1 (dADSC-P1)-treated, and dADSCs induced by Protocol 2 (dADSC-P2)-treated groups, significantly improved locomotor functional recovery in SCI rats, compared with the saline-treated group. Furthermore, functional recovery was better in the uADSC-treated and dADSC-P2-treated groups than in the dADSC-P1-treated group at week 12 postinjury (Pxa0<xa00.05 for dADSC-P1 group vs. uADSCs or dADSC-P2 groups). Although both protocols could induce high percentages of cells expressing neural markers in vitro, few BrdU-labeled cells survived at the injury sites in the three cell-treated groups, and only a small percentage of BrdU-positive cells expressed neural markers. On the other hand, the number of NF200-positive axons in the uADSC-treated and dADSC-P2-treated groups was significantly larger than those in the dADSC-P1-treated and saline-treated control groups. Our results indicate that ADSCs are able to differentiate into neural-like cells in vitro and in vivo. However, neural differentiated ADSCs did not result in better functional recovery than undifferentiated ones, following SCI. In vitro neural transdifferentiation of ADSCs might therefore not be a necessary pretransplantation step. Furthermore, cellular replacement or integration might not contribute to the functional recovery of the injured spinal cord.

Umbilical cord blood cell-derived neurospheres differentiate into Schwann-like cells.

In this study, we examined the phenotypic and bioassay characteristics of human umbilical cord blood-derived mesenchymal stromal cells (UCB–MSCs) differentiated along a Schwann cells lineage. Initially, we induced human UCB–MSCs into floating neurospheres, and then, neurospheres were induced to differentiate into Schwann-like cells using glia growth factors. Differentiated UCB–MSCs showed morphological changes similar to those of Schwann cells. Expression of the Schwann cell markers was determined by immunocytochemical staining and western blotting. Furthermore, differentiated UCB–MSCs could promote neurite outgrowth in coculture with dorsal root ganglia neurons. These results show that UCB–MSCs can be differentiated into cells that are Schwann-like in terms of morphology, phenotype, and function.