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The Road to Maturity - Lineage Commitment in early Hematopoiesis

Böiers, Charlotta LU (2011) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2011:26.
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)
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)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Professor Dzierzak, Elaine, Department of Cell Biology and Genetics, Erasmus University, the Netherlands
organization
publishing date
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
ISSN
1652-8220
ISBN
978-91-86671-74-7
language
English
LU publication?
yes
id
1fda102c-d3b1-4ac5-8e8c-6917cb117417 (old id 1790164)
date added to LUP
2011-02-24 09:24:14
date last changed
2016-09-19 08:44:52
@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},
  pages        = {69},
  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},
}