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Hematopoietic stem ...
Hematopoietic stem and progenitor cells and potentials for application in fetal cell replacement therapy
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- Liuba, Karina (författare)
- Lund University,Lunds universitet,Obstetrik och gynekologi, Lund,Sektion V,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Stamcellscentrum (SCC),Avdelningen för stamcellsforskning,Institutionen för laboratoriemedicin,Obstetrics and Gynaecology (Lund),Section V,Department of Clinical Sciences, Lund,Faculty of Medicine,Stem Cell Center,Division of stem cell research,Department of Laboratory Medicine
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(creator_code:org_t)
- ISBN 9789186253769
- 2009
- Engelska 71 s.
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Serie: Lund University Faculty of Medicine Doctoral Dissertation Series, 1652-8220
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Abstract
Ämnesord
Stäng
- Fetal cell replacement therapy or in utero hematopoietic cell transplantation (IUHCT) is proposed as a non-myeloablative alternative to bone marrow transplantation (BMT) for a number of inborn immunologic, hematologic and metabolic disorders. IUHCT represents the method through which variable amounts of natural or genetically modified hematopoietic cells can be transferred to the fetal recipient in hope of correcting the disorder and preventing postnatal permanent organ damage. Although proof-of-principle has been achieved by succesful correction of X linked severe combined immune deficiency (X-SCID), in the majority of target diseases treated with IUHCT engraftment was insufficient for clinical benefit. Thus, the therapeutical promise of IUHCT remains unfullfilled and many challenges stand. In the present thesis we investigate the optimal cell population for IUHCT by first identifying a novel commitment/differentiation step of hematopoietic stem cells (HSCs) in adult murine hematopoiesis and then evaluating the therapeutical potential of the lymphoid primed multipotent progenitors (LMPPs) for immune reconstitution in a model of fetal X-SCID transplantation. We find that LMPPs generate rapid and sustained lymphoid reconstitution with polyclonal T cells, but that HSCs are most likely required for long term engraftment. We also find that the fetal microenvironment is apparently more receptive to donor HSCs (but also LMPPs) as it allows higher levels of chimerism after IUHCT then after BMT in neonatal or adult age. In the last part we investigate in adult and fetal animal models the proposed plasticity of HSCs, a feature that holds promise for clinical BMT (or IUHCT) to non-hematopoietic disorders. We find that HSCs plasticity is a result of heterotypic cell fusion, probably induced by inflammation/injury in the target tissue. We also show that heterotypic cell fusion is not a physiological frequently occuring event during development and we demonstrate that not only myeloid, but also lymphoid cells are efficient fusogenic partners to non-hematopoietic tissues.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Reproduktionsmedicin och gynekologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Obstetrics, Gynaecology and Reproductive Medicine (hsv//eng)
Nyckelord
- in utero hematopoietic cell transplantation
- hematopoietic stem cell
- multipotent progenitor
- fetal therapy
- heterotypic cell fusion
Publikations- och innehållstyp
- dok (ämneskategori)
- vet (ämneskategori)
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