The role of TGF-§ in hematopoiesis

Research output: ThesisDoctoral Thesis (compilation)

Abstract

Transforming growth factor-§ (TGF-§) is a potent, multifunctional growth factor affecting virtually all cell types, regulating critical physiological processes like immune response, wound healing, angiogenesis, and tumor development. A large number of studies in vitro have also implicated a critical role of TGF-§ in regulating hematopoiesis by inhibiting proliferation of hematopoietic stem cells (HSCs). However, how TGF-§ regulates hematopoiesis and HSCs in vivo has been poorly understood. In order to address this, Cre/loxP gene targeting in mice was used to generate knockout mice with either ubiquitous or inducible disruption of the TGF-§ receptors type I and type II (T§RI and T§RII). Mice lacking T§RI in all cells die at midgestation exhibiting defective yolk sac vessels and an absence of circulating red blood cells. The hematopoietic potential is, however, intact in these embryos as demonstrated by efficient in vitro colony formation by hematopoietic progenitors from the yolk sacs. Endothelial cells isolated from T§RI null embryos had several abnormal functions associated with the defective vasculature, including increased proliferation, deficient fibronectin synthesis and impaired migration. Adult mice with an induced disruption of either T§RI or T§RII, develop a rapidly progressing lethal inflammatory disorder. The inflammatory phenotype can be transferred by transplantation of bone marrow (BM) from induced knockout mice into lethally irradiated normal recipient mice. These mice die 8-9 weeks following BM transfer and exhibit multiple inflammatory lesions in various organs. Analysis of hematopoiesis in induced T§RI knockout mice, before onset of disease, showed normal blood cell counts and BM cellularity as well as normal numbers and cell cycle activity of progenitors and HSCs. Furthermore, the repopulation kinetics of HSCs following BM transplantation were normal, as measured by competitive repoulation in both primary and secondary recipients. Together, these findings demonstrate that TGF-§ signaling through T§RI is essential for endothelial cell function and vessel development in vivo. Moreover, and that lack of TGF-§ signalling in cells of hematopoietic origin is both necessary and sufficient to cause a lethal inflammatory disorder. In contrast to previous studies, these in vivo models show that TGF-§ signaling is dispensable for normal development of hematopietic precursors during embryogenesis as well as for normal hematopoiesis and HSC function in adult mice.

Details

Authors
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Hematology

Keywords

  • Transforming growth factor-§, Cre/loxP system, receptor, knockout, embryogenesis, angiogenesis, hematopoiesis, hematopoietic stem cell, inflammation, Medicine (human and vertebrates), Medicin (människa och djur)
Original languageEnglish
QualificationDoctor
Awarding Institution
Supervisors/Assistant supervisor
  • [unknown], [unknown], Supervisor, External person
Award date2002 Nov 16
Publisher
  • Jonas Larsson, BMC A12, 221 84 Lund,
Print ISBNs91-628-5388-0
Publication statusPublished - 2002
Publication categoryResearch

Bibliographic note

Defence details Date: 2002-11-16 Time: 10:15 Place: Segerfalksalen, Wallenberg Neurocentrum, Sölvegatan 17, Lund External reviewer(s) Name: Scadden, David T. Title: [unknown] Affiliation: MD, Massachusetts General Hospital, Harvard Medical School, Boston USA --- Article: I Larsson, J., Goumans, M.-J., Jansson Sjöstrand, L., van Rooijen, M.A., Ward, D., Levéen, P., Xu, X., ten Dijke, P., Mummery, C.L., Karlsson, S. (2001) Abnormal angiogenesis but intact hematopoietic potential in TGF-b type I receptor deficient mice. EMBO J. 20(7): 1663-1673 Article: II Levéen, P., Larsson, J., Ehinger, M., Sundler, M., Jansson Sjöstrand, L., Holmdahl, R., and Karlsson, S. (2002) Induced Disruption of the TGF-b Type II Receptor Gene in Mice Leads to a Lethal Inflammatory Disorder that is Transplantable. Blood 100(2): 560-568 Article: III Larsson, J., Blank, U., Helgadottir, H., Levéen, P., Björnsson, JM., Fan, X., Karlsson, S. TGF-b signaling is dispensable for normal hematopoietic stem cell function in adult mice. Submitted