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Heat Shock Factor 1 Contributes to Ischemia-Induced Angiogenesis by Regulating the Mobilization and Recruitment of Bone Marrow Stem/Progenitor Cells  [PDF]
Masayuki Kubo, Tao-Sheng Li, Hiroshi Kurazumi, Yoshihiro Takemoto, Mako Ohshima, Yumi Yamamoto, Arata Nishimoto, Akihito Mikamo, Mitsuaki Fujimoto, Akira Nakai, Kimikazu Hamano
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0037934
Abstract: Bone marrow (BM)-derived stem/progenitor cells play an important role in ischemia-induced angiogenesis in cardiovascular diseases. Heat shock factor 1 (HSF1) is known to be induced in response to hypoxia and ischemia. We examined whether HSF1 contributes to ischemia-induced angiogenesis through the mobilization and recruitment of BM-derived stem/progenitor cells using HSF1-knockout (KO) mice. After the induction of ischemia, blood flow and microvessel density in the ischemic hindlimb were significantly lower in the HSF1-KO mice than in the wild-type (WT) mice. The mobilization of BM-derived Sca-1- and c-kit-positive cells in peripheral blood after ischemia was significantly lower in the HSF1-KO mice than in the WT mice. BM stem/progenitor cells from HSF1-KO mice showed a significant decrease in their recruitment to ischemic tissue and in migration, adhesion, and survival when compared with WT mice. Blood flow recovery in the ischemic hindlimb significantly decreased in WT mice receiving BM reconstitution with donor cells from HSF1-KO mice. Conversely, blood flow recovery in the ischemic hindlimb significantly increased in HSF1-KO mice receiving BM reconstitution with donor cells from WT mice. These findings suggest that HSF1 contributes to ischemia-induced angiogenesis by regulating the mobilization and recruitment of BM-derived stem/progenitor cells.
Anti-angiogenesis therapy based on the bone marrow-derived stromal cells genetically engineered to express sFlt-1 in mouse tumor model
M Hu, J-L Yang, H Teng, Y-Q Jia, R Wang, X-W Zhang, Y Wu, Y Luo, X-C Chen, R Zhang, L Tian, X Zhao, Y-Q Wei
BMC Cancer , 2008, DOI: 10.1186/1471-2407-8-306
Abstract: Mouse BMSCs were loaded with recombinant adenoviruses which express soluble Vascular Endothelial Growth Factor Receptor-1 (sFlt-1). The anti-angiogenesis of sFlt-1 in BMSCs was determined using endothelial cells proliferation inhibition assay and alginate encapsulation assay. The anti-tumor effects of BMSCs expressing sFlt-1 through tail-vein infusion were evaluated in two mouse tumor metastases models.BMSCs genetically modified with Adv-GFP-sFlt-1 could effectively express and secret sFlt-1. BMSCs loaded with sFlt-1 gene could preferentially home to tumor loci and decrease lung metastases and prolong lifespan in mouse tumor model through inducing anti-angiogenesis and apoptosis in tumors.We demonstrated that BMSCs might be employed as a promising vehicle for tumor gene therapy which can effectively not only improve the concentration of anticancer therapeutics in tumors, but also modify the tumor microenvironment.Bone marrow-derived stromal cells (BMSCs), also known as mesenchymal stem cells or nonhematopoietic progenitor cells, are precursors that can be differentiated into chondrocytes, osteoblasts, adipocytes, neurons and other cell types [1]. They are important for development and cell replenishment of active proliferating tissues in physiological conditions, such as blood, skin and gut. In pathological conditions, they are involved in the process of wound healing and tissue regeneration. In animal and clinical experiments, BMSCs have been used for tissue damage repair and functional reconstruction of organs, such as myocardial infarction, osteogenesis imperfecta, syndrome of multiple organ failure and rebuilding of hematopoietic system after chemotherapy of breast cancer [2-5].It has been reported that the conditions featured by enhanced cell proliferation and tissue remodeling, such as bone fractures, embryo growth and tumorigenesis, offer an appropriate microenvironment for migration, proliferation and differentiation of stem cells delivered systemically [3,6
Transdifferentiation of Bone Marrow Stromal Cells into Tyrosine Hydroxylase Immunoreactive Cells Associated with Angiogenesis in Parkinsonian Rats  [PDF]
Maryam Haji Ghasem Kashani,Taghi Tiraihi,Mohammad Taghi Ghorbanian
Cell Journal , 2011,
Abstract: Objective: This study is an attempt to examine the transdifferentiation of bone marrowstromal cells (BMSCs) into tyrosine hydroxylase immunoreactive cells in parkinsonian ratsassociated with angiogenesis.Materials and Methods: In this study, Sprague-Dawley rats received unilateral stereotaxicinjections of 6-hydroxydopamine(6-OHDA) into the left corpus striatum and then weredivided into two groups. One group, the negative control, received only medium while theother group was treated with BMSCs. BMSCs were harvested from femur bones, labeledwith bromodeoxyuridine (BrdU) and then transplanted into parkinsonian rats, where a behavioralstudy and immunohistochemistry were used to evaluate the treatment.Results: The results showed statistically significant improvement in rotational behavior.Anti-BrdU antibody showed engraftment of the transplanted cells at the transplantationsite. Additionally, double immunolabeling confirmed that these cells were positive for neurofilament-200 and tyrosine hydroxylase (TH).Conclusion: It may be concluded that BMSCs transplants could engraft and differentiateinto TH immunoreactive cells which may cause recovery from motor deficits. Also, BMSCsmay contribute to angiogenesis at the transplantation site.
Effects of transplanted GDNF gene modified marrow stromal cells on focal cerebral ischemia in rats  [PDF]
Yunliang Wang
Frontiers in Integrative Neuroscience , 2011, DOI: 10.3389/fnint.2011.00089
Abstract: Objective: To evaluate the therapeutic effect of transplanted glial cell derived neurotrophic factor (GDNF) modified marrow stromal cells (MSCs) on an experimental ischemic brain injury based on the behavioral, morphological, and immunohistochemical observations. Methods: The MSCs from four-week newborn rats were cultured in vitro. The cerebral ischemia and reperfusion model was established in adult Sprague–Dawley (SD) rats by using the suture method. Three days after model establishment, the animals were injected with prepared MSCs via their caudal veins. The animals were then divided into a sham-operation group, ischemia group, MSCs transplantation group, or GDNF+MSCs transplantation group and were scored for their neurobehavioral manifestations at 3, 14, and 28 days after the transplantation was performed. At this time, the survival condition of intracerebral transplanted cells was measured by laser confocal microscopy while the effect of transplantation on the Generic Digital Beam Former (GDNF) expression in the ischemic brain tissue was evaluated. Results: The MSCs cells transfected with GDNF gene were characterized by green fluorescence. Three days after the transplantation, the animals that underwent the cell transplantation showed significantly better behavioral data than the controls. Fourteen days after transplantation, the animals transplanted with GDNF gene modified MSCs were better than those transplanted with common MSCs. As compared with common MSCs transplantation, GDNF+MSCs transplantation was significantly more effective in reducing apoptotic cell volume and enhancing Bcl-2 expression, which was favorable for the ischemic brain injury. Conclusions: Transplanted GDNF modified MSCs can improve the nervous function and have a protective effect on the ischemic brain injury through reducing apoptotic cell volume and enhancing the expression of anti-apoptotic gene Bcl-2.
Niaspan Attenuates the Adverse Effects of Bone Marrow Stromal Cell Treatment of Stroke in Type One Diabetic Rats  [PDF]
Tao Yan, Xinchun Ye, Michael Chopp, Alex Zacharek, Ruizhuo Ning, Poornima Venkat, Cynthia Roberts, Mei Lu, Jieli Chen
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0081199
Abstract: Aims Our previous studies have found that bone-marrow-stromal cells (BMSC) therapy improves functional recovery after stroke in non-diabetic rats while increases brain hemorrhage and induces arteriosclerosis-like changes in type-one-diabetic (T1DM) rats. Niaspan treatment of stroke increases vascular stabilization, decreases brain hemorrhage and blood-brain-barrier (BBB) leakage in T1DM rats. We therefore tested the hypothesis that combination therapy of BMSC with Niaspan attenuates the side effects of BMSC monotherapy in T1DM rats. Methods T1DM-rats induced by streptozotocin were subjected to 2 hours of middle-cerebral-artery occlusion (MCAo) and treated with: 1) PBS; 2) BMSC (5×106); 3) Niaspan (40 mg/kg) daily for 14 days; 4) BMSC (5×106) +Niaspan (40 mg/kg, daily for 14 days) combination starting at 24 hours after MCAo. All rats were monitored for 14 days. Results Combination BMSC+Niaspan treatment of T1DM-MCAo rats did not increase brain hemorrhage, and significantly decreased BBB leakage and vascular arteriosclerosis-like changes as well as decreased Angiogenin, matrix metalloproteinase 9 (MMP9) and ED1 expression in ischemic brain and internal-carotid-artery compared to non-treatment control and BMSC monotherapy animals. Conclusions Combination therapy using BMSC with Niaspan decreases BBB leakage and cerebral arteriosclerosis-like changes. These beneficial effects may be attributed to the decreased expression of Angiogenin, MMP9 and ED1.
Bone marrow stem cells and their role in angiogenesis
Reis, Paulo Eduardo Ocke;
Jornal Vascular Brasileiro , 2005, DOI: 10.1590/S1677-54492005000400012
Abstract: the degree of symptomatology of a patient with peripheral arterial disease dictates the kind of treatment. despite the known therapies, some patients continue to have pain with ambulation, which affects their quality of life. the therapeutic implications of the angiogenic growth factors were identified by the pioneering studies of folkman et al. 2 decades ago. further investigations established the possibility of the use of formulations of recombinant angiogenic growth factors, with the objective of developing or increasing the network of collaterals in animal models of chronic myocardial or limb ischemia. researches suggest that primitive stem cells with whole bone marrow possess greater functional plasticity, capable of contributing to regeneration of ischemic limb muscle and vascular endothelium by adult stem cells. local autologous marrow stromal cells implantation induces a neovascular response resulting in a significant increase in blood flow to the ischemic limb. in this article we review the studies that have established how the implantation of bone marrow cells into ischemic limbs increases collateral vessel formation.
Mobilization of Endogenous Bone Marrow Derived Endothelial Progenitor Cells and Therapeutic Potential of Parathyroid Hormone after Ischemic Stroke in Mice  [PDF]
Li-Li Wang, Dongdong Chen, Jinhwan Lee, Xiaohuan Gu, Ghina Alaaeddine, Jimei Li, Ling Wei, Shan Ping Yu
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0087284
Abstract: Stroke is a major neurovascular disorder threatening human life and health. Very limited clinical treatments are currently available for stroke patients. Stem cell transplantation has shown promising potential as a regenerative treatment after ischemic stroke. The present investigation explores a new concept of mobilizing endogenous stem cells/progenitor cells from the bone marrow using a parathyroid hormone (PTH) therapy after ischemic stroke in adult mice. PTH 1-34 (80 μg/kg, i.p.) was administered 1 hour after focal ischemia and then daily for 6 consecutive days. After 6 days of PTH treatment, there was a significant increase in bone marrow derived CD-34/Fetal liver kinase-1 (Flk-1) positive endothelial progenitor cells (EPCs) in the peripheral blood. PTH treatment significantly increased the expression of trophic/regenerative factors including VEGF, SDF-1, BDNF and Tie-1 in the brain peri-infarct region. Angiogenesis, assessed by co-labeled Glut-1 and BrdU vessels, was significantly increased in PTH-treated ischemic brain compared to vehicle controls. PTH treatment also promoted neuroblast migration from the subventricular zone (SVZ) and increased the number of newly formed neurons in the peri-infarct cortex. PTH-treated mice showed significantly better sensorimotor functional recovery compared to stroke controls. Our data suggests that PTH therapy improves endogenous repair mechanisms after ischemic stroke with functional benefits. Mobilizing endogenous bone marrow-derived stem cells/progenitor cells using PTH and other mobilizers appears an effective and feasible regenerative treatment after ischemic stroke.
The establishment of a bank of stored clinical bone marrow stromal cell products
Marianna Sabatino, Jiaqiang Ren, Virginia David-Ocampo, Lee England, Michael McGann, Minh Tran, Sergei A Kuznetsov, Hanh Khuu, Arun Balakumaran, Harvey G Klein, Pamela G Robey, David F Stroncek
Journal of Translational Medicine , 2012, DOI: 10.1186/1479-5876-10-23
Abstract: The recruitment of healthy subjects willing to donate marrow for BMSC production and the Good Manufacturing Practices (GMP) used for assessing potential donors, collecting marrow, culturing BMSCs and BMSC cryopreservation are described.Seventeen subjects were enrolled in our marrow collection protocol for BMSC production. Six of the 17 subjects were found to be ineligible during the donor screening process and one became ill and their donation was cancelled. Approximately 12 ml of marrow was aspirated from one posterior iliac crest of 10 donors; one donor donated twice. The BMSCs were initially cultured in T-75 flasks and then expanded for three passages in multilayer cell factories. The final BMSC product was packaged into units of 100 × 106 viable cells, cryopreserved and stored in a vapor phase liquid nitrogen tank under continuous monitoring. BMSC products meeting all lot release criteria were obtained from 8 of the 11 marrow collections. The rate of growth of the primary cultures was similar for all products except those generated from the two oldest donors. One lot did not meet the criteria for final release; its CD34 antigen expression was greater than the cut off set at 5%. The mean number of BMSC units obtained from each donor was 17 and ranged from 3 to 40.The production of large numbers of BMSCs from bone marrow aspirates of healthy donors is feasible, but is limited by the high number of donors that did not meet eligibility criteria and products that did not meet lot release criteria.Bone marrow-derived stromal cells (BMSCs) are adult multipotent cells that can be isolated from bone marrow [1,2]. For their multitude of actions they represent a very attractive tool in cellular therapies; osteogenesis imperfecta [3,4], acute and chronic graft versus host disease (GVHD) [5-11] , inflammatory bowel disease [12], ischemic heart disease [13], non-healing ulcers [14], ischemic stroke [15], multiple sclerosis [16], amyotrophic lateral sclerosis [16,17], Parkinso
Lysophosphatidic Acid Enhances Stromal Cell-Directed Angiogenesis  [PDF]
Bernard Y. K. Binder, Claus S. Sondergaard, Jan A. Nolta, J. Kent Leach
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0082134
Abstract: Ischemic diseases such as peripheral vascular disease (PVD) affect more than 15% of the general population and in severe cases result in ulcers, necrosis, and limb loss. While the therapeutic delivery of growth factors to promote angiogenesis has been widely investigated, large-scale implementation is limited by strategies to effectively deliver costly recombinant proteins. Multipotent adipose-derived stromal cells (ASC) and progenitor cells from other tissue compartments secrete bioactive concentrations of angiogenic molecules, making cell-based strategies for in situ delivery of angiogenic cytokines an exciting alternative to the use of recombinant proteins. Here, we show that the phospholipid lysophosphatidic acid (LPA) synergistically improves the proangiogenic effects of ASC in ischemia. We found that LPA upregulates angiogenic growth factor production by ASC under two- and three-dimensional in vitro models of serum deprivation and hypoxia (SD/H), and that these factors significantly enhance endothelial cell migration. The concurrent delivery of LPA and ASC in fibrin gels significantly improves vascularization in a murine critical hindlimb ischemia model compared to LPA or ASC alone, thus exhibiting the translational potential of this method. Furthermore, these results are achieved using an inexpensive lipid molecule, which is orders-of-magnitude less costly than recombinant growth factors that are under investigation for similar use. Our results demonstrate a novel strategy for enhancing cell-based strategies for therapeutic angiogenesis, with significant applications for treating ischemic diseases.
Role and Mechanism of Arsenic in Regulating Angiogenesis  [PDF]
Ling-Zhi Liu,Yue Jiang,Richard L. Carpenter,Yi Jing,Stephen C. Peiper,Bing-Hua Jiang
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0020858
Abstract: Arsenic is a wide spread carcinogen associated with several kinds of cancers including skin, lung, bladder, and liver cancers. Lung is one of the major targets of arsenic exposure. Angiogenesis is the pivotal process during carcinogenesis and chronic pulmonary diseases, but the role and mechanism of arsenic in regulating angiogenesis remain to be elucidated. In this study we show that short time exposure of arsenic induces angiogenesis in both human immortalized lung epithelial cells BEAS-2B and adenocarcinoma cells A549. To study the molecular mechanism of arsenic-inducing angiogenesis, we find that arsenic induces reactive oxygen species (ROS) generation, which activates AKT and ERK1/2 signaling pathways and increases the expression of hypoxia-inducible factor 1 (HIF-1) and vascular endothelial growth factor (VEGF). Inhibition of ROS production suppresses angiogenesis by decreasing AKT and ERK activation and HIF-1 expression. Inhibition of ROS, AKT and ERK1/2 signaling pathways is sufficient to attenuate arsenic-inducing angiogenesis. HIF-1 and VEGF are downstream effectors of AKT and ERK1/2 that are required for arsenic-inducing angiogenesis. These results shed light on the mechanism of arsenic in regulating angiogenesis, and are helpful to develop mechanism-based intervention to prevent arsenic-induced carcinogenesis and angiogenesis in the future.
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