David M Smadja

Université Paris-Sorbonne - Paris IV, Lutetia Parisorum, Île-de-France, France

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Publications (52)225.79 Total impact

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    ABSTRACT: Fibrotic diseases of the lung are associated with a vascular remodelling process. Fibrocytes (Fy) are a distinct population of blood-borne cells that co-express haematopoietic cell antigens and fibroblast markers, and have been shown to contribute to organ fibrosis. The purpose of this study was to determine whether fibrocytes cooperate with endothelial colony-forming cells (ECFC) to induce angiogenesis. We isolated fibrocytes from blood of patient with idiopathic pulmonary fibrosis (IPF) and characterised them by flow cytometry, quantitative reverse transcriptase PCR (RTQ-PCR), and confocal microscopy. We then investigated the angiogenic interaction between fibrocytes and cord-blood-derived ECFC, both in vitro and in an in vivo Matrigel implant model. Compared to fibroblast culture medium, fibrocyte culture medium increased ECFC proliferation and differentiation via the SDF-1/CXCR4 pathway. IPF-Fy co-implanted with human ECFC in Matrigel plugs in immunodeficient mice formed functional microvascular beds, whereas fibroblasts did not. Evaluation of implants after two weeks revealed an extensive network of erythrocyte-containing blood vessels. CXCR4 blockade significantly inhibited this blood vessel formation. The clinical relevance of these data was confirmed by strong CXCR4 expression in vessels close to fibrotic areas in biopsy specimens from patients with IPF, by comparison with control lungs. In conclusion, circulating fibrocytes might contribute to the intense remodelling of the pulmonary vasculature in patients with idiopathic pulmonary fibrosis.
    Thrombosis and haemostasis. 08/2014; 112(5).
  • David M. Smadja
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    ABSTRACT: Endothelial progenitor cells (EPC) and stem cells have therapeutic potential for the treatment of peripheral arterial disease (PAD) and acute coronary syndrome (ACS) (1). These cells are thought to act either by giving rise to new vessels in situ, or as helper cells to mature endothelial cells during the re-endothelialisation process following vascular injury. Within the context of thrombosis, different EPC subtypes can be recruited to sites of vessel damage, and, depending on the model used, they have been shown to be either beneficial for thrombus resolution, or conversely to exhibit deleterious thrombotic effects.This article is protected by copyright. All rights reserved.
    Journal of Thrombosis and Haemostasis 04/2014; · 6.08 Impact Factor
  • David M Smadja
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    ABSTRACT: Endothelial progenitor cell therapy and stem cell therapy have been proposed in regeneration of acute myocardial infarction (AMI). In the previous issue of Stem Cell Research & Therapy, Lamirault and colleagues described a strong analysis of progenitors in blood and bone marrow of patients collected after AMI, and correlated these levels to bone marrow mononuclear cell (BM-MNC) therapy efficacy and smoking status. The main results are that BM-MNCs can override smoking alteration in endothelial lineage and confirm that endothelial progenitor cells are probably not by themselves the active component of BM-MNC in AMI. This paper allows one to better appreciate the cellular complexity of cell therapy approach in AMI.
    Stem Cell Research & Therapy 01/2014; 5(1):16. · 3.65 Impact Factor
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    ABSTRACT: We studied whether plasma levels of angiogenic factors VEGF and placental growth factor (PlGF) in coronary artery disease patients or undergoing cardiac surgery are modified, and whether those factors modulate endothelial progenitor's angiogenic potential. A total of 143 patients' plasmas from two different studies were analyzed (30 coronary artery disease patients, 30 patients with stable angina, coupled with 30 age and sex-matched controls; 53 patients underwent cardiac surgery). Among factors screened, only PlGF was found significantly increased in these pathological populations. PlGF-1 and PlGF-2 were then tested on human endothelial-colony-forming cells (ECFCs). We found that PlGF-1 and PlGF-2 induce VEGFR1 phosphorylation and potentiate ECFCs tubulogenesis in vitro. ECFCs VEGFR1 was further inhibited using a specific small interfering RNA (siRNA) and the chemical compound 4321. We then observed that the VEGFR1-siRNA and the compound 4321 decrease ECFCs tubulogenesis potential in vitro. Finally, we tested the compound 4321 in the preclinical Matrigel(®)-plug model with C57Bl/6J mice as well as in the murine hindlimb ischemia model. We found that 4321 inhibited the plug vascularization, attested by the hemoglobin content and the VE-Cadherin expression level and that 4321 inhibited the post-ischemic revascularization. PlGF plasma levels were found increased in cardiovascular patients. Disrupting PlGF/VEGFR1 pathway could modulate ECFC-induced tubulogenesis, the cell type responsible for newly formed vessels in vivo.
    Angiogenesis 01/2014; · 3.97 Impact Factor
  • David M Smadja
    La Revue du praticien 10/2013; 63(8):1044-7.
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    ABSTRACT: After the onset of ischemia, cardiac or skeletal muscle undergoes a continuum of molecular, cellular, and extracellular responses that determine the function and the remodeling of the ischemic tissue. Hypoxia-related pathways, immunoinflammatory balance, circulating or local vascular progenitor cells, as well as changes in hemodynamical forces within vascular wall trigger all the processes regulating vascular homeostasis, including vasculogenesis, angiogenesis, arteriogenesis, and collateral growth, which act in concert to establish a functional vascular network in ischemic zones. In patients with ischemic diseases, most of the cellular (mainly those involving bone marrow-derived cells and local stem/progenitor cells) and molecular mechanisms involved in the activation of vessel growth and vascular remodeling are markedly impaired by the deleterious microenvironment characterized by fibrosis, inflammation, hypoperfusion, and inhibition of endogenous angiogenic and regenerative programs. Furthermore, cardiovascular risk factors, including diabetes, hypercholesterolemia, hypertension, diabetes, and aging, constitute a deleterious macroenvironment that participates to the abrogation of postischemic revascularization and tissue regeneration observed in these patient populations. Thus stimulation of vessel growth and/or remodeling has emerged as a new therapeutic option in patients with ischemic diseases. Many strategies of therapeutic revascularization, based on the administration of growth factors or stem/progenitor cells from diverse sources, have been proposed and are currently tested in patients with peripheral arterial disease or cardiac diseases. This review provides an overview from our current knowledge regarding molecular and cellular mechanisms involved in postischemic revascularization, as well as advances in the clinical application of such strategies of therapeutic revascularization.
    Physiological Reviews 10/2013; 93(4):1743-802. · 30.17 Impact Factor
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    ABSTRACT: Upregulation of HIF-1α, through prolyl-hydroxylase domain protein (PHDs) inhibition, can be thought of as a master switch that coordinates the expression of a wide repertoire of genes involved in regulating vascular growth and remodelling. We aimed to unravel the effect of specific PHD2 isoform silencing in cell-based strategies designed to promote therapeutic revascularization in patients with critical limb ischemia (CLI). PHD2 mRNA levels were up-regulated whereas that of HIF-1α were down-regulated in blood cells from patients with CLI. We therefore assessed the putative beneficial effects of PHD2 silencing on human bone-marrow derived mesenchymal stem cells (hBM-MSC)-based therapy. PHD2 silencing enhanced hBM-MSC therapeutic effect in an experimental model of CLI in Nude mice, through an up-regulation of HIF-1α and its target gene, VEGF-A. In addition, PHD2-transfected hBM-MSC displayed higher protection against apoptosis in vitro and increased rate of survival in the ischemic tissue, as assessed by Fluorescence Molecular Tomography. Co-transfection with HIF1α or VEGF-A short interfering RNAs fully abrogated the beneficial effect of PHD2 silencing on the pro-angiogenic capacity of hBM-MSC. We finally investigated the effect of PHD2 inhibition on the revascularization potential of ischemic targeted tissues in the diabetic pathological context. Inhibition of PHD-2 with shRNAs increased post-ischemic neovascularisation in diabetic mice with CLI. This increase was associated with an up-regulation of pro-angiogenic and pro-arteriogenic factors and was blunted by concomitant silencing of HIF-1α. In conclusion, silencing of PHD2, by the transient upregulation of HIF-1α and its target gene VEGF-A, might improve the efficiency of hBM-MSC-based therapies. Stem Cells 2013.
    Stem Cells 09/2013; · 7.70 Impact Factor
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    ABSTRACT: Background: Infantile hemangioma (IH) is the most common tumor of infancy. Hemangioma stem cells (HemSC) are a mesenchymal subpopulation isolated from IH CD133+ cells. HemSC can differentiate into endothelial and pericyte/smooth muscle cells and form vascular networks when injected in immune-deficient mice. α6-Integrin subunit has been implicated in the tumorgenicity of glioblastoma stem cells and the homing properties of hematopoietic, endothelial and mesenchymal progenitor cells. Therefore, we investigated the possible function(s) of α6-integrin in HemSC. Methods/Results: We documented α6-integrin expression in IH tumor specimens and HemSC by RT-qPCR and flow cytometry. We examined the effect of blocking or silencing α6-integrin on the adhesive and proliferative properties of HemSCin vitro and the vasculogenic and homing properties of HemSCin vivo. Targeting α6-integrin in cultured HemSC inhibited adhesion to laminin but had no effect on proliferation. Vessel-forming ability in Matrigel implants and hepatic homing after intravenous delivery were significantly decreased in α6-integrin siRNA transfected HemSC. Conclusion: α6-Integrin is required for HemSC adherence to laminin, vessel formation in vivo and for homing to the liver. Thus, we uncovered an important role for α6 integrin in the vasculogenic properties of HemSC. Our results suggest that α6-integrin expression on HemSC could be a new target for anti-hemangioma therapy. Stem Cells 2013.
    Stem Cells 09/2013; · 7.70 Impact Factor
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    ABSTRACT: Late evolution of peripheral arterial disease consists in the apparition of critical limb ischemia. Surgical treatments allow to treat these patients during long time; however, in most patients, especially the diabetic ones, there a very few options and the clinical evolution is rapidly dramatic. For these reasons, the critical limb ischemia is one of the first diseases treated by genic or cellular therapies aiming to improve blood flow perfusion in the lower-limbs. In this short review, we describe the main clinical trials of genic therapy; most of them have been abandoned because serious side effects, modest effects and major risks. Different types of stem cells are now used for cell therapy: endothelial progenitor cells, early or late, activated or not, mesenchymal stem cells, embryonic stem cells and human induced pluripotent stem cells. Problems of characterization are described and the results of the most important clinical trials are reported.
    Transfusion Clinique et Biologique 05/2013; 20(2):211–220. · 0.64 Impact Factor
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    ABSTRACT: Late evolution of peripheral arterial disease consists in the apparition of critical limb ischemia. Surgical treatments allow to treat these patients during long time; however, in most patients, especially the diabetic ones, there a very few options and the clinical evolution is rapidly dramatic. For these reasons, the critical limb ischemia is one of the first diseases treated by genic or cellular therapies aiming to improve blood flow perfusion in the lower-limbs. In this short review, we describe the main clinical trials of genic therapy; most of them have been abandoned because serious side effects, modest effects and major risks. Different types of stem cells are now used for cell therapy: endothelial progenitor cells, early or late, activated or not, mesenchymal stem cells, embryonic stem cells and human induced pluripotent stem cells. Problems of characterization are described and the results of the most important clinical trials are reported.
    Transfusion Clinique et Biologique 04/2013; · 0.64 Impact Factor
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    ABSTRACT: Pulmonary vasodilators in general and prostacyclin analogues in particular have improved the outcome of patients with pulmonary arterial hypertension (PAH). Endothelial dysfunction is a key feature of PAH and we previously described that circulating endothelial cell (CEC) level could be used as a biomarker of endothelial dysfunction in PAH. We now hypothesized that an efficient PAH-specific vasodilator therapy might decrease CEC level. METHODSRESULTS: CECs were prospectively quantified by immunomagnetic separation with mAb CD146-coated beads in peripheral blood from children with idiopathic PAH (iPAH, n = 30) or PAH secondary to congenital heart disease (PAH-CHD, n = 30): before, after treatment and during follow up. Controls were 23 children with reversible PAH. Oral treatment with endothelin receptor antagonists (ERA) and/or phosphodiesterase 5 inhibitors (PDE5) significantly reduced CEC counts in children. In 10 children with refractory PAH despite oral combination therapy, subcutaneous (SC) treprostinil was added and we observed a significant decrease in CEC counts during the first month of such treatment. CECs were quantified during a 6 to 36 month-follow-up after initiation of SC treprostinil and we found that CEC counts changed over time, with rising counts always preceding clinical deterioration. CECs might be useful as a biomarker during follow-up of pediatric iPAH and PAH-CHD to assess response to treatment and to anticipate clinical worsening.
    PLoS ONE 01/2013; 8(6):e65114. · 3.73 Impact Factor
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    ABSTRACT: Background aims Circulating endothelial progenitor cells and especially endothelial colony-forming cells (ECFCs) are promising candidate cells for endothelial regenerative medicine of ischemic diseases, but the conditions for an optimal collection from adult blood must be improved. Methods On the basis of a recently reported vascular niche of ECFCs, we hypothesized that a local ischemia could trigger ECFC mobilization from the vascular wall into peripheral blood to optimize their collection for autologous implantation in critical leg ischemia. Because the target population with critical leg ischemia is composed of elderly patients in whom a vascular impairment has been documented, we also analyzed the impact of aging on ECFC mobilization and vascular integrity. Results After having defined optimized ECFC culture conditions, we studied the effect of forearm ischemia on ECFC numbers and functions in 26 healthy volunteers (13 volunteers ages 20–30-years old versus 13 volunteers ages 60–70 years old). The results show that forearm ischemia induced an efficient local ischemia and a normal endothelial response but did not mobilize ECFCs regardless of the age group. Moreover, we report an alteration of angiogenic properties of ECFCs obtained after forearm ischemia, in vitro as well as in vivo in a hindlimb ischemia murine model. This impaired ECFC angiogenic potential was not associated with a quantitative modification of the circulating endothelial compartment. Conclusions The procedure of local ischemia, although reulting in a preserved endothelial reactivity, did not mobilize ECFCs but altered their angiogenic potential.
    Cytotherapy 01/2013; · 3.06 Impact Factor
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    Réanimation 01/2013; 22(1).
  • Réanimation 01/2013; 22(1).
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    David M Smadja, John B Mulliken, Joyce Bischoff
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    ABSTRACT: Hemangioma stem cells (HemSCs) are multipotent cells isolated from infantile hemangioma (IH), which form hemangioma-like lesions when injected subcutaneously into immune-deficient mice. In this murine model, HemSCs are the primary target of corticosteroid, a mainstay therapy for problematic IH. The relationship between HemSCs and endothelial cells that reside in IH is not clearly understood. Adhesive interactions might be critical for the preferential accumulation of HemSCs and/or endothelial cells in the tumor. Therefore, we studied the interactions between HemSCs and endothelial cells (HemECs) isolated from IH surgical specimens. We found that HemECs isolated from proliferating phase IH, but not involuting phase, constitutively express E-selectin, a cell adhesion molecule not present in quiescent endothelial cells. E-selectin was further increased when HemECs were exposed to vascular endothelial growth factor-A or tumor necrosis factor-α. In vitro, HemSC migration and adhesion was enhanced by recombinant E-selectin but not P-selectin; both processes were neutralized by E-selectin-blocking antibodies. E-selectin-positive HemECs also stimulated migration and adhesion of HemSCs. In vivo, neutralizing antibodies to E-selectin strongly inhibited formation of blood vessels when HemSCs and HemECs were co-implanted in Matrigel. These data suggest that endothelial E-selectin could be a major ligand for HemSCs and thereby promote cellular interactions and vasculogenesis in IH. We propose that constitutively expressed E-selectin on endothelial cells in the proliferating phase is one mediator of the stem cell tropism in IH.
    American Journal Of Pathology 10/2012; · 4.52 Impact Factor
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    ABSTRACT: BACKGROUND: Fibrogenesis during idiopathic pulmonary fibrosis (IPF) is strongly associated with abnormal vascular remodeling. Respective abundance of circulating endothelial cells (CEC) and endothelial progenitor cells (EPC) might reflect the balance between vascular injury and repair and potentially serve as biomarkers of the disease. OBJECTIVES AND METHODS: We postulated that CEC and EPC subtypes might be differently modulated in IPF. Sixty-four consecutive patients with newly diagnosed IPF were prospectively enrolled and compared to thirteen healthy volunteers. CEC were counted with immunomagnetic CD146-coated beads; progenitors CD34+45(dim)/CD34+133+/CD34+KDR+were assessed through flow cytometry and EPC (colony-forming-units-Endothelial Cells, CFU-EC, and endothelial colonies forming cells, ECFC) were quantified by cell culture assays. RESULTS: IPF patients were characterized by a marked increase in CEC associated to an EPC defect: both CD34(+)KDR(+) cells and CFU-EC were decreased versus controls. Moreover, in IPF subjects with a low diffusing capacity of the lung for carbon monoxide (DL(CO)) < 40 %, CFU-EC and ECFC were higher compared to those with DL(CO) > 40 %. Finally, ECFC were negatively correlated with DL(CO). During an 18 month follow up, CEC levels increased in patients with exacerbation, including those who died during follow up. Finally, ECFC from patients with exacerbation proliferative potential was strongly increased. CONCLUSION: IPF is basically associated with both a vascular injury and a repair defect. This study highlights an adaptative process of EPC mobilization in the most severe forms of IPF, that could reflect enhanced homing to the pulmonary vasculature, which clinical consequences remain to be determined.
    Angiogenesis 09/2012; · 3.97 Impact Factor
  • D M Smadja, D Borgel, J-L Diehl, P Gaussem
    Journal of Thrombosis and Haemostasis 03/2012; 10(5):974-6. · 6.08 Impact Factor
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    ABSTRACT: Endothelial progenitor cells (EPC) have been proposed for autologous angiogenic therapy. The objectives of this study were to quantify EPC in the peripheral blood and bone marrow mononuclear cells (BM-MNC) of patients with critical limb ischemia that had received BM-MNC as a cell therapy product, and to study the putative relationship between the presence of EPC and the process of neovascularization in toe or transmetatarsal amputation specimens. Early and late endothelial progenitor cells (CFU-EC and ECFC) were cultivated and quantified according to published methods in peripheral blood and BM-MNC from patients with critical limb ischemia (CLI; n = 11) enrolled in the OPTIPEC trial ( http://clinicaltrials.gov/ct2/show/NCT00377897 ) to receive BM-MNC as a cell therapy product. Eight out of the 11 patients had undergone amputations. Three of the patients displayed a neoangiogenic process that was associated with a higher number of CFU-EC in BM-MNC, while CD3+ , CFU-GM and CD34+ in BM-MNC, and EPC in peripheral blood, did not correlate with the appearance of newly formed vessels. As expected, circulating CFU-EC and ECFC counts were significantly lower in CLI patients compared with age-matched controls. In patients with critical limb ischemia, EPC in peripheral blood were decreased compared with healthy individuals. However, in BM-MNC we found that relative numbers of CFU-EC could be used as an indicator to discriminate patients with neoangiogenic processes. These results need to be confirmed in a randomized study.
    Cytotherapy 02/2012; 14(2):232-9. · 3.06 Impact Factor
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    ABSTRACT: Transforming growth factor-β1 (TGF-β1) is a profibrotic cytokine that plays a major role in vascular biology, and is known to regulate the phenotype and activity of various vascular cell populations. Because most fibrotic diseases, such as idiopathic pulmonary fibrosis (IPF), are associated with vascular remodeling, and as endothelial progenitor cells (EPCs) may be involved in this process, we investigated the impact of TGF-β1 modulation of EPC angiogenic properties. TGF-β1 plasma levels were determined in 64 patients with IPF and compared with those in controls. The effect of TGF-β1 on angiogenesis was studied in vivo in a Matrigel plug model and in vitro on endothelial colony-forming cells (ECFCs). We studied the effects of inhibiting the expression of the three main receptors of TGF-β1 in ECFCs by using short interfering RNA. Total TGF-β1 plasma levels were significantly increased in patients with IPF as compared with controls (P < 0.0001). TGF-β1 had proangiogenic effects in vivo by increasing hemoglobin content and blood vessel formation in Matrigel plugs implanted in C57/Bl6 mice, and in vitro by enhancing ECFC viability and migration. The effects were abolished by silencing the three main TGF-β1 receptors. TGF-β1 is proangiogenic in vivo and induces ECFC angiogenic properties in vitro, suggesting that TGF-β1 may play a role during vascular remodeling in fibrotic disease states via EPCs.
    Journal of Thrombosis and Haemostasis 01/2012; 10(4):670-9. · 6.08 Impact Factor

Publication Stats

483 Citations
225.79 Total Impact Points

Institutions

  • 2014
    • Université Paris-Sorbonne - Paris IV
      Lutetia Parisorum, Île-de-France, France
  • 2011–2013
    • Harvard Medical School
      Boston, Massachusetts, United States
  • 2006–2013
    • Université René Descartes - Paris 5
      • Faculté des Sciences Pharmaceutiques et Biologiques de Paris
      Lutetia Parisorum, Île-de-France, France
    • Hôpital Européen Georges-Pompidou (Hôpitaux Universitaires Paris-Ouest)
      Lutetia Parisorum, Île-de-France, France
  • 2012
    • Boston Children's Hospital
      Boston, Massachusetts, United States
  • 2005–2007
    • Unité Inserm U1077
      Caen, Lower Normandy, France