Transplanted human umbilical cord blood mononuclear cells improve left ventricular function through angiogenesis in myocardial infarction

Background Human umbilical cord blood contains an abundance of immature stem/progenitor cells, which may participate in the repair of hearts that have been damaged by myocardial infarction （MI）. This study aimed to evaluate the effects of human umbilical cord blood mononuclear cells （hUCBC） transplantation on cardiac function and left ventricular remodeling in rat model of MI. Methods Forty-five male Wistar rats were randomized into three groups： MI or control group （n=15）, MI plus cell transplantation （n=15）, and sham group （n=15）. Acute myocardial infarction （AMI） was established by ligating the left anterior descending artery, thereafter, hUCBC were implanted into the marginal area of infarcted myocardium. In MI/control group, DMEM was injected instead of hUCBC following the same protocol. Left ventricular function assessment was carded out by echocardiography and invasive hemodynamic measurements one month post MI. All rats were sacrificed for histological and immunochemical examinations.Results The transplanted hUCBC survived and engaged in the process of myocardial repair in the host heart. Echocardiography demonstrated that left ventricular function improved significantly in the rats that underwent cell transplantation. Hemodynamic studies found a significantly decreased left ventricular end-diastolic pressure （LVEDP） [（21.08±8.10） mmHg vs （30.82±9.59） mmHg, P〈0.05], increase in ＋dp/dtmax [（4.29± 1.27） mmHg/ms vs （3.24±0.75） mmHg/ms, P〈0.05）, and increase in -dp/dtmax [（3.71 ±0.79） mmHg/ms vs （3.00± 0.49） mmHg/ms, P〈0.05] among MI group with hUCBC transplantation when compared with MI/control group. Masson＇s trichrome staining revealed that the collagen density in the left ventricle was significantly lower in rats of transplantation group than that in the MI control groups [（6.33±2.69）% vs （11.10±3.75）%, P〈 0.01]. Based on immunostaining of α-actin, the numbers of microvessels were significantly （P〈0.01） increased at the boundary of infarction site. Similarly higher mRNA expression of vascular endothelial growth factor （VEGF） 164 and VEGF188 were found at 7- and 28-day post cell transplantation in MI group with hUCBC transplantation when compared with MI/control group. Conclusions Transplanted hUCBC can survive in host myocardium without immunorejection, significantly improve left ventricular remodeling after AMI and promote a higher level of angiogenesis in the infarct zones. All these factors beneficially affect cardiac repair in the setting of MI. Therefore human umbilical cord blood may be potential source for cell-based therapy for AMI.

Human umbilical cord-derived endothelial progenitor cells promote growth cytokines-mediated neorevascularization in rat myocardial infarction

Background Cell-based vascular therapies of endothelial progenitor cells （EPCs） mediated neovascularization is still a novel but promising approach for the treatment of ischemic disease. The present study was designed to investigate the therapeutic potentials of human umbilical cord blood-derived EPCs （hUCB-EPCs） in rat with acute myocardial infarction. Methods Human umbilical cord blood （hUCB） mononuclear cells were isolated using density gradient centrifugation from the fresh human umbilical cord in healthy delivery woman, and cultured in M199 medium for 7 days. The EPCs were identified by double-positive staining with 1,1＇-dioctadecyl-3,3,3＇,3＇-tetramethylindocarbocyanine percholorate-labeled acetylated low-density lipoprotein （DiI-Ac-LDL） and fluorescein isothiocyanate-conjugated Ulex europaeus lectin （FITC-UEA-I）. The rat acute myocardial infarction model was established by the ligation of the left anterior descending artery. The hUCB-EPCs were intramyocardially injected into the peri-infarct area. Four weeks later, left ventricular function was assessed by a pressure-volume catheter. The average capillary density （CAD） was evaluated by anti-VIII immunohistochemistry staining to reflect the development of neovascularization at the peri-infarct area. The graft cells were identified by double immunofluorescence staining with human nuclear antigen （HNA） and CD31 antibody, representing human origin of EPCs and vascular endothelium, respectively. Expressions of cytokines, proliferating cell nuclear angigen （PCNA）, platelet endothelial cell adhesion molecule （PECAM） and vascular endothelial growth factor （VEGF） were detected to investigate the underlying mechanisms of cell differentiation and revascularization. Results The donor EPCs were detectable and integrated into the host myocardium as confirmed by double-positive immunofluorescence staining with HNA and CD31. And the anti-VIII staining demonstrated a higher degree of microvessel formation in EPCs transplanted rats, associated with a significant improvement of global heart function in terms of the increase of left ventricular end-systolic pressure （LVESP）, ＋dp/dtmax and -dp/dtmax as well as the decrease of LVEDP in rats with EPCs therapy comparing to the control rats （P〈0.05）. Moreover, the expression of the rat PCNA mRNA and PECAM were both enhanced in the EPCs group compared with that of the control group. Conclusions The human umbilical cord blood-derived EPCs could incorporate into new-born capillaries in rat myocardium, induce revascularization and improve the proliferation activity in the peri-infarct area, resulting in the improvement of global heart function. This may indicate a promising stem cell resource in cell-based therapy for ischaemic diseases.

Berberine-Promoted CXCR4 Expression Accelerates Endothelial Repair Capacity of Early Endothelial Progenitor Cells in Persons with Prehypertension

Objective： To evaluate whether the berberine treatment can improve endothelial repair capacity of early endothelial progenitor cells （EPCs） from prehypertensive subjects through increasing CXC chemokine receptor 4 （CXCR4） signaling. Methods： EPCs were isolated from prehypertensive and healthy subjects and cultured. In vivo reendothelialization capacity of EPCs from prehypertensive patients with or without in vitro berberine treatment was examined in a nude mouse model of carotid artery injury. The protein expressions of CXCR4/Janus kinase-2 （JAK-2） signaling of in vitro EPCs were detected by Western blot analysis. Results： CXCR4 signaling and alteration in migration and adhesion functions of EPCs were evaluated. Basal CXCR4 expression was significantly reduced in EPCs from prehypertensive patients compared with normal subjects （P〈0.01）. Also, the phosphorylation of JAK-2 of EPCs, a CXCR4 downstream signaling, was significantly decreased （P〈0.01）. Berberine promoted CXCR4/JAK-2 signaling expression of in vitro EPCs （P〈0.01）. Transplantation of EPCs pretreated with berberine markedly accelerated in vivo reendothelialization （P〈0.01）. The increased in vitro function and in vivo reendothelialization capacity of EPCs were inhibited by CXCR4 neutralizing antibody or pretreatment with JAK-2 inhibitor AG490, respectively （P〈0.01）. Conclusion： Berberine- modified EPCs via up-regulation of CXCR4 signaling contributes to enhanced endothelial repair capacity in prehypertension, indicating that berberine may be used as a novel potential primary prevention means against prehypertension-related atherosclerotic cardiovascular disease.

Transplantation of human umbilical cord-derived endothelial progenitor cells promotes re-endothelialization of the injured carotid artery after balloon injury in New Zealand white rabbits

Background Cell transplantation has great potential for promoting endothelial repair and reducing the complications of percutaneous coronary intervention （PCI）. The aim of this study was to investigate the effect of transplantation of human umbilical cord blood endothelial progenitor ceils （EPCs） on injured arteries. Methods Umbilical cord blood mononuclear cells were obtained from post-partum lying-in women, and EPCs were isolated, cultured, expanded and identified by immunofiuorescence. The carotid arterial endothelium of New Zealand white rabbits was injured by dilatation with a 3F balloon, and the EPCs were injected into the lumen of the injured artery in the transplanted group （n=16）, while an equal volume of phosphated buffered saline （PBS） was injected into the control group after balloon injury （n=16）. The animals were sacrificed after either 2 or 4 weeks, and the grafted cells were identified by double immunofluorescence staining with human nuclear antigen （HNA） and CD31 antibodies. Arterial cross sections were analyzed by pathology, immunohistochemisty and morphometry to evaluate the reparative effects of EPCs. Proliferating cell nuclear antigen （PCNA） and transforming growth factor （TGF）-131 mRNA expression were detected by reverse transcription-polymerase chain reaction （RT-PCR）. Results Fluorescence-labeled EPCs were found in the neointima. The neointimal area and the neointimal/medial area ratio were significantly lower in the transplanted group than in the control group （P 〈0.05）. von Willebrand factor （vWF） immunohistostaining showed more VWF-positive cells in the transplanted animals than in the controls （8.75±2.92 vs. 4.50±1.77, P 〈0.05）. Compared with the control group, the transplanted group had lower expression of PCNA mRNA （0.67±0.11 vs. 1.25±0.40, P 〈0.01 ）and higher expression of TGF-β1 mRNA （1.10±0.21 vs. 0.82±0.07, P 〈0.05）. Conclusions EPCs derived from human umbilical cord blood were successfully transplanted into injured vessels. The transplanted EPCs inhibited neointimal hyperplasia and promoted vascular re-endothelialization.

Erectile dysfunction is associated with subclinical carotid vascular disease in young men lacking widely-known risk factors

This study aimed to gain insight into the underlying pathogenesis of erectile dysfunction in young men under the age of 40 years without widely-known risk factors. Compared with normal controls, patients with erectile dysfunction had increased carotid intima- media thickness, fasting levels of blood glucose and insulin, and homeostatic model assessment index, as well as lower flow-mediated vasodilation and testosterone levels （P 〈 0.05）, though all of these values were within their respective normal range. Multivariate logistic regression analysis identified carotid intima-media thickness, flow-mediated vasodilation, insulin level, and homeostatic model assessment index as significant predictors of erectile dysfunction. Young men with flow-mediated vasodilation 〈10.65% were 11.645 times more likely to have erectile dysfunction, young men with carotid intima-media thickness 〉0.623 mm had a 4.16-fold, and young men with homeostatic model assessment index 〉1.614 had a 5.993-fold greater risk of having erectile dysfunction. In conclusions, in young men with normal results from general clinical screening, an increased carotid intima-media thickness and homeostatic model assessment index and reduced flow-mediated vasodilation were associated with a higher incidence of erectile dysfunction. Erectile dysfunction may appear before the detection of traditional cardiovascular risk factors and may be the earliest clinical sign of subclinical cardiovascular disease.

NAD^(+) exhaustion by CD38 upregulation contributes to blood pressuree elevation and vascular damage in hypertension

Hypertension is characterized by endothelial dysfunction and arterial stiffness,which contribute to the pathogenesis of atherosclerotic cardiovascular diseases.Nicotinamide adenine dinucleotide(NAD^(+))is an indispensable cofactor in all living cells that is involved in fundamental biological processes.However,in hypertensive patients,alterations in NAD^(+)levels and their relation with blood pressure(BP)elevation and vascular damage have not yet been studied.

An engineered lamellar bone mimicking full-scale hierarchical architecture for bone regeneration

Lamellar bone,compactly and ingeniously organized in the hierarchical pattern with 6 ordered scales,is the structural motif of mature bone.Each hierarchical scale exerts an essential role in determining physiological behavior and osteogenic bioactivity of bone.Engineering lamellar bone with full-scale hierarchy remains a longstanding challenge.Herein,using bioskiving and mineralization,we attempt to engineer compact constructs resembling full-scale hierarchy of lamellar bone.Through systematically investigating the effect of mineralization on physicochemical properties and bioactivities of multi-sheeted collagen matrix fabricated by bioskiving,the hierarchical mimicry and hierarchy-property relationship are elucidated.With prolongation of mineralization,hierarchical mimicry and osteogenic bioactivity of constructs are performed in a bidirectional manner,i.e.first rising and then descending,which is supposed to be related with transformation of mineralization mechanism from nonclassical to classical crystallization.Construct mineralized 9 days can accurately mimic each hierarchical scale and efficiently promote osteogenesis.Bioinformatic analysis further reveals that this construct potently activates integrinα5-PI3K/AKT signaling pathway through mechanical and biophysical cues,and thereby repairing critical-sized bone defect.The present study provides a bioinspired strategy for completely resembling complex hierarchy of compact mineralized tissue,and offers a critical research model for in-depth studying the structure-function relationship of bone.

Enhanced External Counterpulsation Treatment Inhibitting Advanced Atherosclerotic Plaque Progression by Augmenting the Plaque Wall Stress： An in vivo FSI Study Based on Animal Experiment

Enhance extemal counterpulsation （ECP） procedure has exhbited itself to be an effective therapy for the m anagem entof ischem ic card iovascu lar diseases, However, considering that EECP significantly increases the acute diastolic pressure, whether it will intervene in the chronic progression of advanced plaque causing great concern in clilical applkation, but yet rein ains elusive presently. In the current paper, a flu id-structure interface （FSI） num erical model of artery with p iaque corn ponent w as developed based on in vivo hem odynam ic m easurem entperfotm ed h a porcine model, to caku late the m echanical stresses of the plaque before and during EECP, and h lum to assess the potential effects of long-term EECP treatm ent on plaque progression. The resu Its show that E E C P augm ented the wall shear stress （WSS） and plaque w all stress （PWS） over the card lac cycles, aswell as the spacial oscillatory of W SS （WSSG ）. Durhg EECP treatm ent, the PW S level respectively raised 6.82% and 6.07% in two simulation cases. The currentpilot study suggests that E E C P treatm entre ay p lay a positive effect on inh biting the conthued plaque progression by hcreashg the PW S level over the card iac cycles. Meanwhile, the plaque morphology should be taken into consideration while m aking patient- specific plan for Ion g- term E E C P treatment in clinic.

Enhanced External Counterpulsation Inducing Arterial Hemodynamic Variations and Its Chronic Effect on Endothelial Function

To make clear the precise hemodynamic mechanism underlying the anti-atherogenesis benefit of enhanced external couterpulsation(EECP) treatment, and to investigate the proper role of some important hemodynamic factors during the atherosclerotic progress, a comprehensive study combining long-term animal experiment and numerical solving was conducted in this paper. An experimentally induced hypercholesterolemic porcine model was developed and the chronic EECP intervention was subjected. Basic hemodynamic measurement was performed in vivo, as well as the arterial endothelial samples were extracted for physiological examination. Meanwhile, a numerical model was introduced to solve the complex hemodynamic factors such as WSS and OSI. The results show that EECP treatment resulted in significant increase of the instant levels of arterial WSS, blood pressure, and OSI. During EECP treatment, the instant OSI level of the common carotid arteries over cardiac cycles raised to a mean value of 8.58 ×10-2±2.13 ×10-2. Meanwhile, the chronic intervention of EECP treatment significantly reduced the atherosclerotic lesions in abdominal aortas and the endothelial cellular adherence. The present study suggests that the unique blood flow pattern induced by EECP treatment and the augmentation of WSS level in cardiac cycles may be the most important hemodynamic mechanism that contribute to its anti-atherogenesis effect. And as one of the indices that cause great concern in current hemodynamic study, OSI may not play a key role during the initiation of atherosclerosis.