Simvastatin combined with bone marrow stromal cells treatment activatesastrocytes to ameliorate neurological function after ischemic stroke in rats

Zhao, Yonghua; Zhang, Qian; Chen, Zhenwei; Liu, Naiwei; Ke, Chien-Chih; Xu, Youhua; Wu, Weikang

doi:10.3906/biy-1507-141

Cited by 4 publications

(3 citation statements)

References 42 publications

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“…Another aspect to take into account in term of the quality of wound angiogenesis is that on day 7 after wounding, increase in the level of vascular endothelial growth factors (VEGF) was observed in all treatment groups. VEGF is one of the key bioactive molecules implicated in the wound healing process that has been reported to possibly enhance endothelial cell proliferation and neovascularization, which is a critical stage in tissue regeneration by MSCs [47–48]. In the diabetic mouse model used in this study, the combination of simvastatin and MSCs was shown to increase the expression of SDF-1, which was demonstrated to have strong correlation with the Akt levels.…”

Section: Discussionmentioning

confidence: 78%

“…Our results show that in the 14-day combined MSCs and simvastatin treatment group, the levels of SDF-1 expression increased almost 26% compared to that of the 14-day MSCs group, and tissue pAkt levels were increased compared with those in the DM group. The study performed by Zhao Y et al, 2016 [48] in ischemic stroke rat model confirmed a similar benefit effect of simvastatin and MSCs, and their results explored in greater details the increased expression of SDF-1 and VEGF associated with the activation of Akt/mTOR signaling pathway [48]. Phosphatidylinositol 3-kinases (PI3Ks) and their downstream target AKT are considered crucial signal transduction enzymes that have been investigated extensively for their roles in cell proliferation, cell transformation, paracrine function and angiogenesis [49–51].…”

Section: Discussionmentioning

confidence: 99%

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A low dose of simvastatin enhanced the therapeutic efficacy of mesenchymal stem cell (MSC) transplantation in skin wound healing in diabetic mice associated with increases in pAkt, SDF-1, and angiogenesis

Sukpat

Israsena

Wongphoom

et al. 2019

Preprint

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21Purpose 22 We aimed to determine the possible mechanisms of underlying the effects of low 23 dose simvastatin on enhancing the therapeutic efficacy of MSC transplantation in 24 diabetic wound healing. 25 Methods 26 Balb/c nude mice were divided into five groups:-control mice (CON), diabetic 27 mice (DM), diabetic mice pretreated with low-dose simvastatin (DM+SIM), 28 diabetic mice implanted with MSCs (DM+MSCs) and diabetic mice pretreated 29 with low-dose simvastatin and implanted with MSCs (DM+MSCs+SIM). Seven 30 days before wound induction, low dose simvastatin was orally administered to 31 the DM+SIM and DM+MSCs+SIM groups. Eleven weeks after the induction of 32diabetes, all mice were given bilateral full-thickness excisional back skin wounds. 33 Results 34By comparing the DM+MSCs+SIM and DM+MSCs groups, the results showed 35 that on day 14; the wound closure (%WC) and capillary vascularity (%CV) in the 36 DM+MSCs+SIM group were significantly increased compared to those in the 37 DM+MSCs group. In addition, by using immunohistochemical techniques, it was 38 also shown that the expression of SDF-1, a chemotactic factor regulating the 39 migration of stem cells, in the DM+SIM+MSCs group was increased compared 40 with that in the DM+MSCs group. Furthermore, using phospho-Akt (S473) Pan 41 4 Specific DuoSet IC ELISA (R&D Systems, USA) kits, the increased tissue Akt 42 levels were found in the DM+SIM+MSCs group but not in the other groups.43 Conclusions 44 Our study suggests that a low dose of simvastatin enhanced the therapeutic 45 efficacy of MSCs in diabetic wound healing, and this effect was associated with 46 increases in pAkt levels, SDF-1 levels, and angiogenesis, and improved wound 47 closure. 48 Introduction 49 50 In diabetes, hyperglycemia-induced oxidative stress resulting from ROS 51 production has been observed in several cell types [1]. Studies have shown that 52 hyperglycemia-induced oxidative stress could lead to impaired wound healing via 53 inducing a prolonged chronic inflammatory state. This prolonged inflammatory 54 phase could in turn disturb collagen metabolism, resulting in poor blood supply, 55 the reduced production of growth factors, and reduced angiogenesis, all of which 56 contribute to delayed diabetic wound healing [2-4]. Nearby 2% to 3% of DM 57 patients suffer from active foot ulcers [5-6]. Diabetic foot ulcers not only affect 58 the physical health of patients, but they lead to 85% of major lower limb 59 amputations in patients with DM. Furthermore, patients and society must bear a 60 substantial financial burden resulting from the treatment and care of diabetic foot 61 ulcers [7].62 5 Currently, novel therapeutic interventions involving cellular therapies and 63 tissue engineering approaches are being rapidly developed. In the context of 64 diabetes research, accumulating evidence has indicated that mesenchymal stem 65 cells (MSCs) could improve wound healing [8-10] . However, it has been 66 suggested that the consequences of hyperglycemia-induced oxidative stress could 67 ca...

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Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

A low dose of simvastatin enhanced the therapeutic efficacy of mesenchymal stem cell (MSC) transplantation in skin wound healing in diabetic mice associated with increases in pAkt, SDF-1, and angiogenesis

Sukpat

Israsena

Wongphoom

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…Combination treatment of BM-MSCs and simvastatin facilitated the expression of VEGF, BDNF, stromal cell-derived factor-1α (SDF-1α), and GDNF in astrocytes during the treatment of stroke. Also, simvastatin was shown to enhance the differentiation into endothelial cells (ECs) and migration of BM-MSCs 13–15 . Our previous study also demonstrated that sodium ferulate (SF; an active component derived from Radix Angelica Sinensis) promoted the migration of BM-MSCs toward the ischemic boundary zone (IBZ) via upregulation of SDF-1α/chemokine (CXC motif) receptor-4 axis and the differentiation into astrocytes via activating the BMP 2/4 signaling pathway on day 3 poststroke 16,17 .…”

Section: Introductionmentioning

confidence: 99%

Bone Marrow Stromal Cells Combined with Sodium Ferulate andn-Butylidenephthalide Promote the Effect of Therapeutic Angiogenesis via Advancing Astrocyte-Derived Trophic Factors after Ischemic Stroke

et al. 2017

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Being a potential candidate for stroke treatment, bone marrow-derived mesenchymal stem/stromal cells (BM-MSCs) have been demonstrated to be able to enhance angiogenesis and proliferation of reactive astrocytes, which subsequently leads to the amelioration of neurological injury. Increasing evidence further indicates that combining BM-MSCs with certain agents, such as simvastatin, may improve therapeutic effects. Sodium ferulate (SF) and n-butylidenephthalide (BP), two main components of Radix Angelica Sinensis, are proven to be important regulators of stem cells in cell migration, differentiation, and pluripotency maintenance. This study aimed to investigate whether combining BM-MSCs with SF and BP had better therapeutic effect in the treatment of stroke, and the underlying molecular basis for the therapeutic effects was also investigated. The results showed that combination treatment notably reduced neurological injury after stroke and increased the expression of astrocyte-derived vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF), and von Willebrand factor-positive vascular density in the ischemic boundary zone as evaluated by immuno fluorescence staining. After treatment with BM-MSCs plus SF and BP, astrocytes showed increased expression of VEGF and BDNF by upregulating protein kinase B/mammalian target of rapamycin (AKT/mTOR) expression in an oxygen-and glucose-deprived (OGD) environment. Human umbilical vein endothelial cells (HUVECs) incubated with the conditioned medium (CM) derived from OGD astrocytes treated with BM-MSCs plus SF and BP showed significantly increased migration and tube formation compared with those incubated with the CM derived from OGD astrocytes treated with BM-MSCs alone. These results demonstrate that combination treatment enhances the expression of astrocyte-derived VEGF and BDNF, which contribute to angiogenesis after cerebral ischemia, and the underlying mechanism is associated with activation of the astrocytic AKT/mTOR signaling pathway. Our study provides a potential therapeutic approach for ischemic stroke.

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Combination Treatment of Mesenchymal Stem Cells (MSCs) and Angelica sinensis’ Active Ingredients for Ischemic Stroke

Zhang

Zhao

2017

Cellular and Molecular Approaches to Regeneration and Repair

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Simvastatin combined with bone marrow stromal cells treatment activatesastrocytes to ameliorate neurological function after ischemic stroke in rats

Cited by 4 publications

References 42 publications

A low dose of simvastatin enhanced the therapeutic efficacy of mesenchymal stem cell (MSC) transplantation in skin wound healing in diabetic mice associated with increases in pAkt, SDF-1, and angiogenesis

A low dose of simvastatin enhanced the therapeutic efficacy of mesenchymal stem cell (MSC) transplantation in skin wound healing in diabetic mice associated with increases in pAkt, SDF-1, and angiogenesis

Bone Marrow Stromal Cells Combined with Sodium Ferulate andn-Butylidenephthalide Promote the Effect of Therapeutic Angiogenesis via Advancing Astrocyte-Derived Trophic Factors after Ischemic Stroke

Combination Treatment of Mesenchymal Stem Cells (MSCs) and Angelica sinensis’ Active Ingredients for Ischemic Stroke

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