Hematopoietic stem and progenitor cells and potentials for application in fetal cell replacement therapy

Research output: ThesisDoctoral Thesis (compilation)

Bibtex

@phdthesis{795f8242bd3040adb9da1fd9bba79ee5,
title = "Hematopoietic stem and progenitor cells and potentials for application in fetal cell replacement therapy",
abstract = "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.",
keywords = "in utero hematopoietic cell transplantation, hematopoietic stem cell, multipotent progenitor, fetal therapy, heterotypic cell fusion",
author = "Karina Liuba",
note = "Defence details Date: 2009-09-11 Time: 13:00 Place: Conference room, Department of Obstetrics and Gynecology, Lund University Hospital External reviewer(s) Name: LeBlanc, Katarina Title: Prof Affiliation: Karolinka Institutet, Stockholm --- The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Department of Obstetrics and Gynaecology (Lund) (013018000), Hematopoietic Stem Cell Laboratory (013022012)",
year = "2009",
language = "English",
isbn = "978-91-86253-76-9",
series = "Lund University Faculty of Medicine Doctoral Dissertation Series",
publisher = "Department of Obstetrics and Gynecology, Lund University",
school = "Department of Obstetrics and Gynaecology (Lund)",

}