Netrin-1 promotes mesenchymal stem cell revascularization of limb ischaemia

Ke, Xianjin; Liu, Chenxiao; Wang, Ying; Ma, Jianhua; Mao, Xiao‐Ming; Li, Qian

doi:10.1177/1479164115611594

Cited by 16 publications

(16 citation statements)

References 45 publications

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“…The Netrin protein family, which acts in the nervous system in axonal guidance [ 3 ], has later been found to be implicated in angiogenesis [ 37 ], cell survival [ 38 ], and morphogenesis [ 39 ]. Moreover, recent studies suggest that Netrin-1 may become a therapeutic target in the treatment of various pathologies, either as a stimulant or inhibitor of angiogenesis such as in diabetes or cancer, respectively, even protecting the heart against ischemia-reperfusion injury [ 2 , 40 , 41 ]. However, the underlying cellular mechanisms and receptor specificity characteristics involved in angiogenesis still require further studies.…”

Section: Discussionmentioning

confidence: 99%

Netrin-1 acts as a non-canonical angiogenic factor produced by human Wharton’s jelly mesenchymal stem cells (WJ-MSC)

et al. 2017

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BackgroundAngiogenesis, the process in which new blood vessels are formed from preexisting ones, is highly dependent on the presence of classical angiogenic factors. Recent evidence suggests that axonal guidance proteins and their receptors can also act as angiogenic regulators. Netrin, a family of laminin-like proteins, specifically Netrin-1 and 4, act via DCC/Neogenin-1 and UNC5 class of receptors to promote or inhibit angiogenesis, depending on the physiological context.MethodsMesenchymal stem cells secrete a broad set of classical angiogenic factors. However, little is known about the expression of non-canonical angiogenic factors such as Netrin-1. The aim was to characterize the possible secretion of Netrin ligands by Wharton’s jelly-derived mesenchymal stem cells (WJ-MSC). We evaluated if Netrin-1 presence in the conditioned media from these cells was capable of inducing angiogenesis both in vitro and in vivo, using human umbilical vein endothelial cells (HUVEC) and chicken chorioallantoic membrane (CAM), respectively. In addition, we investigated if the RhoA/ROCK pathway is responsible for the integration of Netrin signaling to control vessel formation.ResultsThe paracrine angiogenic effect of the WJ-MSC-conditioned media is mediated at least in part by Netrin-1 given that pharmacological blockage of Netrin-1 in WJ-MSC resulted in diminished angiogenesis on HUVEC. When HUVEC were stimulated with exogenous Netrin-1 assayed at physiological concentrations (10–200 ng/mL), endothelial vascular migration occurred in a concentration-dependent manner. In line with our determination of Netrin-1 present in WJ-MSC-conditioned media we were able to obtain endothelial tubule formation even in the pg/mL range. Through CAM assays we validated that WJ-MSC-secreted Netrin-1 promotes an increased angiogenesis in vivo. Netrin-1, secreted by WJ-MSC, might mediate its angiogenic effect through specific cell surface receptors on the endothelium, such as UNC5b and/or integrin α6β1, expressed in HUVEC. However, the angiogenic response of Netrin-1 seems not to be mediated through the RhoA/ROCK pathway.ConclusionsThus, here we show that stromal production of Netrin-1 is a critical component of the vascular regulatory machinery. This signaling event may have deep implications in the modulation of several processes related to a number of diseases where angiogenesis plays a key role in vascular homeostasis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-017-0494-5) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Netrin-1 acts as a non-canonical angiogenic factor produced by human Wharton’s jelly mesenchymal stem cells (WJ-MSC)

et al. 2017

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“…Ke et al studied the positive effect of Netrin-1 on BMSCs in proliferation, migration, tube formation, and promotion in revascularization of rat limb ischemia. The study measured the plasma and tissue levels of VEGF and confirmed the upregulation of VEGF as the leading cause of the positive effect of Netrin-1-carrying BMSCs in the revascularization of rat limb ischemia [ 33 ].…”

Section: Discussionmentioning

confidence: 98%

Netrin-1 improves adipose-derived stem cell proliferation, migration, and treatment effect in type 2 diabetic mice with sciatic denervation

et al. 2018

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BackgroundDiabetic peripheral neurovascular diseases (DPNVs) are complex, lacking effective treatment. Autologous/allogeneic transplantation of adipose-derived stem cells (ADSCs) is a promising strategy for DPNVs. Nonetheless, the transplanted ADSCs demonstrate unsatisfying viability, migration, adhesion, and differentiation in vivo, which reduce the treatment efficiency. Netrin-1 secreted as an axon guidance molecule and served as an angiogenic factor, demonstrating its ability in enhancing cell proliferation, migration, adhesion, and neovascularization.MethodsADSCs acquired from adipose tissue were modified by Netrin-1 gene (NTN-1) using the adenovirus method (N-ADSCs) and proliferation, migration, adhesion, and apoptosis examined under high-glucose condition. The sciatic denervated mice (db/db) with type 2 diabetes mellitus (T2DM) were transplanted with N-ADSCs and treatment efficiency assessed based on the laser Doppler perfusion index, immunofluorescence, and histopathological assay. Also, the molecular mechanisms underlying Netrin-1-mediated proliferation, migration, adhesion, differentiation, proangiogenic capacity, and apoptosis of ADSCs were explored.ResultsN-ADSCs improved the proliferation, migration, and adhesion and inhibited the apoptosis of ADSCs in vitro in the condition of high glucose. The N-ADSCs group demonstrated an elevated laser Doppler perfusion index in the ADSCs and control groups. N-ADSCs analyzed by immunofluorescence and histopathological staining demonstrated the distribution of the cells in the injected limb muscles, indicating chronic ischemia; capillaries and endothelium were formed by differentiation of N-ADSCs. The N-ADSCs group showed a significantly high density of the microvessels than the ADSCs group. The upregulation of AKT/PI3K/eNOS/P-38/NF-κB signaling pathways and secretion of multiple growth factors might explain the positive effects of Netrin-1 on ADSCs.ConclusionThe overexpression of Netrin-1 in ADSCs improves proliferation, migration, and treatment effect in type 2 diabetic mice with sciatic denervation, which directs the clinical treatment of patients with DPNVs.

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“…Fan et al demonstrated that netrin-1 induced blood vessel formation in the brain of adult mice and ameliorated cerebrovascular development and remodeling [ 52 ]. Other studies have reported that netrin-1 accelerated revascularization and reperfusion in mice suffering from hindlimb ischemia [ 20 , 53 ], and that netrin-1 augmented the angiogenesis of mesenchymal stem cells and improved the function of the ischemic hindlimb [ 51 ]. Also, netrin-1 is found to be superior to vascular endothelial growth factor in restoring nerve conduction velocity, possibly due to its strong biological effects on both the nervous and vascular system [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

Effects of intra-arterial transplantation of adipose-derived stem cells on the expression of netrin-1 and its receptor DCC in the peri-infarct cortex after experimental stroke

et al. 2017

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BackgroundStem cell transplantation has been documented to promote functional recovery in animal models of stroke; however, the underlying mechanisms are not yet fully understood. As netrin-1 and its receptor deleted in colorectal cancer (DCC) are important regulators in neuronal and vascular activities, the present study attempted to explore whether netrin-1 and DCC are involved in the neuroprotection of stem cell-based therapies in a rat ischemic stroke model.MethodsAdult male Sprague–Dawley rats were subjected to a transient middle cerebral artery occlusion (MCAO) and subsequently received an intra-arterial injection of 2 × 106 PKH26-labeled adipose-derived stem cells (ADSCs) or saline 24 h later. Neurological function was evaluated by behavioral tests before the rats were sacrificed at days 7 and 14 after MCAO. The migration of ADSCs and regeneration of neuronal fibers and blood vessels were determined by immunofluorescence staining. The expression of netrin-1 and DCC was analyzed by Western blot and immunofluorescence staining.ResultsADSC transplantation significantly improved the neurological recovery at days 7 and 14, and noticeably promoted the regeneration of neuronal fibers and blood vessels in the peri-infarct cortex at day 14. PKH26-labeled ADSCs located mainly in the peri-infarct area at days 7 and 14. In ADSC-treated rats, the expression of netrin-1 and DCC significantly increased in the peri-infarct cortex at days 7 and 14. Immunofluorescence staining showed that netrin-1 was mainly expressed by neuronal perikaryal in the peri-infarct cortex, and DCC was mainly expressed by neuronal fibers and was present around the blood vessels in the peri-infarct cortex.ConclusionsThese findings suggest that ADSC transplantation facilitates the regeneration of neuronal fibers and blood vessels in the peri-infarct cortex and improves neurological functions, which may be attributed, at least in part, to the involvement of upregulated netrin-1 and DCC in the remodeling of neuronal and vascular networks in the peri-infarct cortex.

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Netrin-1 promotes mesenchymal stem cell revascularization of limb ischaemia

Cited by 16 publications

References 45 publications

Netrin-1 acts as a non-canonical angiogenic factor produced by human Wharton’s jelly mesenchymal stem cells (WJ-MSC)

Netrin-1 acts as a non-canonical angiogenic factor produced by human Wharton’s jelly mesenchymal stem cells (WJ-MSC)

Netrin-1 improves adipose-derived stem cell proliferation, migration, and treatment effect in type 2 diabetic mice with sciatic denervation

Effects of intra-arterial transplantation of adipose-derived stem cells on the expression of netrin-1 and its receptor DCC in the peri-infarct cortex after experimental stroke

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