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1.  Timing of Umbilical Cord Blood Derived Mesenchymal Stem Cells Transplantation Determines Therapeutic Efficacy in the Neonatal Hyperoxic Lung Injury 
PLoS ONE  2013;8(1):e52419.
Intratracheal transplantation of human umbilical cord blood (UCB)-derived mesenchymal stem cells (MSCs) attenuates the hyperoxia-induced neonatal lung injury. The aim of this study was to optimize the timing of MSCs transplantation. Newborn Sprague-Dawley rats were randomly exposed to hyperoxia (90% for 2 weeks and 60% for 1 week) or normoxia after birth for 21 days. Human UCB-derived MSCs (5×105 cells) were delivered intratracheally early at postnatal day (P) 3 (HT3), late at P10 (HT10) or combined early+late at P3+10 (HT3+10). Hyperoxia-induced increase in mortality, TUNEL positive cells, ED1 positive alveolar macrophages, myeloperoxidase activity and collagen levels, retarded growth and reduced alveolarization as evidenced by increased mean linear intercept and mean alveolar volume were significantly better attenuated in both HT3 and HT3+10 than in HT10. Hyperoxia-induced up-regulation of both cytosolic and membrane p47phox indicative of oxidative stress, and increased inflammatory markers such as tumor necrosis factor-α, interleukin (IL) -1α, IL-1β, IL-6, and transforming growth factor-β measured by ELISA, and tissue inhibitor of metalloproteinase-1, CXCL7, RANTES, L-selectin and soluble intercellular adhesion molecule-1 measured by protein array were consistently more attenuated in both HT3 and HT3+10 than in HT10. Hyperoxia-induced decrease in hepatocyte growth factor and vascular endothelial growth factor was significantly up-regulated in both HT3 and HT3+10, but not in HT10. In summary, intratracheal transplantation of human UCB derived MSCs time-dependently attenuated hyperoxia-induced lung injury in neonatal rats, showing significant protection only in the early but not in the late phase of inflammation. There were no synergies with combined early+late MSCs transplantation.
PMCID: PMC3549907  PMID: 23349686
2.  Long-Term (Postnatal Day 70) Outcome and Safety of Intratracheal Transplantation of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells in Neonatal Hyperoxic Lung Injury 
Yonsei Medical Journal  2013;54(2):416-424.
This study was performed to evaluate the long-term effects and safety of intratracheal (IT) transplantation of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) in neonatal hyperoxic lung injury at postnatal day (P)70 in a rat model.
Materials and Methods
Newborn Sprague Dawley rat pups were subjected to 14 days of hyperoxia (90% oxygen) within 10 hours after birth and allowed to recover at room air until sacrificed at P70. In the transplantation groups, hUCB-MSCs (5×105) were administered intratracheally at P5. At P70, various organs including the heart, lung, liver, and spleen were histologically examined, and the harvested lungs were assessed for morphometric analyses of alveolarization. ED-1, von Willebrand factor, and human-specific nuclear mitotic apparatus protein (NuMA) staining in the lungs and the hematologic profile of blood were evaluated.
Impaired alveolar and vascular growth, which evidenced by an increased mean linear intercept and decreased amount of von Willebrand factor, respectively, and the hyperoxia-induced inflammatory responses, as evidenced by inflammatory foci and ED-1 positive alveolar macrophages, were attenuated in the P70 rat lungs by IT transplantation of hUCB-MSCs. Although rare, donor cells with human specific NuMA staining were persistently present in the P70 rat lungs. There were no gross or microscopic abnormal findings in the heart, liver, or spleen, related to the MSCs transplantation.
The protective and beneficial effects of IT transplantation of hUCB-MSCs in neonatal hyperoxic lung injuries were sustained for a prolonged recovery period without any long-term adverse effects up to P70.
PMCID: PMC3575965  PMID: 23364976
Stem cells; cell transplantation; animal model; newborn; inflammation
3.  Angiogenesis Induced by Autologous Whole Bone Marrow Stem Cells Transplantation 
Background and Objectives:
It has been presumed that unknown cells and growth factors in bone marrow might promote angiogenesis, so angiogenesis effect could be enhanced by autologous whole bone marrow (WBM) stem cell transplantation. We compared capillary ratio induced by autologous WBM and bone marrow-mononuclear cells (BM-MNCs) to evaluate the anigiogenic effect of auotologous WBM. In addition, the combined effect of WBM transplantation and granulocyte colony-stimulating factor (G-CSF) injection was examined in an ischemic canine model.
Methods and Results:
After creating ischemic limb model, autologous WBM and isolated BM-MNCs were transplanted into the ischemic muscle. In other experiments, autologous WBM with recombinant human G-CSF (rhG-CSF) and autologous WBM without rhG-CSF were transplanted into the ischemic muscle. In this study, normal saline was injected into the contralateral sites in each ischemic model as a control group. After 8 weeks of transplantation, angiography and muscle harvest were performed, and then the anigiographic findings and capillary density, as assessed by immunohistochemical staining, were investigated and analyzed. In comparison with the control group, BM-MNCs and WBM transplantation groups showed higher ratios of the capillary density (1.5±0.01 times, p<0.001 and 1.6±0.15 times, p=0.005, respectively). Between the BM-MNCs and WBM transplantation groups, the capillary ratio was 1.2 folds higher in the WBM group than that in the BM-MNCs group, but there was no significantly different (p=0.116). The angiogensis ratios of both the WBM without G-CSF group and the WBM with G-CSF groups were higher (1.6±0.15 times, p=0.004 and 1.8 ±0.01 times, p=0.005, respectively) than that of the control groups. In comparison with the WBM without G-CSF group, the WBM with G-CSF transplantation group revealed a 1.1 folds higher angiogenesis ratio, but there was no statistically significant difference (p=0.095).
Autologous WBM transplantation is a simpler method and it is not inferior for inducing therapeutic angiogenesis as compared with isolated BM-MNCs transplantation. In addition to autologous WBM transplantation, intravenous G-CSF injection enhances the angiogenic effect of autologous WBM in an ischemic limb.
PMCID: PMC4021777  PMID: 24855510
Stem cells; Bone marrow; Angiogenesis and ischemia
4.  Cotransplanted Bone Marrow Derived Mesenchymal Stem Cells (MSC) Enhanced Engraftment of Hematopoietic Stem Cells in a MSC-dose Dependent Manner in NOD/SCID Mice 
Journal of Korean Medical Science  2006;21(6):1000-1004.
Transplantation of marrow-derived mesenchymal stem cells (MSCs), expanded by culture in addition to whole bone marrow, has been shown to enhance engraftment of human hematopoietic stem cells (HSCs). Our hypothesis was that there might be an optimum ratio range that could enhance engraftment. We examined the percent donor chimerism according to the ratio of HSCs to MSCs in non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice. We tested a series of ratios of co-transplanted CD34+-selected bone marrow cells, and marrow-derived MSCs into sublethally irradiated NOD/SCID mice. In all experiments, 1×105 bone marrow derived human CD34+ cells were administered to each mouse and human MSCs from different donors were infused concomitantly. We repeated the procedure three times and evaluated engraftment with flow cytometry four weeks after each transplantation. Serial ratios of HSCs to MSCs were 1:0, 1:1, 1:2 and 1:4, in the first experiment, 1:0, 1:1, 1:2, 1:4 and 1:8 in the second and 1:0, 1:1, 1:4, 1:8 and 1:16 in the third. Cotransplantation of HSCs and MSCs enhanced engraftment as the dose of MSCs increased. Our results suggest that the optimal ratio of HSCs and MSCs for cotransplantation might be in the range of 1:8-1:16; whereas, an excessive dose of MSCs might decrease engraftment efficiency.
PMCID: PMC2721918  PMID: 17179676
Hematopoietic Stem Cells; Mesenchymal Stem Cells; Transplantation; Mice, SCID; Engraftment

Results 1-4 (4)