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High-density lipoprotein-mimicking nanodiscs carrying peptide for enhanced therapeutic angiogenesis in diabetic hindlimb ischemia.

ABSTRACT: Therapeutic strategies using endogenous stem cell mobilizer can provide effective cell-free therapy for addressing various ischemic diseases. In particular, substance P (SP) exhibited therapeutic regeneration by facilitating mobilization of endogenous stem cells from bone marrow to the injured sites. However, its therapeutic effect has been limited due to short half-life and rapid degradation of administered SP peptides in vivo. Here we sought to develop high-density lipoprotein (HDL)-mimicking nanodiscs conjugated with SP (HDL-SP) in order to increase the in vivo half-life, bone marrow targeting, and therapeutic efficacy of SP for the treatment of diabetic peripheral ischemia. Conjugation of SP onto HDL nanodisc led to remarkable ?3215- and ?1060-fold increase in the ex vivo and in vivo half-lives of SP, respectively. Accordingly, HDL-SP nanodiscs improved retention of SP in bone marrow after systemic administration, leading to efficient mobilization of stem cells from bone marrow into blood circulation and reduction of systemic inflammation. Consequently, nanodisc based SP peptide delivery promoted blood vessel formation, blood perfusion recovery and markedly improved limb salvage in diabetic hindlimb ischemia model relative to administration of free SP without nanodisc modification. Therefore, HDL-SP nanodisc can provide a novel strategy for the treatment of diabetic ischemia and HDL nanodisc modification could be potentially useful for the extension of plasma circulation of other labile peptides.

SUBMITTER: Park HJ

PROVIDER: S-EPMC5817004 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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High-density lipoprotein-mimicking nanodiscs carrying peptide for enhanced therapeutic angiogenesis in diabetic hindlimb ischemia.

Park Hyun-Ji HJ Kuai Rui R Jeon Eun Je EJ Seo Yoojin Y Jung Youngmee Y Moon James J JJ Schwendeman Anna A Cho Seung-Woo SW

Biomaterials 20180119

Therapeutic strategies using endogenous stem cell mobilizer can provide effective cell-free therapy for addressing various ischemic diseases. In particular, substance P (SP) exhibited therapeutic regeneration by facilitating mobilization of endogenous stem cells from bone marrow to the injured sites. However, its therapeutic effect has been limited due to short half-life and rapid degradation of administered SP peptides in vivo. Here we sought to develop high-density lipoprotein (HDL)-mimicking ...[more]

PMID: 29421564

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Project description:BACKGROUND:Mesenchymal stem cells (MSCs) can improve limb perfusion and increase vessel density in a murine model of hindlimb ischemia. But low engraftment rate of those cells limited their therapeutic effect. Endothelial cells (ECs) play an important role in neovascularization. And MSCs can differentiate into ECs in vitro. The aim of this study is to investigate if EC differentiation of MSCs in vitro before transplantation is effective in improving therapeutic outcomes in the treatment of ischemic disease in a murine ischemia animal model. METHODS:MSCs were isolated from the bone marrow of EGFP-transgenic mice by density gradient centrifugation. The identity of the MSCs was determined by their cluster of differentiation (CD) marker profile by flow cytometry. Inducing medium containing a few cytokines was applied to induce the MSCs to differentiate into ECs. Endothelial differentiation was quantitatively evaluated using flow cytometry, quantitative real-time PCR (qRT-PCR), immunofluorescence, Matrigel tube formation assay, and Dil-labeled acetylated low-density lipoprotein uptake assay. Mouse hindlimb ischemia model was made by excision of the femoral artery. Uninduced EGFP+ MSCs, induced EGFP+ MSCs, and PBS were intramuscularly injected into the gastrocnemius following ischemia no later than 24?h after operation. Restoration of blood flow and muscle function was evaluated by laser Doppler perfusion imaging. Immunofluorescence was conducted to evaluate the engraftment of transplanted MSCs. Histological analysis was performed to evaluate blood vessel formation. RESULTS:Induced EGFP+ MSCs expressed endothelial markers and exhibited tube formation capacity. Mice in the induced EGFP+ MSCs group had a better blood perfusion recovery, enhanced vessel densities, higher engraftment, and improved function of the ischemic limb than those in the uninduced EGFP+ MSCs or PBS groups. CONCLUSIONS:This study reveals that after short-term pre-treatment in the EC-inducing medium, induced MSCs acquire stronger vessel formation capability and enhanced angiogenic therapeutic effect in the murine hindlimb ischemia model.

Project description:Cholesterol is an essential component of eukaryotic cellular membranes that regulates the order and phase behaviour of dynamic lipid bilayers. Although cholesterol performs many vital physiological roles, hypercholesterolaemia and the accumulation of cholesterol in atherosclerotic plaques can increase the risk of coronary heart disease morbidity. The risk is mitigated by the transportation of cholesterol from peripheral tissue to the liver by high-density lipoprotein (HDL), 6-20 nm-diameter particles of lipid bilayers constrained by an annular belt of the protein apolipoprotein A-I (apoA-I). Information on the dynamics and orientation of cholesterol in HDL is pertinent to the essential role of HDL in cholesterol cycling. This work investigates whether the molecular orientation of cholesterol in HDL differs from that in the unconstrained lipid bilayers of multilamellar vesicles (MLVs). Solid-state NMR (ssNMR) measurements of dynamically-averaged 13C-13C and 13C-1H dipolar couplings were used to determine the average orientation of triple 13C-labelled cholesterol in palmitoyloleoylphosphatidylcholine (POPC) lipid bilayers in reconstituted HDL (rHDL) nanodiscs and in MLVs. Individual 13C-13C dipolar couplings were measured from [2,3,4-13C3]cholesterol in a one-dimensional NMR experiment, by using a novel application of a method to excite double quantum coherence at rotational resonance. The measured dipolar couplings were compared with average values calculated from orientational distributions of cholesterol generated using a Gaussian probability density function. The data were consistent with small differences in the average orientation of cholesterol in rHDL and MLVs, which may reflect the effects of the constrained and unconstrained lipid bilayers in the two environments. The calculated distributions of cholesterol in rHDL and MLVs that were consistent with the NMR data also agreed well with orientational distributions extracted from previous molecular dynamics simulations of HDL nanodiscs and planar POPC bilayers.

Dataset Information

High-density lipoprotein-mimicking nanodiscs carrying peptide for enhanced therapeutic angiogenesis in diabetic hindlimb ischemia.

Publications

High-density lipoprotein-mimicking nanodiscs carrying peptide for enhanced therapeutic angiogenesis in diabetic hindlimb ischemia.

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