The Road to Maturity - Lineage Commitment in early Hematopoiesis

Charlotta Böiers

The Road to Maturity - Lineage Commitment in early Hematopoiesis

Stamcellscentrum (SCC)

Forskningsoutput: Avhandling › Doktorsavhandling (sammanläggning)

Sammanfattning

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.

Originalspråk	engelska
Kvalifikation	Doktor
Tilldelande institution	Stamcellscentrum (SCC)
Handledare	Jacobsen, Sten Eirik W, handledare Sitnicka Quinn, Ewa, handledare Hultquist, Anne, handledare
Tilldelningsdatum	2011 mars 18
Förlag	Lund Stem Cell Center
ISBN (tryckt)	978-91-86671-74-7
Status	Published - 2011

Bibliografisk information

Defence details

Date: 2011-03-18
Time: 13:00
Place: Segerfalksalen, BMC A10

External reviewer(s)

Name: Dzierzak, Elaine
Title: Professor
Affiliation: Department of Cell Biology and Genetics, Erasmus University, the Netherlands

---

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)

Ämnesklassifikation (UKÄ)

Cell- och molekylärbiologi

2 Artikel i vetenskaplig tidskrift
1 Letter

Expression and role of FLT3 in regulation of the earliest stage of normal granulocyte-monocyte progenitor development.
Böiers, C., Buza-Vidas, N., Jensen, C., Pronk, K-J., Kharazi, S., Wittmann, L., Sitnicka Quinn, E., Hultquist, A. & Jacobsen, S. E. W., 2010, I: Blood. May 4, s. 5061-5068
Forskningsoutput: Tidskriftsbidrag › Artikel i vetenskaplig tidskrift › Peer review
FLT3 ligand and not TSLP is the key regulator of IL-7-independent B-1 and B-2 B Lymphopoiesis.
Jensen, C., Kharazi, S., Böiers, C., Cheng, M., Lübking, A., Sitnicka Quinn, E. & Jacobsen, S. E. W., 2008, I: Blood. 112, s. 2297-2304
Forskningsoutput: Tidskriftsbidrag › Artikel i vetenskaplig tidskrift › Peer review

Öppen tillgång
TSLP-mediated fetal B lymphopoiesis?
Jensen, C., Kharazi, S., Böiers, C., Liuba, K. & Jacobsen, S. E. W., 2007, I: Nature Immunology. 8, 9, s. 897-897
Forskningsoutput: Tidskriftsbidrag › Letter › Peer review

Citera det här

@phdthesis{1fda102cd3b14ac58e8c6917cb117417,

title = "The Road to Maturity - Lineage Commitment in early Hematopoiesis",

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 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.",

author = "Charlotta B{\"o}iers",

note = "Defence details Date: 2011-03-18 Time: 13:00 Place: Segerfalksalen, BMC A10 External reviewer(s) Name: Dzierzak, Elaine Title: Professor Affiliation: Department of Cell Biology and Genetics, Erasmus University, the Netherlands --- 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)",

year = "2011",

language = "English",

isbn = "978-91-86671-74-7",

series = "Lund University Faculty of Medicine Doctoral Dissertation Series ",

publisher = "Lund Stem Cell Center",

school = "Stem Cell Center",

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N2 - 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.

AB - 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.

M3 - Doctoral Thesis (compilation)

SN - 978-91-86671-74-7

T3 - Lund University Faculty of Medicine Doctoral Dissertation Series

PB - Lund Stem Cell Center

ER -

The Road to Maturity - Lineage Commitment in early Hematopoiesis

Sammanfattning

Bibliografisk information

Ämnesklassifikation (UKÄ)

Fingeravtryck

Forskningsoutput

Expression and role of FLT3 in regulation of the earliest stage of normal granulocyte-monocyte progenitor development.

FLT3 ligand and not TSLP is the key regulator of IL-7-independent B-1 and B-2 B Lymphopoiesis.

TSLP-mediated fetal B lymphopoiesis?

Citera det här