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Stem Cell Expansion - Expansion and engraftment of haematopoietic and mesenchymal stem cells

Periodic Report Summary - STEMEXPAND (Stem cell expansion - expansion and engraftment of haematopoietic and mesenchymal stem cells)

STEMEXPAND aims to find methods to increase the number of human hematopoietic stem cells from umbilical cord blood and of mesenchymal stem cells to be used for transplantation into patients with serious blood disorders.

Work performed, results achieved so far, expected final results and their potential impact and use

The health issues related to serious blood disorders like leukaemia and genetic diseases remain a considerable burden to the EU countries, both in human and economic terms. In Sweden, the incident cases diagnosed with leukaemia during 2008 were 1 651. Extrapolated to the European population, this would mean over 100 000 annual cases of leukaemia in Europe. Despite considerable success with treatment using blood and marrow transplantation, during the last decades, lack of suitable donors, engraftment failure and graft versus host disease remain serious problems that need to be addressed. This project aims to address these issues through approaches that will allow expansion, i.e. increasing the number, of human hematopoietic stem cells from umbilical cord blood and of mesenchymal stem cells for transplantation.

Successful expansion of cord blood stem cells will increase the number of hematopoietic stem cells in cord blood samples enough to generate suitable donor samples for adult patients that die from their disease today due to lack of donors. During this process, a range of stem- and progenitor cells will be generated under GMP conditions to increase their number and improve their engraftment after transplantation to the patient. Both short-term and long-term engraftment is expected to improve and this in turn will increase the number of patients that will be cured and will also reduce the potential complications that can ensue upon transplantation. Therefore, the project is expected to have a major impact for healthcare in Europe and beyond.

We have through forward genetic screens and functional genomics delineated genes and pathways of importance for stem cell regulation and identified 12 candidate shRNAs that appear to dramatically increase the numbers of primitive hematopoietic cells in culture. These factors that induce expansion or enhanced survival of stem cells in will be considered for further testing in combination with other factors using conditions developed in this project. We have characterised and compared MSCs derived from bone marrow and subcutaneous fat from mamma reduction surgery, from subcutaneous fat from various orthopaedic procedures and from visceral fat from islet transplantation procedures. To develop serum free culture expansion conditions for mesenchymal stem cells we have performed direct comparisons of expansion conditions, including expansion on microcarriers in our bioreactor system, for both bone marrow and adipose tissue derived MCS. We found that expansion in complete serum-free medium is possible but far less efficient than in FBS-medium.

We are currently working on getting approval from the French competent authorities for a phase I transplantation trial using expanded umbilical cord blood stem cells. Two preclinical runs have been performed with CD34+ selected and expanded cells in GMP condition using clinical grade material. The trail will ultimately include 5-10 patients and the cells for transplantation will consist of one 'unmanipulated' unit of cord blood and one expanded unit. Before actually moving to clinical trials it will be necessary to perform additional pre-clinical runs, which are under way.

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