Superconducting routing platform for large-scale integration of quantum technologies

To reach large-scale quantum computing, three-dimensional integration of scalable qubit arrays and their control electronics in multi-chip assemblies is promising. Within these assemblies, the use of superconducting interconnections, as routing layers, offers interesting perspective in terms of (1) thermal management to protect the qubits from control electronics self-heating, (2) passive device performance with significant increase of quality factors and (3) density rise of low and high frequency signals thanks to minimal dispersion. We report on the fabrication, using 200 mm silicon wafer technologies, of a multi-layer routing platform designed for the hybridization of spin qubit and control electronics chips. A routing level couples the qubits and the control circuits through one layer of Al0.995Cu0.005 and superconducting layers of TiN, Nb or NbN, connected between them by W-based vias. Wafer-level parametric tests at 300 K validate the yield of these technologies and low temperature electrical measurements in cryostat are used to extract the superconducting properties of the routing layers. Preliminary low temperature radio-frequency characterizations of superconducting passive elements, embedded in these routing levels, are presented

Pericyte-Like Progenitors Show High Immaturity and Engraftment Potential as Compared with Mesenchymal Stem Cells

Mesenchymal stem cells (MSCs) and pericyte progenitors (PPs) are both perivascular cells with similar multipotential properties regardless of tissue of origin. We compared the phenotype and function of the 2 cell types derived from the same bone-marrow samples but expanded in their respective media – pericyte conditions (endothelial cell growth medium 2 [EGM-2]) for PPs and standard medium (mesenchymal stem cell medium [MSM]) for MSCs. After 3 weeks of culture, whatever the expansion medium, all cells showed similar characteristics (MSC markers and adipo-osteo-chondroblastic differentiation potential), although neuronal potential was greater in EGM-2– than MSM-cultured cells. As compared with MSM-cultured MSCs, EGM-2–cultured PPs showed higher expression of the pericyte-specific antigen 3G5 than a-smooth muscle actin. In addition, EGM-2–cultured PPs showed an immature phenotype, with upregulation of stemness OCT4 and SOX2 proteins and downregulation of markers of osteoblastic, chondroblastic, adipocytic and vascular smooth muscle lineages. Despite having less effective in vitro immunosuppression capacities than standard MSCs, EGM-2–cultured PPs had higher engraftment potentials when combined with biomaterials heterotopically-transplanted in Nude mice. Furthermore, these engrafted cells generated more collagen matrix and were preferentially perivascular or lined trabeculae as compared with MSM-cultured MSCs. In conclusion, EGM-2–cultured PPs are highly immature cells with increased plasticity and engraftment potential

Safety Concern between Autologous Fat Graft, Mesenchymal Stem Cell and Osteosarcoma Recurrence

Background: Osteosarcoma is the most common malignant primary bone tumour in young adult treated by neo adjuvant chemotherapy, surgical tumor removal and adjuvant multidrug chemotherapy. For correction of soft tissue defect consecutive to surgery and/or tumor treatment, autologous fat graft has been proposed in plastic and reconstructive surgery. Principal Findings: We report here a case of a late local recurrence of osteosarcoma which occurred 13 years after the initial pathology and 18 months after a lipofilling procedure. Because such recurrence was highly unexpected, we investigated the possible relationship of tumor growth with fat injections and with mesenchymal stem/stromal cell like cells which are largely found in fatty tissue. Results obtained in osteosarcoma pre-clinical models show that fat grafts or progenitor cells promoted tumor growth. Significance: These observations and results raise the question of whether autologous fat grafting is a safe reconstructive procedure in a known post neoplasic context

Investigation au niveau de la caractérisation phénotypique et fonctionnelle des cellules souches mésenchymateuses natives et cultivées de moelle osseuse

Pendant la décennie passée, le champ d'étude sur les cellules souches mésenchymateuses (CSM) de moelle osseuse a considérablement augmenté, motivé par leurs applications en médecine régénérative. Aujourd'hui, nous distinguons deux types de CSM : les cellules fraîchement isolées par sélection directe, dont le phénotype est proche de celui retrouvé in vivo (CSM natives ou CSMn), et les cellules obtenues après expansion in vitro des CSMn : les CSM cultivées (CSMc). Contrairement aux CSMc, il existe peu de données sur les CSMn, et l'aspect immunosupresseur des CSMc n'a pas encore été totalement élucidé. - Grâce à un tri immunomagnétique dirigé contre la molécule CD49a (protéine fortement conservée entre les espèces), nous avons pu préciser le caractère souche des CSMn murines et humaines. Les cellules ainsi isolées expriment des marqueurs d'immaturité comme le CD133, c-kit ou Sca-1. Ainsi, le tri via le CD49a est un bon moyen pour enrichir les CSMn aussi bien chez le murin que chez l'humain. - Dans un deuxième temps, nous avons aussi tenté de déterminer si les CSMn étaient mobilisées dans le sang périphérique comme les progéniteurs endothéliaux (PE) chez des patients traités par un agent mobilisateur : les statines. Les résultats ont montré qu'il n'y avait pas de CSMn circulantes dans le sang contrairement aux PE. - Enfin, nous avons démontré pour la première fois l'expression par les CSMc de la molécule immunosuppressive HLA-G5 et montré son implication significative dans l'induction de lymphocytes T régulateurs, dans l'inhibition de la prolifération T en condition allogénique, et dans l'inhibition de la lyse des cellules NK. Par ailleurs, cette inhibition dépendante de l 'IL-10 nécessite un contact cellulaire. - Nos résultats ont donc permis d'obtenir de nouvelles données phénotypiques et fonctionnelles des CSMn et CSMc. Ces données faciliteront la compréhension des mécanismes régénératifs et immunomodulateurs des CSM.During the previous decade our knowledge of mesenchymal stem cells (MSC) bas been stimulated by their application in regenerative medecine. Today we can distinguish two types of MSC : fresh cells (MSCn), which are enriched directly from bone marrow and resemble more closely to in vivo MSC ; the second type (MSCc) can be obtained after isolation and in vitro expansion of MSCn. Here we have characterized MSCn and investigated the immunosuppressive potential of MSCc. - Due to our ability to isolate MSCn by immunomagnetic separation using an antibody against CD49a (highly conserved protein between species), we have been able to characterize MSCn from different species showing that they express common stem cell markeTs such as CD133, c-kit and Sca-1 (murine). - Secondly, we showed that in contrast to endothelial progenitors (PE), MSCn are not mobilized into the peripheral blood of patients treated by statins. - Lastly, we demonstrated for the first time that MSCc express the immunosuppressive molecule HLA-G5. This molecule is implicated in the induction of regulatory T-cells, is able also to both inhibit the proliferation of allogeneic T cells and prevent NK cells lysis. Moreover, these properties were shown to be dependent on cell contact and IL-10 expression. - ln summary this work shed light on the functional and phenotypic properties of mesenchymal stem cells.BESANCON-BU Médecine pharmacie (250562102) / SudocSudocFranceF

Les cellules souches mésenchymateuses

Les cellules souches/stromales mésenchymateuses sont une population cellulaire capable d’agir sur la réparation et la régénération tissulaires par différents mécanismes allant du remplacement cellulaire à la modulation des réponses immunitaires et inflammatoires. Du fait de leurs différentes potentialités, les CSM ont été utilisées dès 1995 d’abord dans un contexte hématologique pour aider au soutien de l’hématopoïèse, puis pour traiter la réaction du greffon contre l’hôte. Leur potentiel de différenciation explique également leur utilisation dans un but de réparation osseuse. Depuis plus de 15 ans les champs d’application potentiels étudiés dans des essais cliniques se sont étendus à des indications aussi variées que les lésions cutanées au cours des brûlures ou les accidents vasculaires cérébraux. Le but des textes regroupés dans cet article n’est pas de donner une vision exhaustive de l’ensemble des indications potentielles en cours d’évaluation, mais de montrer ce que peuvent être des applications combinant les différents moyens d’action des CSM dans quatre domaines particuliers : les pathologies dysimmunitaires, la réparation osseuse, la régénération vasculaire et l’ophtalmologie

Osteodifferentiated Mesenchymal Stem Cells from Bone Marrow and Adipose Tissue Express HLA-G and Display Immunomodulatory Properties in HLA-Mismatched Settings: Implications in Bone Repair Therapy

Mesenchymal stem cells (MSCs) are multipotent cells that can be obtained from several sources such as bone marrow and adipose tissue. Depending on the culture conditions, they can differentiate into osteoblasts, chondroblasts, adipocytes, or neurons. In this regard, they constitute promising candidates for cell-based therapy aimed at repairing damaged tissues. In addition, MSCs display immunomodulatory properties through the expression of soluble factors including HLA-G. We here analyse both immunogenicity and immunosuppressive capacity of MSCs derived from bone marrow and adipose tissue before and after osteodifferentiation. Results show that HLA-G expression is maintained after osteodifferentiation and can be boosted in inflammatory conditions mimicked by the addition of IFN-γ and TNF-α. Both MSCs and osteodifferentiated MSCs are hypoimmunogenic and exert immunomodulatory properties in HLA-mismatched settings as they suppress T cell alloproliferation in mixed lymphocyte reactions. Finally, addition of biomaterials that stimulate bone tissue formation did not modify MSC immune properties. As MSCs combine both abilities of osteoregeneration and immunomodulation, they may be considered as allogenic sources for the treatment of bone defects

Human and rodent bone marrow mesenchymal stem cells that express primitive stem cell markers can be directly enriched by using the CD49a molecule.

International audienceBone marrow (BM) from human and rodent species contains a population of multipotential cells referred to as mesenchymal stem cells (MSCs). Currently, MSCs are isolated indirectly by using a culture step and then the generation of fibroblast colony-forming units (CFU-fs). Unprocessed or native BM MSCs have not yet been fully characterised. We have previously developed a direct enrichment method for the isolation of MSCs from human BM by using the CD49a protein (alpha1-integrin subunit). As the CD49a gene is highly conserved in mammals, we have evaluated whether this direct enrichment can be employed for BM cells from rodent strains (rat and mouse). We have also studied the native phenotype by using both immunodetection and immunomagnetic methods and have compared MSCs from mouse, rat and human BM. As is the case for human BM, we have demonstrated that all rodent multipotential CFU-fs are contained within the CD49a-positive cell population. However, in the mouse, the number of CFU-fs is strain-dependent. Interestingly, all rat and mouse Sca-1-positive cells are concentrated within the CD49a-positive fraction and also contain all CFU-fs. In human, the colonies have been detected in the CD49a/CD133 double-positive population. Thus, the CD49a protein is a conserved marker that permits the direct enrichment of BM MSCs from various mammalian species; these cells have been phenotyped as true BM stem cells

Human cord blood-derived hematopoietic and neural-like stem/progenitor cells are attracted by the neurotransmitter GABA.

International audienceMigration of stem/progenitor cells is a crucial event for homing toward tissue where cells need to be renewed. The neurotransmitter gamma-aminobutyric acid (GABA) has been shown to have a crucial role in migration of neuronal stem/progenitor cells. Since human umbilical cord blood (HUCB) contains stem/progenitor cells able to generate either neuronal or hematopoietic cells, we evaluated the effect of GABA on this type of cells. While whole fraction of mononuclear cells expressed GABA(A) and GABA(B) receptor subunits (GABA-R), only GABA(B)R subunits were found to be expressed on immature CD133+ cells. Functional experiments revealed that both cell fractions of HUCB were attracted by a gradient of GABA concentration and furthermore were blocked by specific antagonists of GABA(A)R and GABA(B)R bicuculline and saclofen, respectively. Moreover, through GABA(B)R activation the migrating fraction was highly enriched by both hematopoietic progenitors and cells able to generate neuron- like cells in culture. Therefore, GABA is a potent chemoattractant of HUCB stem/progenitor cells specifically through GABA(B)R activation

Mesenchymal stem/stromal cell function in modulating cell death

Abstract Mesenchymal stem/stromal cells (MSCs) delivered as cell therapy to individuals with degenerative and/or inflammatory disorders can help improve organ features and resolve inflammation, as demonstrated in preclinical studies and to some extent in clinical studies. MSCs have trophic, homing/migration, and immunosuppression functions, with many benefits in therapeutics. MSC functions are thought to depend on the paracrine action of soluble factors and/or the expression of membrane-bound molecules, mostly belonging to the molecular class of adhesion molecules, chemokines, enzymes, growth factors, and interleukins. Cutting-edge studies underline bioactive exchanges, including that of ions, nucleic acids, proteins, and organelles transferred from MSCs to stressed cells, thereby improving the cells’ survival and function. From this aspect, MSC death modulation function appears as a decisive biological function that could carry a significant part of the therapeutic effects of MSCs. Identifying the function and modes of actions of MSCs in modulating cell death may be exploited to enhance consistency and efficiency of cell therapy that is based on MSCs as medical treatment for degenerative and/or inflammatory diseases. Here, we review the essentials of MSC functions in modulating cell death in unfit cells, and its modes of actions based on current advances and outline the clinical implications

In vitro functional defects of bone marrow-derived CD34+ progenitors from newly diagnosed mature B-cell malignancies with bone marrow tumor involvement.

International audienceOBJECTIVE: We hypothesized that the presence of tumor cells in bone marrow (BM) could alter hematopoietic progenitor cell functions. Therefore, we evaluated phenotypic and in vitro functional properties of BM-derived CD34+ progenitors issued from untreated and newly diagnosed patients presenting a mature B-lymphoproliferative disorder (LPD) involving the BM (Inv+). PATIENTS AND METHODS: In vitro proliferation and differentiation capacities of primitive and committed progenitors were evaluated by cobblestone area-forming cell (CAFC) and colony-forming cell (CFC) assays, and ex vivo cell expansion. Migratory capacities of CD34+ cells were explored by chemotaxis assays using a CXCL12alpha gradient. RESULTS: Our results showed that CD34+ cells from Inv+ patients overexpressed CD117 and had a significant decrease of week-3 and -6 CAFC, and CFC frequencies, compared to cells obtained from healthy volunteers and LPD patients without BM involvement (Inv-). In addition, progenitors from Inv+ patients maintained a significantly decreased CFC capacity after ex vivo cell expansion, compared to healthy volunteers. However, the former cells held their migratory capacity in response to CXCL12alpha. CONCLUSION: Functional defects of primitive and committed CD34+ progenitors detected among LPD patients with BM tumor involvement suggest either that tumor cells may induced bystander effects on progenitors or that "unusual" CD34+ cells may exist in the BM that could belong to the proliferating tumor tissue