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Defining regulators of hematopoietic stem cell homing and engraftment

Transplantation of hematopoietic stem cells (HSC) is a life-saving treatment for many serious diseases. Unfortunately, the procedure is often hampered by insufficient numbers of donor stem cells and attempts to expand HSCs ex vivo... ver más

24/02/2013

172K€

Presupuesto del proyecto: 172K€

Líder del proyecto

MAX IV Laboratory, Lund University No se ha especificado una descripción o un objeto social para esta compañía.

Fecha límite participación Sin fecha límite de participación.

Financiación concedida El organismo FP7 notifico la concesión del proyecto el día 2013-02-24 No tenemos la información de la convocatoria

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Este proyecto no cuenta con búsquedas de partenariado abiertas en este momento.

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1 Participantes

171.83K€ | Lider

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Líder del proyecto

MAX IV Laboratory, Lund University No se ha especificado una descripción o un objeto social para esta compañía.

Presupuesto del proyecto 172K€

Fecha límite de participación Sin fecha límite de participación.

Descripción del proyecto Transplantation of hematopoietic stem cells (HSC) is a life-saving treatment for many serious diseases. Unfortunately, the procedure is often hampered by insufficient numbers of donor stem cells and attempts to expand HSCs ex vivo prior to transplantation have remained unsuccessful. An important alternative, which significantly would reduce the required number of donor cells, is to enhance the engraftment efficiency of the transplanted HSCs. The aim of this project is to identify factors that regulate homing and adhesion of HSCs using an RNA interference based screening approach. The principle of the approach is to use lentiviral short-hairpin RNA (shRNA) libraries targeted to HSCs to screen for modifiers of cell adhesion. Adhesive interactions with extracellular matrix and surrounding cells, the so-called niche, are essential for HSC biology. Mesenchymal stroma cells (MSCs) will be used as a model for the adhesive interactions in the hematopoietic niche. When seeded on a layer of MSCs, the vast majority of human HSCs remain adherent to the MSCs. These highly adhesive properties of HSCs constitute a baseline for functional selection of shRNAs interfering with adhesion. Large numbers of HSCs will be targeted with pooled shRNA libraries and candidate shRNAs will be retrieved by functional selection of cells with reduced adhesive properties. The method has been standardized using shRNAs targeting the known mediator of cell adhesion, CD29 (β1 integrin). Knock down of CD29 in HSCs dramatically decreased their adhesion to MSCs. Candidate genes from the screens will be characterized for their role in homing and engraftment of HSCs by assays in vitro as well as in vivo through the ability to repopulate bone marrow of immundeficient NOD/SCID mice. Understanding the basic mechanisms that regulate homing and adhesion of HSCs to their niche is essential in order to develop strategies that may enhance the engraftment process in clinical settings.

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