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Integrin α2 and Akt in early hematopoiesis

Wong, Wan Man LU (2013) In Lund University Faculty of Medicine Doctoral Dissertation Series 2013:144.
Abstract
Hematopoiesis is a tightly regulated process in which hematopoietic stem cells reside at the apex of the hierarchy,

and produce all kinds of mature blood cells by differentiation to replenish the cell loss in homeostasis and acute

injury. In past few decades, much effort has been made to purify hematopoietic stem cells (HSCs) and lineagecommitted

progenitor cells both in mouse and human, enabling further characterization of these cell populations

not only in normal hematopoiesis, but also in various hematological malignancies. However, while the isolation of

different cell populations in mouse hematopoietic system is achieved with a very high purity, purification of

human hematopoietic... (More)
Hematopoiesis is a tightly regulated process in which hematopoietic stem cells reside at the apex of the hierarchy,

and produce all kinds of mature blood cells by differentiation to replenish the cell loss in homeostasis and acute

injury. In past few decades, much effort has been made to purify hematopoietic stem cells (HSCs) and lineagecommitted

progenitor cells both in mouse and human, enabling further characterization of these cell populations

not only in normal hematopoiesis, but also in various hematological malignancies. However, while the isolation of

different cell populations in mouse hematopoietic system is achieved with a very high purity, purification of

human hematopoietic stem and progenitor cells still far lags behind.



Integrins are heterodimeric transmembrane protein receptors regulating many important cellular processes

including homing of HSCs by binding to neighboring cells or extracellular matrix proteins. First, we showed that

integrin α2 is a novel marker improving the prospective isolation of human cord blood HSCs. We found integrin

α2 receptor was preferentially expressed in cord blood-derived CD34+CD38-CD90+ in vivo long-term

repopulating cells, demonstrated by 24-week limiting-dilution xenotransplantations using immunodeficient mice.

Second, we revealed that integrin α2, which is a marker for megakaryoctyes and platelets, was not expressed in the

immature CD34+CD38-CD45RA- bipotential megakaryocyte-erythrocyte progenitors in human bone marrow,

providing a means for enriching this novel bipotent progenitor population for further studies on early

megakaryocytic and erythroid lineage fate decisions. In addition, we demonstrated that hyperactivation of Akt,

which is a key intrinsic factor regulating the homeostasis of HSCs, was incompatible with the survival and growth

promoting ability of FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) signaling in murine stem

and progenitor cells.



Prospective isolation of more homogenous stem and progenitor cell populations in human and understanding the

instrinsic regulation of HSC homeostasis will give important insights into the HSC maintenance and fate decisions

in normal hematopoiesis, as well as the pathogenesis of various hematological disorders. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Porse, Bo Torben, Biotech Research and Innovation Centre, University of Copenhagen
organization
publishing date
type
Thesis
publication status
published
subject
in
Lund University Faculty of Medicine Doctoral Dissertation Series
volume
2013:144
pages
87 pages
publisher
Stem Cell Center, Lund University
defense location
Segerfalk Lecture Hall, BMC A10, Sölvegatan 17
defense date
2013-12-18 13:00:00
ISSN
1652-8220
ISBN
978-91-87651-19-9
language
English
LU publication?
yes
id
11edcfae-2131-48ea-ac8b-a9a7f47dccaa (old id 4174628)
date added to LUP
2016-04-01 14:21:07
date last changed
2019-05-22 04:24:58
@phdthesis{11edcfae-2131-48ea-ac8b-a9a7f47dccaa,
  abstract     = {Hematopoiesis is a tightly regulated process in which hematopoietic stem cells reside at the apex of the hierarchy,<br/><br>
and produce all kinds of mature blood cells by differentiation to replenish the cell loss in homeostasis and acute<br/><br>
injury. In past few decades, much effort has been made to purify hematopoietic stem cells (HSCs) and lineagecommitted<br/><br>
progenitor cells both in mouse and human, enabling further characterization of these cell populations<br/><br>
not only in normal hematopoiesis, but also in various hematological malignancies. However, while the isolation of<br/><br>
different cell populations in mouse hematopoietic system is achieved with a very high purity, purification of<br/><br>
human hematopoietic stem and progenitor cells still far lags behind.<br/><br>
<br/><br>
Integrins are heterodimeric transmembrane protein receptors regulating many important cellular processes<br/><br>
including homing of HSCs by binding to neighboring cells or extracellular matrix proteins. First, we showed that<br/><br>
integrin α2 is a novel marker improving the prospective isolation of human cord blood HSCs. We found integrin<br/><br>
α2 receptor was preferentially expressed in cord blood-derived CD34+CD38-CD90+ in vivo long-term<br/><br>
repopulating cells, demonstrated by 24-week limiting-dilution xenotransplantations using immunodeficient mice.<br/><br>
Second, we revealed that integrin α2, which is a marker for megakaryoctyes and platelets, was not expressed in the<br/><br>
immature CD34+CD38-CD45RA- bipotential megakaryocyte-erythrocyte progenitors in human bone marrow,<br/><br>
providing a means for enriching this novel bipotent progenitor population for further studies on early<br/><br>
megakaryocytic and erythroid lineage fate decisions. In addition, we demonstrated that hyperactivation of Akt,<br/><br>
which is a key intrinsic factor regulating the homeostasis of HSCs, was incompatible with the survival and growth<br/><br>
promoting ability of FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) signaling in murine stem<br/><br>
and progenitor cells.<br/><br>
<br/><br>
Prospective isolation of more homogenous stem and progenitor cell populations in human and understanding the<br/><br>
instrinsic regulation of HSC homeostasis will give important insights into the HSC maintenance and fate decisions<br/><br>
in normal hematopoiesis, as well as the pathogenesis of various hematological disorders.},
  author       = {Wong, Wan Man},
  isbn         = {978-91-87651-19-9},
  issn         = {1652-8220},
  language     = {eng},
  publisher    = {Stem Cell Center, Lund University},
  school       = {Lund University},
  series       = {Lund University Faculty of Medicine Doctoral Dissertation Series },
  title        = {Integrin α2 and Akt in early hematopoiesis},
  url          = {https://lup.lub.lu.se/search/ws/files/3926598/4174629.pdf},
  volume       = {2013:144},
  year         = {2013},
}