Endothelial progenitor cell

Résumé

Endothelial progenitor cell (or EPC) is a term that has been applied to multiple different cell types that play roles in the regeneration of the endothelial lining of blood vessels. Outgrowth endothelial cells are an EPC subtype committed to endothelial cell formation. Despite the history and controversy, the EPC in all its forms remains a promising target of regenerative medicine research. History and controversy Developmentally, the endothelium arises in close contact with the hematopoietic system. This, and the existence of hemogenic endothelium, led to a belief and search for adult hemangioblast- or angioblast-like cells; cells which could give rise to functional vasculature in adults. The existence of endothelial progenitor cells has been posited since the mid-twentieth century, however their existence was not confirmed until the 1990s when Asahara et al. published the discovery of the first putative EPC. Recently, controversy has developed over the definition of true e

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https://en.wikipedia.org/wiki/Endothelial_progenitor_cell

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L’angiogenèse est le processus de croissance de nouveaux vaisseaux sanguins à partir de vaisseaux préexistants. C'est un processus physiologique normal, que l'on retrouve notamment lors du développem

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Tissue engineering for prenatal applications

Anna-Sofia Johanna Kiveliö

Fetal therapies have become available for a restricted number of life-threatening clinical conditions. Harnessing tissue engineering for prenatal applications has not been widely pursued even though isolating cells from fetal and extraembryonic tissues has been routinely done for years. The objectives of this thesis were twofold: i) the development of materials based and tissue engineering based strategies to prevent iatrogenic preterm prelabour rupture of fetal membranes (iPPROM) after diagnostic or therapeutic interventions into the amniotic cavity and ii) the generation of tissue substitutes from patient derived fetal cells, which can be employed for prenatal or perinanal transplantation to restore or replace defective tissues. For the prevention of iPPROM, mussel-mimetic tissue adhesive (mussel glue) a biomaterial which was recently described to not compromise cell viability and to have good tissue sealing capability was compared to fibrin glue. In this in vivo study we assessed whether in a mid-gestational rabbit model punctured fetal membranes could be efficiently sealed with mussel glue. Mussel glue showed comparable in vivo performance to fibrin glue in sealing fetal membranes though no apparent healing of the membranes could be observed in any of the samples. The limited ability of naturally derived scaffolds to promote fetal membrane healing inspired the engineering of synthetic plugging material with specifically tailored biological and mechanical properties which could activate the cells in the amnion and induce a healing response. In this thesis the modularly designed biomimetic poly(ethylene glycol) (PEG)-based hydrogel platform (called TG-PEG from here on) was used together with fetal cells to demonstrate that upon presentation of appropriate biological cues in 3D tissue mimicking environment, mesenchymal progenitor cells from amnion can be mobilized, induced to proliferate and supported in maintaining their native extracellular matrix production, thus creating a suitable environment for healing to take place. These data provide the basis for future engineering of materials with defined mechanical and biochemical properties and the ability to present migration and proliferation inducing factors, namely PDGF, bFGF, or EGF which could be key in resolving the clinical problem of iPPROM and allowing the field of fetal surgery to move forward. Cleft palate, where the bones of the palatal halves fail to fuse properly, is one of the most common birth defects. Tissue engineering has been envisioned as a treatment option but current approaches have been limited by the lack of i) appropriate autologous cell sources and ii) structural organization and vascularization. Tissue engineering of cleft palates using of autologous amniocentesis-derived and thus ethically unproblematic fetal amniotic fluid cells (AFCs) could be done parallel to the ongoing pregnancy with living reconstruction material being ready when the child is born. We describe using TG-PEG hydrogels to first evaluate 3D osteogenic differentiation of AFCs and creation of vascular structures from AFC derived endothelial cells (enAFC) and undifferentiated AFC either in random or organized channel cocultures in vitro and in vivo. Next, these approaches were combined in an osteogenic matrix with a channel perfused with enAFC and finally the integration and functional properties of these fetal bone constructs was tested in ectopic mouse model.

EPFL2015

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Radiotherapy Suppresses Angiogenesis in Mice through TGF-beta RI/ALK5-Dependent Inhibition of Endothelial Cell Sprouting

Natsuko Imaizumi

Background: Radiotherapy is widely used to treat cancer. While rapidly dividing cancer cells are naturally considered the main target of radiotherapy, emerging evidence indicates that radiotherapy also affects endothelial cell functions, and possibly also their angiogenic capacity. In spite of its clinical relevance, such putative anti-angiogenic effect of radiotherapy has not been thoroughly characterized. We have investigated the effect of ionizing radiation on angiogenesis using in vivo, ex vivo and in vitro experimental models in combination with genetic and pharmacological interventions.

Public Library of Science2010

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The bone marrow (BM) microenvironment, or niche, significantly affects behaviors of its resident stem cell populations. Disruptions in the BM niche contribute to a number of severe clinical pathologies. Discovery of novel therapeutic strategies for BM-related diseases necessitates development of superior preclinical models to study parameters affecting BM homeostasis. To address this, a poly(ethylene glycol) hydrogel featuring a particular crosslinking chemistry based on the enzyme transglutaminase factor XIII, dubbed TG-PEG, was utilized to engineer humanized bone marrow models. Its modular nature was exploited throughout this work to systematically evaluate contributions of biophysical, cellular, and biochemical BM niche components to stem cell biology. Stiffness of TG-PEG hydrogels was optimized for each cell type and individual application explored. For bone formation by bone marrow stromal cells (BMSCs), an intermediate stiffness was optimal and significantly improved total bone volume over softer TG-PEG gels or natural materials. Results indicated that stability of the scaffold was more important than their chemical and biological properties. Alternatively, for hematopoietic stem and progenitor cells (HSPCs), softer gels were optimal for preserving multipotency while promoting cell proliferation. A number of BM-specific stem and progenitor cell types with richly diverse functions were explored. Skeletal stem cells (SSCs) encapsulated in TG-PEG hydrogels demonstrated their ability to form de novo bone in healing critically sized calvaria defects in mice. Next, subcutaneous implantation of BMSC-laden gels revealed their significant contribution to formation of ossicles. For some BMSC donors, ossicles could be formed in absence of bone morphogenetic protein (BMP)-2 offering a novel tool to evaluate their intrinsic capacity. Later, titration of BMSC seeding densities and BMP-2 doses yielded optimal conditions for robust BM formation, regardless of donor, enabling reproducibility for follow-on studies involving BM models. In humanized mice, homing of HSPCs to BMSC-laden TG-PEG gels was observed. Finally, humanized xenograft models were employed to determine vulnerability of the BM niche to subversion by cancer cells simulating osteotropism for both leukemia and breast cancer metastasis. Molecular factors known to trigger particular cell reactions within the niche were also investigated. Including RGD cell-adhesion ligands, as well as matrix metalloproteinase (MMP)-susceptible crosslinks to render the gels degradable, were critical for facilitating migration of recruited BM cells from murine hosts in xenograft studies. Hyaluronic acid (HA), when added to the hydrogel backbone, conferred superior engraftment to transplanted BMSCs and afforded reduced immunogenicity. Incorporation of the Notch-signaling ligands Jagged1 or DLL-4 into soft TG-PEG gels during in vitro HSPC expansion substantially stimulated proliferation, but recovered cells could no longer ensure long-term reconstitution. Aging, trauma, or cancer can cause disruptions of the tightly controlled balance between cells and their microenvironment in the BM niche. This body of work presents a number of bioengineered tools optimized for studying how niche components are affected by or contribute to such pathologies. Further work with these or similar models will no doubt highlight key clinically relevant targets and inform novel therapeutic approaches.

EPFL2019

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Tissue engineering for prenatal applications

Anna-Sofia Johanna Kiveliö

EPFL2015

EPFL2019