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The ambiguous results of multiple CD34+ cell-based therapeutic trials for patients with heart disease have halted the large-scale application of stem/progenitor cell treatment. This study aimed to delineate the biological functions of heterogenous CD34+ cell populations and investigate the net effect of CD34+ cell intervention on cardiac remodeling. We confirmed, by combining single-cell RNA sequencing on human and mouse ischemic hearts and an inducible Cd34 lineage-tracing mouse model, that Cd34+ cells mainly contributed to the commitment of mesenchymal cells, endothelial cells (ECs), and monocytes/macrophages during heart remodeling with distinct pathological functions. The Cd34+-lineage-activated mesenchymal cells were responsible for cardiac fibrosis, while CD34+Sca-1high was an active precursor and intercellular player that facilitated Cd34+-lineage angiogenic EC-induced postinjury vessel development. We found through bone marrow transplantation that bone marrow-derived CD34+ cells only accounted for inflammatory response. We confirmed using a Cd34-CreERT2; R26-DTA mouse model that the depletion of Cd34+ cells could alleviate the severity of ventricular fibrosis after ischemia/reperfusion (I/R) injury with improved cardiac function. This study provided a transcriptional and cellular landscape of CD34+ cells in normal and ischemic hearts and illustrated that the heterogeneous population of Cd34+ cell-derived cells served as crucial contributors to cardiac remodeling and function after the I/R injury, with their capacity to generate diverse cellular lineages.
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Células Endoteliais , Traumatismo por Reperfusão , Camundongos , Animais , Humanos , Remodelação Ventricular , Coração , Antígenos CD34 , IsquemiaRESUMO
RATIONALE: Transplant arteriosclerosis is the major limitation to long-term survival of solid organ transplantation. Although both immune and nonimmune cells have been suggested to contribute to this process, the complex cellular heterogeneity within the grafts, and the underlying mechanisms regulating the disease progression remain largely uncharacterized. OBJECTIVE: We aimed to delineate the cellular heterogeneity within the allografts, and to explore possible mechanisms underlying this process. METHODS AND RESULTS: Here, we reported the transcriptional profiling of 11 868 cells in a mouse model of transplant arteriosclerosis by single-cell RNA sequencing. Unbiased clustering analyses identified 21 cell clusters at different stages of diseases, and focused analysis revealed several previously unknown subpopulations enriched in the allografts. Interestingly, we found evidence of the local formation of tertiary lymphoid tissues and suggested a possible local modulation of alloimmune responses within the grafts. Intercellular communication analyses uncovered a potential role of several ligands and receptors, including Ccl21a and Cxcr3, in regulating lymphatic endothelial cell-induced early chemotaxis and infiltration of immune cells. In vivo mouse experiments confirmed the therapeutic potential of CCL21 and CXCR3 neutralizing antibodies in transplant arteriosclerosis. Combinational use of genetic lineage tracing and single-cell techniques further indicate the infiltration of host-derived c-Kit+ stem cells as heterogeneous populations in the allografts. Finally, we compared the immune response between mouse allograft and atherosclerosis models in single-cell RNA-seq analysis. By analyzing susceptibility genes of disease traits, we also identified several cell clusters expressing genes associated with disease risk. CONCLUSIONS: Our study provides a transcriptional and cellular landscape of transplant arteriosclerosis, which could be fundamental to understanding the initiation and progression of this disease. CCL21/CXCR3 was also identified as important regulators of immune response and may serve as potential therapeutic targets in disease treatment.
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Aorta/transplante , Arteriosclerose/genética , Sobrevivência de Enxerto/genética , Transcriptoma , Tolerância ao Transplante/genética , Animais , Aorta/imunologia , Aorta/metabolismo , Aorta/patologia , Arteriosclerose/imunologia , Arteriosclerose/metabolismo , Arteriosclerose/patologia , Linhagem da Célula/efeitos dos fármacos , Quimiocina CCL21/genética , Quimiocina CCL21/metabolismo , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Imunidade Celular/genética , Imunidade Inata/genética , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , RNA-Seq , Receptores CXCR3/genética , Receptores CXCR3/metabolismo , Análise de Célula Única , Fatores de TempoRESUMO
Cardiovascular diseases are leading causes that threaten people's life. To investigate cells that are involved in disease development and tissue repair, various technologies have been introduced. Among these technologies, lineage tracing is a powerful tool to track the fate of cells in vivo, providing deep insights into cellular behavior and plasticity. In cardiac diseases, newly formed cardiomyocytes and endothelial cells are found from proliferation of local cells, while fibroblasts and macrophages are originated from diverse cell sources. Similarly, in response to vascular injury, various sources of cells including media smooth muscle cells, endothelium, resident progenitors and bone marrow cells are involved in lesion formation and/or vessel regeneration. In summary, current review summarizes the development of lineage tracing techniques and their utilizations in investigating roles of different cell types in cardiovascular diseases.
Assuntos
Biomarcadores , Doenças Cardiovasculares/etiologia , Linhagem da Célula/genética , Rastreamento de Células/métodos , Suscetibilidade a Doenças , Variação Genética , Miócitos Cardíacos/metabolismo , Animais , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/metabolismo , Células Endoteliais/metabolismo , Humanos , Macrófagos/metabolismo , Microscopia/métodos , Miócitos Cardíacos/citologia , Miócitos de Músculo Liso/metabolismo , Organogênese/genética , Células-Tronco/metabolismo , Imagem com Lapso de Tempo/métodosRESUMO
RATIONALE: Transplantation-accelerated arteriosclerosis is one of the major challenges for long-term survival of patients with solid organ transplantation. Although stem/progenitor cells have been implicated to participate in this process, the cells of origin and underlying mechanisms have not been fully defined. OBJECTIVE: The objective of our study was to investigate the role of c-Kit lineage cells in allograft-induced neointima formation and to explore the mechanisms underlying this process. METHODS AND RESULTS: Using an inducible lineage tracing Kit-CreER;Rosa26-tdTomato mouse model, we observed that c-Kit is expressed in multiple cell types in the blood vessels, rather than a specific stem/progenitor cell marker. We performed allograft transplantation between different donor and recipient mice, as well as bone marrow transplantation experiments, demonstrating that recipient c-Kit+ cells repopulate neointimal smooth muscle cells (SMCs) and leukocytes, and contribute to neointima formation in an allograft transplantation model. c-Kit-derived SMCs originate from nonbone marrow tissues, whereas bone marrow-derived c-Kit+ cells mainly generate CD45+ leukocytes. However, the exact identity of c-Kit lineage cells contributing to neointimal SMCs remains unclear. ACK2 (anti-c-Kit antibody), which specifically binds and blocks c-Kit function, ameliorates allograft-induced arteriosclerosis. Stem cell factor and TGF (transforming growth factor)-ß1 levels were significantly increased in blood and neointimal lesions after allograft transplantation, by which stem cell factor facilitated c-Kit+ cell migration through the stem cell factor/c-Kit axis and downstream activation of small GTPases, MEK (mitogen-activated protein kinase kinase)/ERK (extracellular signal-regulated kinase)/MLC (myosin light chain), and JNK (c-Jun N-terminal kinase)/c-Jun signaling pathways, whereas TGF-ß1 induces c-Kit+ cell differentiation into SMCs via HK (hexokinase)-1-dependent metabolic reprogramming and a possible downstream O-GlcNAcylation of myocardin and serum response factor. CONCLUSIONS: Our findings provide evidence that recipient c-Kit lineage cells contribute to vascular remodeling in an allograft transplantation model, in which the stem cell factor/c-Kit axis is responsible for cell migration and HK-1-dependent metabolic reprogramming for SMC differentiation.
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Arteriosclerose/terapia , Movimento Celular , Miócitos de Músculo Liso/fisiologia , Animais , Aorta/fisiologia , Aorta/transplante , Células Cultivadas , Reprogramação Celular , Camundongos , Camundongos Endogâmicos C57BL , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/metabolismo , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Regeneração , Fator de Células-Tronco/metabolismo , Túnica Íntima/citologia , Túnica Íntima/fisiologiaRESUMO
Stem/progenitor cells (SPCs) have been implicated to participate in vascular repair. However, the exact role of SPCs in endothelial repair of large vessels still remains controversial. This study aimed to delineate the cellular heterogeneity and possible functional role of endogenous vascular SPCs in large vessels. Using single-cell RNA-sequencing (scRNA-seq) and genetic lineage tracing mouse models, we uncovered the cellular heterogeneity of SPCs, i.e., c-Kit+ cells in the mouse aorta, and found that endogenous c-Kit+ cells acquire endothelial cell fate in the aorta under both physiological and pathological conditions. While c-Kit+ cells contribute to aortic endothelial turnover in the atheroprone regions during homeostasis, recipient c-Kit+ cells of nonbone marrow source replace both luminal and microvessel endothelial cells in transplant arteriosclerosis. Single-cell pseudotime analysis of scRNA-seq data and in vitro cell experiments suggest that vascular SPCs display endothelial differentiation potential and undergo metabolic reprogramming during cell differentiation, in which AKT/mTOR-dependent glycolysis is critical for endothelial gene expression. These findings demonstrate a critical role for c-Kit lineage cells in aortic endothelial turnover and replacement, and may provide insights into therapeutic strategies for vascular diseases.
Assuntos
Linhagem da Célula/genética , Endotélio Vascular/crescimento & desenvolvimento , Análise de Célula Única/métodos , Células-Tronco/metabolismo , Animais , Aorta/crescimento & desenvolvimento , Aorta/metabolismo , Diferenciação Celular/genética , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Humanos , Camundongos , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-kit/genética , RNA-Seq , Células-Tronco/citologia , Serina-Treonina Quinases TOR/genéticaRESUMO
Objective- Vascular adventitia encompasses progenitors and is getting recognized as the major site of inflammation in early stage of atherosclerosis. However, the cellular atlas of the heterogeneous adventitial cells, the intercellular communication, the cellular response of adventitia to hyperlipidemia, and its contribution to atherosclerosis have been elusive. Approach and Results- Single-cell RNA sequencing was applied to wt (wild type) and ApoE (apolipoprotein E)-deficient aortic adventitia from 12-week-old C57BL/6J mice fed on normal laboratory diet with early stage of atherosclerosis. Unbiased clustering analysis revealed that the landscape of adventitial cells encompassed adventitial mesenchyme cells, immune cells (macrophages, T cells, and B cells), and some types of rare cells, for example, neuron, lymphatic endothelial cells, and innate lymphoid cells. Seurat clustering analysis singled out 6 nonimmune clusters with distinct transcriptomic profiles, in which there predominantly were stem/progenitor cell-like and proinflammatory population (Mesen II). In ApoE-deficient adventitia, resident macrophages were activated and related to increased myeloid cell infiltration in the adventitia. Cell communication analysis further elucidated enhanced interaction between a mesenchyme cluster and inflammatory macrophages in ApoE-deficient adventitia. In vitro transwell assay confirmed the proinflammatory role of SCA1+ (stem cell antigen 1 positive) Mesen II population with increased CCL2 (chemokine [C-C motif] ligand 2) secretion and thus increased capacity to attract immune cells in ApoE-deficient adventitia. Conclusions- Cell atlas defined by single-cell RNA sequencing depicted the heterogeneous cellular landscape of the adventitia and uncovered several types of cell populations. Furthermore, resident cell interaction with immune cells appears crucial at the early stage of atherosclerosis.
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Túnica Adventícia/metabolismo , Apolipoproteínas E/genética , Aterosclerose/genética , Células Endoteliais/metabolismo , Hiperlipidemias/genética , Túnica Adventícia/citologia , Animais , Aterosclerose/fisiopatologia , Células Cultivadas , Análise por Conglomerados , Modelos Animais de Doenças , Células Endoteliais/citologia , Linfócitos/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pericitos/metabolismo , Distribuição Aleatória , Valores de Referência , Análise de Sequência de RNA/métodosRESUMO
BACKGROUND: Acupuncture has been shown for the treatment of allergic rhinitis in previous studies. Nevertheless, relevant evidence was lacked for paediatric patients with allergic rhinitis. We aim to validate the efficacy of acupuncture for allergic rhinitis in children by meta-analysis and trial sequence analysis. METHOD: Comprehensive search of eight databases were conducted until August 27, 2023. Randomized controlled trials comparing acupuncture alone or in combination with drugs versus medication in children with AR were included. The primary outcome was total nasal symptom score (TNSS). The secondary outcomes were serum immunoglobulin E levels, and relapse rates. RESULTS: Thirteen studies involving 1186 participants were included. In results, acupuncture group (AC group) versus medication group (Med group) shows no significant difference in the treatment of AR in children (risk ratio [RR] = 1.10, 95% CI = 0.97 to 1.24, p = 0.13), while TSA suggested the included sample size did not exceed required information size (RIS). Significant differences were found between the AC + Med group versus the Med group (RR = 1.29, 95% CI = 1.17 to 1.42, p < 0.00001), with sufficient sample size. Results in serum IgE after treatment which favored the Med group (MD = 51.94, 95% CI [22.24, 81.65], p = 0.0006). In terms of relapse rate, The AC group had a lower relapse rate than the Med group (RR = 0.40, 95% CI = 0.26-0.63, p < 0.0001). CONCLUSIONS: Acupuncture is an efficacious treatment for allergic rhinitis in children, but this conclusion might be limited by the generally low quality of evidence. TSA suggested additional high-quality trials with larger sample sizes and longer treatment durations were needed.
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Acute gouty arthritis (AGA) is a metabolic disorder in which recurrent pain episodes can severely affect the quality of life of gout sufferers. Electroacupuncture (EA) is a non-pharmacologic therapy. This systematic review aimed to assess the efficacy and safety of electroacupuncture in treating acute gouty arthritis. We searched eight Chinese and English databases from inception to July 30, 2023, and 242 studies were retrieved. Finally, 15 randomized controlled trials (n=1076) were included in a meta-analysis using Review Manager V.5.4.1. meta-analysis results included efficacy rate, visual rating scale (VAS) for pain, serum uric acid level (SUA), immediate analgesic effect, and incidence of adverse events. Electroacupuncture (or combined non-pharmacologic) treatment of AGA was significantly different from treatment with conventional medications (RR = 1.14, 95% confidence interval CI = 1.10 to 1.19, P < 0.00001). The analgesic effect of the electroacupuncture group was superior to that of conventional Western drug treatment (MD = -2.26, 95% CI = -2.71 to -1.81, P < 0.00001). The electroacupuncture group was better at lowering serum uric acid than the conventional western drug group (MD =-31.60, CI -44.24 to -18.96], P < 0.00001). In addition, electroacupuncture combined with Western drugs had better immediate analgesic effects than conventional Western drug treatment (MD = -1.85, CI -2.65 to -1.05, P < 0.00001). Five studies reported adverse events in the electroacupuncture group versus the drug group, including 19 cases of gastrointestinal symptoms and 6 cases of neurological symptoms (RR = 0.20, 95% CI = 0.04 to 0.88, P = 0.03). Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=450037, identifier CRD42023450037.
Assuntos
Artrite Gotosa , Eletroacupuntura , Humanos , Eletroacupuntura/métodos , Artrite Gotosa/terapia , Ácido Úrico , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Dor , AnalgésicosRESUMO
Vein graft failure remains a significant clinical problem. Similar to other vascular diseases, stenosis of vein grafts is caused by several cell lines; however, the sources of these cells remain unclear. The objective of this study was to investigate the cellular sources that reshape vein grafts. By analyzing transcriptomics data and constructing inducible lineage-tracing mouse models, we investigated the cellular components of vein grafts and their fates. The sc-RNAseq data suggested that Sca-1+ cells were vital players in vein grafts and might serve as progenitors for multilineage commitment. By generating a vein graft model in which the venae cavae from C57BL/6J wild-type mice were transplanted adjacent to the carotid arteries of Sca-1(Ly6a)-CreERT2; Rosa26-tdTomato mice, we demonstrated that the recipient Sca-1+ cells dominated reendothelialization and the formation of adventitial microvessels, especially at the perianastomotic regions. In turn, using chimeric mouse models, we confirmed that the Sca-1+ cells that participated in reendothelialization and the formation of adventitial microvessels all had a non-bone-marrow origin, whereas bone-marrow-derived Sca-1+ cells differentiated into inflammatory cells in vein grafts. Furthermore, using a parabiosis mouse model, we confirmed that non-bone-marrow-derived circulatory Sca-1+ cells were vital for the formation of adventitial microvessels, whereas Sca-1+ cells derived from local carotid arteries were the source of endothelium restoration. Using another mouse model in which venae cavae from Sca-1 (Ly6a)-CreERT2; Rosa26-tdTomato mice were transplanted adjacent to the carotid arteries of C57BL/6J wild-type mice, we confirmed that the donor Sca-1+ cells were mainly responsible for smooth muscle cells commitment in the neointima, particularly at the middle bodies of vein grafts. In addition, we provided evidence that knockdown/knockout of Pdgfrα in Sca-1+ cells decreased the cell potential to generate SMCs in vitro and decreased number of intimal SMCs in vein grafts. Our findings provided cell atlases of vein grafts, which demonstrated that recipient carotid arteries, donor veins, non-bone-marrow circulation, and the bone marrow provided diverse Sca-1+ cells/progenitors that participated in the reshaping of vein grafts.
Assuntos
Veias , Veias Cavas , Camundongos , Animais , Camundongos Endogâmicos C57BL , Veias/transplante , Veias Cavas/transplante , Túnica Íntima , NeointimaRESUMO
BACKGROUND: Lung injury is a severe complication of sepsis, which brings great threats and challenges to human health. CircVMA21 has exhibited powerful anti- inflammation capacity. However, its underlying molecule mechanism remains blurry. METHODS: Lipopolysaccharide (LPS) was used to treat mice and WI-38 cells to establish models of lung injury caused by sepsis. Lung injury was evaluated using HE staining. Cell apoptosis was tested by TUNEL and flow cytometry. Levels of inflammatory cytokines were detected using ELISA assay. CircVMA21 and SOCS3 expression was measured using RT-qPCR. The ROS, MDA, SOD and GSH production were monitored by commercial kits. The protein expression was examined with western blot. The correlations among circVMA21, SOCS3 and TAF15 were confirmed using RIP and RNA-pull down. RESULTS: The expression of circVMA21 and SOCS3 was downregulated in LPS-induced lung injury of mice and WI-38 cells. Overexpressing circVMA21 or SOCS3 assuaged LPS-induced cell injury through repressing the levels of inflammatory factors, oxidative stress and cell apoptosis. NF-κB signaling pathway was inactivated by circVMA21 or SOCS3 overexpression. circVMA21 enhanced the stabilization of SOCS3 mRNA via interplaying with TAF15. SOCS3 knockdown destroyed the beneficial impacts of circVMA21 overexpression on LPS-induced cell injury. CONCLUSION: CircVMA21 suppressed LPS-induced the levels of inflammatory factors, oxidative stress and cell apoptosis and improved LPS-induced lung injury by mediating TAF15/SOCS3/NF-κB axis.
Assuntos
Lesão Pulmonar Aguda , Sepse , Fatores Associados à Proteína de Ligação a TATA , Lesão Pulmonar Aguda/induzido quimicamente , Apoptose , Citocinas/metabolismo , Humanos , Lipopolissacarídeos/farmacologia , NF-kappa B/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sepse/complicações , Transdução de Sinais , Superóxido Dismutase/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas/genética , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Fatores Associados à Proteína de Ligação a TATA/metabolismoRESUMO
Perivascular tissue including adipose layer and adventitia have been considered to play pivotal roles in vascular development and disease progression. Recent studies showed that abundant stem/progenitorcells (SPCs) are present in perivascular tissues. These SPCs exhibit capability to proliferate and differentiate into specific terminal cells. Adult perivascular SPCs are quiescent in normal condition, once activated by specific molecules (e.g., cytokines), they migrate toward the lumen side where they differentiate into both smooth muscle cells (SMCs) and endothelial cells (ECs), thus promoting intima hyperplasia or endothelial regeneration. In addition, perivascular SPCs can also regulate vascular diseases via other ways including but not limited to paracrine effects, matrix protein modulation and microvessel formation. Perivascular SPCs have also been shown to possess therapeutic potentials due to the capability to differentiate into vascular cells and regenerate vascular structures. This review summarizes current knowledge on resident SPCs features and discusses the potential benefits of SPCs therapy in vascular diseases.
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Células Endoteliais , Doenças Vasculares , Humanos , Miócitos de Músculo Liso , Regeneração , Células-Tronco , Doenças Vasculares/terapiaRESUMO
AIMS: Hypertension is a major risk factor for cardiovascular diseases. However, vascular remodelling, a hallmark of hypertension, has not been systematically characterized yet. We described systematic vascular remodelling, especially the artery type- and cell type-specific changes, in hypertension using spontaneously hypertensive rats (SHRs). METHODS AND RESULTS: Single-cell RNA sequencing was used to depict the cell atlas of mesenteric artery (MA) and aortic artery (AA) from SHRs. More than 20 000 cells were included in the analysis. The number of immune cells more than doubled in aortic aorta in SHRs compared to Wistar Kyoto controls, whereas an expansion of MA mesenchymal stromal cells (MSCs) was observed in SHRs. Comparison of corresponding artery types and cell types identified in integrated datasets unravels dysregulated genes specific for artery types and cell types. Intersection of dysregulated genes with curated gene sets including cytokines, growth factors, extracellular matrix (ECM), receptors, etc. revealed vascular remodelling events involving cell-cell interaction and ECM re-organization. Particularly, AA remodelling encompasses upregulated cytokine genes in smooth muscle cells, endothelial cells, and especially MSCs, whereas in MA, change of genes involving the contractile machinery and downregulation of ECM-related genes were more prominent. Macrophages and T cells within the aorta demonstrated significant dysregulation of cellular interaction with vascular cells. CONCLUSION: Our findings provide the first cell landscape of resistant and conductive arteries in hypertensive animal models. Moreover, it also offers a systematic characterization of the dysregulated gene profiles with unbiased, artery type-specific and cell type-specific manners during hypertensive vascular remodelling.
Assuntos
Aorta/patologia , Hipertensão/genética , Artérias Mesentéricas/patologia , RNA-Seq , Análise de Célula Única , Transcriptoma , Remodelação Vascular/genética , Animais , Aorta/metabolismo , Modelos Animais de Doenças , Redes Reguladoras de Genes , Hipertensão/metabolismo , Hipertensão/patologia , Masculino , Artérias Mesentéricas/metabolismo , Ratos Endogâmicos SHR , Ratos Endogâmicos WKYRESUMO
Adventitial progenitor cells, including SCA-1+ and mesenchymal stem cells, are believed to be important in vascular remodeling. It has been shown that SCA-1+ progenitor cells are involved in neointimal hyperplasia of vein grafts, but little is known concerning their involvement in hyperlipidemia-induced atherosclerosis. We employed single-cell sequencing technology on primary adventitial mouse SCA-1+ cells from wild-type and atherosclerotic-prone (ApoE-deficient) mice and found that a group of genes controlling cell migration and matrix protein degradation was highly altered. Adventitial progenitors from ApoE-deficient mice displayed an augmented migratory potential both in vitro and in vivo. This increased migratory ability was mimicked by lipid loading to SCA-1+ cells. Furthermore, we show that lipid loading increased miRNA-29b expression and induced sirtuin-1 and matrix metalloproteinase-9 levels to promote cell migration. These results provide direct evidence that blood cholesterol levels influence vascular progenitor cell function, which could be a potential target cell for treatment of vascular disease.