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

Research output: ThesisDoctoral Thesis (compilation)

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.

Details

Authors
  • Karina Liuba
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cell and Molecular Biology
  • Obstetrics, Gynecology and Reproductive Medicine

Keywords

  • in utero hematopoietic cell transplantation, hematopoietic stem cell, multipotent progenitor, fetal therapy, heterotypic cell fusion
Original languageEnglish
QualificationDoctor
Awarding Institution
Supervisors/Assistant supervisor
Award date2009 Sep 11
Publisher
  • Department of Obstetrics and Gynecology, Lund University
Print ISBNs978-91-86253-76-9
Publication statusPublished - 2009
Publication categoryResearch

Bibliographic 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)

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Related research output

Liuba, K., Kees-Jan Pronk, Stott, S. & Jacobsen, S. E. W., 2009, In : Blood. 113, 19, p. 4790-4798

Research output: Contribution to journalArticle

Nygren, J., Liuba, K., Breitbach, M., Stott, S., Thorén, L., Roell, W., Geisen, C., Sasse, P., Deniz Kirik, Anders Björklund, Nerlov, C., Fleischmann, B. K., Jovinge, S. & Jacobsen, S. E. W., 2008, In : Nature Cell Biology. 10, 5, p. 584-592

Research output: Contribution to journalArticle

Adolfsson, J., Månsson, R., Buza-Vidas, N., Anne Hultquist, Liuba, K., Christina Jensen, David Bryder, Yang, L., Borge, OJ., Thorén, L., Anderson, K., Ewa Sitnicka Quinn, Sasaki, Y., Mikael Sigvardsson & Jacobsen, S. E. W., 2005, In : Cell. 121, 2, p. 295-306

Research output: Contribution to journalArticle

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