Understanding the heterogeneity of the hematopoietic stem cells
Author: Somuncular, Ece
Date: 2022-12-16
Location: Neo Gene, Blickagången 16, Karolinska Institutet, Flemingsberg
Time: 09.00
Department: Inst för medicin, Huddinge / Dept of Medicine, Huddinge
View/ Open:
Thesis (1.491Mb)
Abstract
The hematopoietic system is replenished and maintained throughout life by rare hematopoietic stem cells (HSCs) that reside in the bone marrow (BM) of adult mammals. Over the last 20 years, the advancement in the field lead to the acknowledgement of the heterogeneity within the HSC compartment unraveling the presence of HSC subsets with certain mature blood lineage preferences so called lineage-biased (Li-bi) HSCs. Studying the heterogeneity and lineage bias within the HSC compartment is crucial not only to understand the functional and molecular mechanisms behind this lineage skewing but can also shed light on the emergence of hematological malignancies subsequently paving the way to find new therapeutic targets, better treatment options and more selective alternatives of BM transplantation.
Recent developments have taken advantage of immunophenotypic markers for prospective isolation of cells. The cell surface markers can be used to enrich for HSCs but cannot purify. Current markers cannot resolve heterogeneity within the HSC compartment, highlighting the importance of continuing efforts on identifying new cell surface markers that enrich Li-bi HSC subtypes. In paper I, we demonstrate that CD49b cell surface marker subfractionates the most primitive HSC compartment into two; CD49b– HSCs with myeloid bias, high self-renewal potential and the most quiescent state, and CD49b+ HSCs with lymphoid bias, lowered selfrenewal potential and more proliferative state. Furthermore, we show that both subsets have similar transcriptome profiles but distinct epigenetic landscapes highlighting that the lineage-bias is regulated via epigenetic mechanisms. In paper III, we show that using the additional cell surface marker CD229, the remaining heterogeneity within the CD49b+ HSCs can be resolved into two functional subsets as CD49b+CD229– and CD49b+CD229+. The CD49b+CD229– fraction shows long-term and stable reconstitution and the CD49b+CD229+ fraction enriches for multipotent progenitor cells having short term activity.
Hematopoietic aging is associated with myeloid skewing, delayed, and reduced immune response and higher incidences of myeloid malignancies. The composition of HSC compartment changes with a shift toward an increased proportion of myeloid biased HSCs in elderly both in human and mice. However, the molecular mechanisms behind this phenomenon are not completely understood. In paper II, we show that the CD49b– HSC maintains its myeloid bias in the peripheral blood of the young, young adult and old age groups whereas the CD49b+ HSC shifts from lymphoid bias in young and young adult to lineage-balance (no bias) in aged mice. In addition, we demonstrate that both subsets are equally active in young and have similar chromatin landscapes with different levels of accessible regions in old mice.
The B cell lineage priming occurs downstream of HSCs starting at the branching point of multipotent progenitors in the hematopoietic hierarchy. The B cell development is highly regulated by transcriptional factors. In paper IV, we show that combined loss of transcription factors FOXO1 and FOXO3 prevents the B cell development by blocking it at the BLP stage. Moreover, we demonstrate that FOXO3 plays a crucial role in regulating the B cell lineage priming higher up in the hematopoietic hierarchy already as early as the LMPP level.
Collectively, this thesis identifies cell surface markers that resolves the functional heterogeneity of the HSCs, gives insights into how the lineage bias is regulated during aging, and unravels the effect of transcription factors in B cell development.
Recent developments have taken advantage of immunophenotypic markers for prospective isolation of cells. The cell surface markers can be used to enrich for HSCs but cannot purify. Current markers cannot resolve heterogeneity within the HSC compartment, highlighting the importance of continuing efforts on identifying new cell surface markers that enrich Li-bi HSC subtypes. In paper I, we demonstrate that CD49b cell surface marker subfractionates the most primitive HSC compartment into two; CD49b– HSCs with myeloid bias, high self-renewal potential and the most quiescent state, and CD49b+ HSCs with lymphoid bias, lowered selfrenewal potential and more proliferative state. Furthermore, we show that both subsets have similar transcriptome profiles but distinct epigenetic landscapes highlighting that the lineage-bias is regulated via epigenetic mechanisms. In paper III, we show that using the additional cell surface marker CD229, the remaining heterogeneity within the CD49b+ HSCs can be resolved into two functional subsets as CD49b+CD229– and CD49b+CD229+. The CD49b+CD229– fraction shows long-term and stable reconstitution and the CD49b+CD229+ fraction enriches for multipotent progenitor cells having short term activity.
Hematopoietic aging is associated with myeloid skewing, delayed, and reduced immune response and higher incidences of myeloid malignancies. The composition of HSC compartment changes with a shift toward an increased proportion of myeloid biased HSCs in elderly both in human and mice. However, the molecular mechanisms behind this phenomenon are not completely understood. In paper II, we show that the CD49b– HSC maintains its myeloid bias in the peripheral blood of the young, young adult and old age groups whereas the CD49b+ HSC shifts from lymphoid bias in young and young adult to lineage-balance (no bias) in aged mice. In addition, we demonstrate that both subsets are equally active in young and have similar chromatin landscapes with different levels of accessible regions in old mice.
The B cell lineage priming occurs downstream of HSCs starting at the branching point of multipotent progenitors in the hematopoietic hierarchy. The B cell development is highly regulated by transcriptional factors. In paper IV, we show that combined loss of transcription factors FOXO1 and FOXO3 prevents the B cell development by blocking it at the BLP stage. Moreover, we demonstrate that FOXO3 plays a crucial role in regulating the B cell lineage priming higher up in the hematopoietic hierarchy already as early as the LMPP level.
Collectively, this thesis identifies cell surface markers that resolves the functional heterogeneity of the HSCs, gives insights into how the lineage bias is regulated during aging, and unravels the effect of transcription factors in B cell development.
List of papers:
I. Ece Somuncular, Julia Hauenstein, Prajakta Khalkar, Anne-Sofie Johansson, Özge Dumral, Nicolai S. Frengen, Charlotte Gustafsson, Giuseppe Mocci, Tsu-Yi Su, Hugo Brouwer, Christine L. Trautmann, Michael Vanlandewijck, Stuart H. Orkin, Robert Månsson, and Sidinh Luc. CD49b identifies functionally and epigenetically distinct subsets of lineage-biased hematopoietic stem cells. Stem Cell Reports. 2022, Vol. 17, 1546-1560.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Ece Somuncular, Julia Hauenstein, Tsu-Yi Su, Özge Dumral, Charlotte Gustafsson, Efthymios Tzortzis, Aurora Forlani, Anne-Sofie Johansson, Robert Månsson and Sidinh Luc. Aging is associated with functional and molecular changes in distinct hematopoietic stem cell subsets. [Manuscript]
III. Ece Somuncular, Tsu-Yi Su, Özge Dumral, Anne-Sofie Johansson and Sidinh Luc. The combination of CD49b and CD229 reveals a subset of multipotent cells with short-term activity within the hematopoietic stem cell compartment. [Manuscript]
IV. Lucia Peña-Pérez, Shabnam Kharazi, Nicolai Frengen, Aleksandra Krstic, Thibault Bouderlique, Julia Hauenstein, Minghui He, Ece Somuncular, Xiaoze Li Wang, Carin Dahlberg, Charlotte Gustafsson, Ann-Sofie Johansson, Julian Walfridsson, Nadir Kadri, Petter Woll, Marcin Kierczak, Hong Qian, Lisa Westerberg, Sidinh Luc and Robert Månsson. FOXO Dictates Initiation of B Cell Development and Myeloid Restriction in Common Lymphoid Progenitors. Frontiers in Immunology. 2022, Vol 13:880668.
Fulltext (DOI)
Pubmed
View record in Web of Science®
I. Ece Somuncular, Julia Hauenstein, Prajakta Khalkar, Anne-Sofie Johansson, Özge Dumral, Nicolai S. Frengen, Charlotte Gustafsson, Giuseppe Mocci, Tsu-Yi Su, Hugo Brouwer, Christine L. Trautmann, Michael Vanlandewijck, Stuart H. Orkin, Robert Månsson, and Sidinh Luc. CD49b identifies functionally and epigenetically distinct subsets of lineage-biased hematopoietic stem cells. Stem Cell Reports. 2022, Vol. 17, 1546-1560.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Ece Somuncular, Julia Hauenstein, Tsu-Yi Su, Özge Dumral, Charlotte Gustafsson, Efthymios Tzortzis, Aurora Forlani, Anne-Sofie Johansson, Robert Månsson and Sidinh Luc. Aging is associated with functional and molecular changes in distinct hematopoietic stem cell subsets. [Manuscript]
III. Ece Somuncular, Tsu-Yi Su, Özge Dumral, Anne-Sofie Johansson and Sidinh Luc. The combination of CD49b and CD229 reveals a subset of multipotent cells with short-term activity within the hematopoietic stem cell compartment. [Manuscript]
IV. Lucia Peña-Pérez, Shabnam Kharazi, Nicolai Frengen, Aleksandra Krstic, Thibault Bouderlique, Julia Hauenstein, Minghui He, Ece Somuncular, Xiaoze Li Wang, Carin Dahlberg, Charlotte Gustafsson, Ann-Sofie Johansson, Julian Walfridsson, Nadir Kadri, Petter Woll, Marcin Kierczak, Hong Qian, Lisa Westerberg, Sidinh Luc and Robert Månsson. FOXO Dictates Initiation of B Cell Development and Myeloid Restriction in Common Lymphoid Progenitors. Frontiers in Immunology. 2022, Vol 13:880668.
Fulltext (DOI)
Pubmed
View record in Web of Science®
Institution: Karolinska Institutet
Supervisor: Luc, Sidinh
Co-supervisor: Jacobsen, Sten Eirik W.; Woll, Petter S.
Issue date: 2022-11-25
Rights:
Publication year: 2022
ISBN: 978-91-8016-827-4
Statistics
Total Visits
Views | |
---|---|
Understanding ... | 395 |
Total Visits Per Month
September 2023 | October 2023 | November 2023 | December 2023 | January 2024 | February 2024 | March 2024 | |
---|---|---|---|---|---|---|---|
Understanding ... | 20 | 16 | 13 | 10 | 16 | 6 | 12 |
File Visits
Views | |
---|---|
Thesis_Ece_Somuncular.pdf | 187 |
Top country views
Views | |
---|---|
Sweden | 92 |
United States | 56 |
Ireland | 35 |
Germany | 23 |
China | 20 |
United Kingdom | 18 |
South Korea | 10 |
France | 7 |
Austria | 6 |
Japan | 6 |
Top cities views
Views | |
---|---|
Dublin | 35 |
Stockholm | 12 |
Ashburn | 9 |
Shenzhen | 6 |
Skövde | 5 |
Gothenburg | 4 |
Helsinki | 4 |
Joerlanda | 4 |
Solna | 4 |
Tianjin | 4 |