The Road to Maturity - Lineage Commitment in early Hematopoiesis
(2011) In Lund University Faculty of Medicine Doctoral Dissertation Series 2011:26.- Abstract
- The road to maturity – how do hematopoietic stem cells (HSC) differentiate
into mature blood cells? The pathways of lineage commitment during normal
hematopoiesis are of great significance in order to understand the underlying
events that lead to leukemia, and to the design of proper treatments for
prevention and remission of the disease. The route of hematopoiesis can be
thought of as a hierarchical tree, with the rare HSCs at the top, transitioning
down along the pathways as different progenitors. These progenitors continue
on their way to become mature blood cells. The roads of blood cell production
have been extensively studied in the adult mouse model, whereas... (More) - The road to maturity – how do hematopoietic stem cells (HSC) differentiate
into mature blood cells? The pathways of lineage commitment during normal
hematopoiesis are of great significance in order to understand the underlying
events that lead to leukemia, and to the design of proper treatments for
prevention and remission of the disease. The route of hematopoiesis can be
thought of as a hierarchical tree, with the rare HSCs at the top, transitioning
down along the pathways as different progenitors. These progenitors continue
on their way to become mature blood cells. The roads of blood cell production
have been extensively studied in the adult mouse model, whereas less is known
about the differentiation of cells during fetal mapping. It is not even known if
blood cell commitment follows the same route in adult as in fetal life. The fetal
map may be even more important to study since some pre-leukemic events are
of prenatal origin. This thesis focuses on the role of different cytokines in
lineage commitment, as well as on identifying the first lymphoid committed
progenitor in the early fetus.
The c-fms like tyrosine kinase 3 receptor (Flt3) is known to be important for
lymphopoiesis. However, Flt3 is often found mutated in acute myeloid
leukemia (AML), and then associated with poor prognosis. Despite the role in
AML, no role for Flt3 or its ligand has been found in myelopoiesis. But more
distinct stages of early myeloid progenitors can now be identified, and the role
of Flt3 in myelopoiesis could be investigated in detail. We found that early
myeloid progenitors express high levels of Flt3, and in mice deficient in Flt3
signaling myeloid progenitors are reduced. Taken together the data clearly
show a role of Flt3 signaling in early myelopoiesis, which has implications for
understanding the role of Flt3 mutations in AML.
In the next study the key cytokines in B lymphopoiesis were investigated. The
role of Flt3 signaling together with interleukin 7 (IL7) and a cytokine called
Thymic stromal lymphopoietin (TSLP) was studied. TSLP has been suggested
to have a key role in IL7 independent B cell development, although direct
evidence has been lacking. By using different knockout mice the role of the
three signaling pathways was investigated side by side in fetal and adult mice.
Mice deficient in all three signaling pathways lacked B cells, as did mice
deficient in IL7 and Flt3 signaling. The conclusion is that the IL7 and Flt3
signaling pathways are the main factors driving both fetal and adult B
lymphopoiesis.
In fetal hematopoiesis, as mentioned previously, the road to maturity is not well
understood. We aimed at identifying the first lymphoid commitment step in the
early embryo. A population in the fetal liver at 11.5 days post coitus (dpc),
expressing the markers Flt3 and IL7 receptor alfa (IL7Rα), was purified. It was
shown to have combined lymphoid and granulocyte/macrophage potential but
no megakaryocyte or erythroid potential at the single cell level. This population
could represent the first lympho-myeloid restricted cells in ontogeny, and
further evidence suggests that it might be the first progenitor that seeds the
thymus. By using a reporter mouse for recombination activating gene 1, Rag1,
(an early sign of lymphoid commitment), a lympho-myeloid restricted
population, expressing IL7Rα and Rag1-GFP, could be traced back to 9.5 dpc.
Fetal liver colonization has been shown to begin at 9.5 dpc and definitive adult
HSCs appear first one day later at 10.5 dpc. This study identifies a lymphomyeloid
restricted progenitor in the early embryo, notably arising prior to the
establishment of definitive HSCs, and suggests that lymphoid commitment
might take place outside the fetal liver niche. (Less) - Abstract (Swedish)
- Popular Abstract in Swedish
Benmärgstransplantation är idag en livsavgörande behandling som används vid
leukemi, men även andra sjukdomar. Trots att behandlingen funnits sedan
1950-talet medför den fortfarande komplikationer. Den är ibland inte heller
tillräckligt effektiv, och nya strategier behöver utvecklas. För att kunna
genomföra detta är det av stor betydelse att förstå hur sjukdomarna uppstår och
var i blodsystemet det blir fel. Man kan tänka sig blodsystemet som en
hierarkisk struktur, med den sällsynta blodstamcellen högst upp, vilken ensam
kan ge upphov till alla andra celler i blodsystemet, samtidigt som den kan
förnya sig själv. Blodsystemet... (More) - Popular Abstract in Swedish
Benmärgstransplantation är idag en livsavgörande behandling som används vid
leukemi, men även andra sjukdomar. Trots att behandlingen funnits sedan
1950-talet medför den fortfarande komplikationer. Den är ibland inte heller
tillräckligt effektiv, och nya strategier behöver utvecklas. För att kunna
genomföra detta är det av stor betydelse att förstå hur sjukdomarna uppstår och
var i blodsystemet det blir fel. Man kan tänka sig blodsystemet som en
hierarkisk struktur, med den sällsynta blodstamcellen högst upp, vilken ensam
kan ge upphov till alla andra celler i blodsystemet, samtidigt som den kan
förnya sig själv. Blodsystemet består av åtta olika mogna cellinjer, där alla har
olika funktioner, t.ex. transporterar erytrocyter syrgas, medan blodplättar
koagulerar blodet vid blödning. De vita blodkropparna försvarar oss mot
infektioner, och kan delas in i myeloida och lymfoida (T och B) celler. Men hur
ser vägen ut från stamcell till mogen blod cell – ”The road to maturity”?
Vägen till mognad sker i olika steg från stamcellen, som utvecklas till så
kallade progenitorer, förstadieceller. Cytokiner och deras receptorer är en
viktig del i regleringen av dessa förstadieceller. En intressant receptor är Flt3
som är viktig för utvecklingen av B och T celler. Receptorn har dock visat sig
vara muterad i akut myeloid leukemi (AML), och associerad med en sämre
prognos. Det är förvånande att receptorn är så frekvent muterad vid AML, då
man i tidigare studier inte kunnat finna att receptorn har någon roll i
utvecklingen av myeloida celler. Nya data har gjort det möjligt att mer i detalj
studera myeloida förstadieceller, och vi har därmed kunnat kartlägga att Flt3
har en roll i tidiga stadier av den myeloida utvecklingen. Detta har betydelse
för att kunna förstå Flt3 mutationer vid AML.
Flt3 är som nämnts viktig vid utveckling av lymfoida celler. Interleukin 7 (IL7)
och dess receptor är en annan faktor som spelar stor roll för immunsystemets
celler. Om båda dessa faktorer saknas utvecklas inga B celler, varken under
fosterlivet eller som vuxen. En annan tillväxtfaktor, TSLP, har föreslagits vara
viktig för B cells utveckling. Genom att använda olika genmodifierade möss
har vi däremot kunnat visa att det är IL7 och Flt3 som är viktiga vid utveckling
av B celler i mus. Vid en immunbristsjukdom som kallas SCID, har man en
defekt i IL7 signaleringen, och patienterna saknar T celler, men har till skillnad
från vår musmodell B celler. Det återstår att undersöka vilka cytokiner som
påverkar utvecklingen av humana B celler. Möjligen kan Flt3 ha en betydande
roll.
Vägen till B och T celler, de lymfoida cellerna har studerats i vuxna möss,
medan det är ganska oklart hur det ser ut under fosterlivet. Framförallt är det
oklart när och hur denna process börjar. Vi har nu studerat lymfoida
progenitorer under fosterlivet i detalj och finner att man kan hitta dessa mycket
tidigt i utvecklingen, innan man hittar definitiva blodstamceller och innan
levern har blivit ett blodbildande organ. Intressant är att vissa av de mutationer
som leder till barnleukemi, akut lymfatisk leukemi (ALL), uppstår redan under
fosterstadiet. Det är därför av största vikt att förstå hur lymfoida celler
utvecklas under fosterlivet. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/1790164
- author
- Böiers, Charlotta LU
- supervisor
- opponent
-
- Professor Dzierzak, Elaine, Department of Cell Biology and Genetics, Erasmus University, the Netherlands
- organization
- publishing date
- 2011
- type
- Thesis
- publication status
- published
- subject
- in
- Lund University Faculty of Medicine Doctoral Dissertation Series
- volume
- 2011:26
- pages
- 69 pages
- publisher
- Lund Stem Cell Center
- defense location
- Segerfalksalen, BMC A10
- defense date
- 2011-03-18 13:00:00
- ISSN
- 1652-8220
- ISBN
- 978-91-86671-74-7
- language
- English
- LU publication?
- yes
- additional info
- The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Hematopoietic Stem Cell Laboratory (013022012)
- id
- 1fda102c-d3b1-4ac5-8e8c-6917cb117417 (old id 1790164)
- date added to LUP
- 2016-04-01 15:04:38
- date last changed
- 2019-05-21 23:39:39
@phdthesis{1fda102c-d3b1-4ac5-8e8c-6917cb117417,
abstract = {{The road to maturity – how do hematopoietic stem cells (HSC) differentiate<br/><br>
into mature blood cells? The pathways of lineage commitment during normal<br/><br>
hematopoiesis are of great significance in order to understand the underlying<br/><br>
events that lead to leukemia, and to the design of proper treatments for<br/><br>
prevention and remission of the disease. The route of hematopoiesis can be<br/><br>
thought of as a hierarchical tree, with the rare HSCs at the top, transitioning<br/><br>
down along the pathways as different progenitors. These progenitors continue<br/><br>
on their way to become mature blood cells. The roads of blood cell production<br/><br>
have been extensively studied in the adult mouse model, whereas less is known<br/><br>
about the differentiation of cells during fetal mapping. It is not even known if<br/><br>
blood cell commitment follows the same route in adult as in fetal life. The fetal<br/><br>
map may be even more important to study since some pre-leukemic events are<br/><br>
of prenatal origin. This thesis focuses on the role of different cytokines in<br/><br>
lineage commitment, as well as on identifying the first lymphoid committed<br/><br>
progenitor in the early fetus.<br/><br>
The c-fms like tyrosine kinase 3 receptor (Flt3) is known to be important for<br/><br>
lymphopoiesis. However, Flt3 is often found mutated in acute myeloid<br/><br>
leukemia (AML), and then associated with poor prognosis. Despite the role in<br/><br>
AML, no role for Flt3 or its ligand has been found in myelopoiesis. But more<br/><br>
distinct stages of early myeloid progenitors can now be identified, and the role<br/><br>
of Flt3 in myelopoiesis could be investigated in detail. We found that early<br/><br>
myeloid progenitors express high levels of Flt3, and in mice deficient in Flt3<br/><br>
signaling myeloid progenitors are reduced. Taken together the data clearly<br/><br>
show a role of Flt3 signaling in early myelopoiesis, which has implications for<br/><br>
understanding the role of Flt3 mutations in AML.<br/><br>
In the next study the key cytokines in B lymphopoiesis were investigated. The<br/><br>
role of Flt3 signaling together with interleukin 7 (IL7) and a cytokine called<br/><br>
Thymic stromal lymphopoietin (TSLP) was studied. TSLP has been suggested<br/><br>
to have a key role in IL7 independent B cell development, although direct<br/><br>
evidence has been lacking. By using different knockout mice the role of the<br/><br>
three signaling pathways was investigated side by side in fetal and adult mice.<br/><br>
Mice deficient in all three signaling pathways lacked B cells, as did mice<br/><br>
deficient in IL7 and Flt3 signaling. The conclusion is that the IL7 and Flt3<br/><br>
signaling pathways are the main factors driving both fetal and adult B<br/><br>
lymphopoiesis.<br/><br>
In fetal hematopoiesis, as mentioned previously, the road to maturity is not well<br/><br>
understood. We aimed at identifying the first lymphoid commitment step in the<br/><br>
early embryo. A population in the fetal liver at 11.5 days post coitus (dpc),<br/><br>
expressing the markers Flt3 and IL7 receptor alfa (IL7Rα), was purified. It was<br/><br>
shown to have combined lymphoid and granulocyte/macrophage potential but<br/><br>
no megakaryocyte or erythroid potential at the single cell level. This population<br/><br>
could represent the first lympho-myeloid restricted cells in ontogeny, and<br/><br>
further evidence suggests that it might be the first progenitor that seeds the<br/><br>
thymus. By using a reporter mouse for recombination activating gene 1, Rag1,<br/><br>
(an early sign of lymphoid commitment), a lympho-myeloid restricted<br/><br>
population, expressing IL7Rα and Rag1-GFP, could be traced back to 9.5 dpc.<br/><br>
Fetal liver colonization has been shown to begin at 9.5 dpc and definitive adult<br/><br>
HSCs appear first one day later at 10.5 dpc. This study identifies a lymphomyeloid<br/><br>
restricted progenitor in the early embryo, notably arising prior to the<br/><br>
establishment of definitive HSCs, and suggests that lymphoid commitment<br/><br>
might take place outside the fetal liver niche.}},
author = {{Böiers, Charlotta}},
isbn = {{978-91-86671-74-7}},
issn = {{1652-8220}},
language = {{eng}},
publisher = {{Lund Stem Cell Center}},
school = {{Lund University}},
series = {{Lund University Faculty of Medicine Doctoral Dissertation Series}},
title = {{The Road to Maturity - Lineage Commitment in early Hematopoiesis}},
volume = {{2011:26}},
year = {{2011}},
}