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

Research output: ThesisDoctoral Thesis (compilation)

Standard

Hematopoietic stem and progenitor cells and potentials for application in fetal cell replacement therapy. / Liuba, Karina.

Department of Obstetrics and Gynecology, Lund University, 2009. 71 p.

Research output: ThesisDoctoral Thesis (compilation)

Harvard

Liuba, K 2009, 'Hematopoietic stem and progenitor cells and potentials for application in fetal cell replacement therapy', Doctor, Department of Obstetrics and Gynaecology (Lund).

APA

Liuba, K. (2009). Hematopoietic stem and progenitor cells and potentials for application in fetal cell replacement therapy. Department of Obstetrics and Gynecology, Lund University.

CBE

Liuba K. 2009. Hematopoietic stem and progenitor cells and potentials for application in fetal cell replacement therapy. Department of Obstetrics and Gynecology, Lund University. 71 p.

MLA

Liuba, Karina Hematopoietic stem and progenitor cells and potentials for application in fetal cell replacement therapy Department of Obstetrics and Gynecology, Lund University. 2009.

Vancouver

Liuba K. Hematopoietic stem and progenitor cells and potentials for application in fetal cell replacement therapy. Department of Obstetrics and Gynecology, Lund University, 2009. 71 p. (Lund University Faculty of Medicine Doctoral Dissertation Series ).

Author

Liuba, Karina. / Hematopoietic stem and progenitor cells and potentials for application in fetal cell replacement therapy. Department of Obstetrics and Gynecology, Lund University, 2009. 71 p.

RIS

TY - THES

T1 - Hematopoietic stem and progenitor cells and potentials for application in fetal cell replacement therapy

AU - Liuba, Karina

N1 - 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)

PY - 2009

Y1 - 2009

N2 - 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.

AB - 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.

KW - in utero hematopoietic cell transplantation

KW - hematopoietic stem cell

KW - multipotent progenitor

KW - fetal therapy

KW - heterotypic cell fusion

M3 - Doctoral Thesis (compilation)

SN - 978-91-86253-76-9

T3 - Lund University Faculty of Medicine Doctoral Dissertation Series

PB - Department of Obstetrics and Gynecology, Lund University

ER -