Research output per year
Research output per year
Abstract
Hematopoietic stem cells (HSCs) are safeguarded from various threats such as stress, injury, or radiation
within specialized microenvironments or niches within the bone marrow. In this thesis, we investigated
various facets of the bone marrow (BM) microenvironment and its critical role in hematopoiesis and
related disorders.
Initially, we elucidated the role of the Early Growth Response 1 (EGR1) gene in bone marrow
mesenchymal stem cells (MSCs). EGR1 expression was found to be significantly elevated in specific BM
MSC populations, particularly lin-CD45-CD271+ CD140a- BM MSCs, exerting a pivotal role in
hematopoietic stroma support. This support function was mediated through both cell-cell interactions and
soluble factors, where EGR1-overexpressing BM MSCs exhibited enhanced secretion of chemokine
ligand 28 and increased expression of vascular cell adhesion molecule 1, crucial for hematopoiesis
support. EGR1 also played a dual role in BM MSC proliferation regulation. Understanding these
mechanisms can improve hematopoietic stem cell transplantation and regenerative medicine.
Further, employing single-cell RNA sequencing, we provided a comprehensive analysis of the cellular
composition of human BM stroma, revealing diverse cell populations and stromal progenitors with varying
differentiation capacities. We identified and characterized multipotent stromal stem cells (MSSCs), highly
adipocytic gene-expressing progenitors (HAGEPs), pre-osteoblasts, and other stromal clusters, offering
valuable insights into BM stromal heterogeneity and its structural organization. We employed in silico
cluster interaction analysis and found that the different stromal populations are predicted to interact and
support HSCs differentially in different niches.
Next, we introduced a meticulous methodology utilizing multicolor immunofluorescence staining and 3D
analysis to investigate human BM architecture. We illustrated the potential of sequential staining,
emphasizing specific structural changes associated with myeloproliferative neoplasms (MPNs) and their
correlation with CD271 expression.
Finally, we investigated human BM architecture and cytokine expression patterns in patients with Acute
Lymphoblastic Leukemia (ALL) and Primary Myelofib(PMF) with elaborate immunofluorescence and
mRNA-based staining methods and compared them to healthy controls. We revealed significant
alterations, including differential numbers of megakaryocytes, differences in cellularity, altered
mesenchymal stem cell density, and distinct cytokine expressions offering critical insights into disease
pathogenesis and progression.
Collectively, these findings illuminate various facets of the BM microenvironment, offering valuable
insights into its critical role in hematopoiesis, stromal heterogeneity, and disease pathology, paving the
way for potential therapeutic advancements in regenerative medicine and hematological disorders.
within specialized microenvironments or niches within the bone marrow. In this thesis, we investigated
various facets of the bone marrow (BM) microenvironment and its critical role in hematopoiesis and
related disorders.
Initially, we elucidated the role of the Early Growth Response 1 (EGR1) gene in bone marrow
mesenchymal stem cells (MSCs). EGR1 expression was found to be significantly elevated in specific BM
MSC populations, particularly lin-CD45-CD271+ CD140a- BM MSCs, exerting a pivotal role in
hematopoietic stroma support. This support function was mediated through both cell-cell interactions and
soluble factors, where EGR1-overexpressing BM MSCs exhibited enhanced secretion of chemokine
ligand 28 and increased expression of vascular cell adhesion molecule 1, crucial for hematopoiesis
support. EGR1 also played a dual role in BM MSC proliferation regulation. Understanding these
mechanisms can improve hematopoietic stem cell transplantation and regenerative medicine.
Further, employing single-cell RNA sequencing, we provided a comprehensive analysis of the cellular
composition of human BM stroma, revealing diverse cell populations and stromal progenitors with varying
differentiation capacities. We identified and characterized multipotent stromal stem cells (MSSCs), highly
adipocytic gene-expressing progenitors (HAGEPs), pre-osteoblasts, and other stromal clusters, offering
valuable insights into BM stromal heterogeneity and its structural organization. We employed in silico
cluster interaction analysis and found that the different stromal populations are predicted to interact and
support HSCs differentially in different niches.
Next, we introduced a meticulous methodology utilizing multicolor immunofluorescence staining and 3D
analysis to investigate human BM architecture. We illustrated the potential of sequential staining,
emphasizing specific structural changes associated with myeloproliferative neoplasms (MPNs) and their
correlation with CD271 expression.
Finally, we investigated human BM architecture and cytokine expression patterns in patients with Acute
Lymphoblastic Leukemia (ALL) and Primary Myelofib(PMF) with elaborate immunofluorescence and
mRNA-based staining methods and compared them to healthy controls. We revealed significant
alterations, including differential numbers of megakaryocytes, differences in cellularity, altered
mesenchymal stem cell density, and distinct cytokine expressions offering critical insights into disease
pathogenesis and progression.
Collectively, these findings illuminate various facets of the BM microenvironment, offering valuable
insights into its critical role in hematopoiesis, stromal heterogeneity, and disease pathology, paving the
way for potential therapeutic advancements in regenerative medicine and hematological disorders.
| Original language | English |
|---|---|
| Qualification | Doctor |
| Awarding Institution |
|
| Supervisors/Advisors |
|
| Award date | 2023 Nov 24 |
| Place of Publication | Lund |
| Publisher | |
| ISBN (Print) | 978-91-8021-483-4 |
| Publication status | Published - 2023 |
Bibliographical note
Defence detailsDate: 2023-11-24
Time: 09:00
Place: Segerfalksalen, BMC A10, Sölvegatan 17 i Lund
External reviewer(s)
Name: Reinisch, Andreas
Title: MD, Ph.D., Ass.Prof.
Affiliation: Division of Hematology & Department of Blood Group Serology and Transfusion Medicine, Medical University Graz, Graz, Austria
Subject classification (UKÄ)
- Clinical Laboratory Medicine
Free keywords
- Hematopoietic microenvironment
- Imaging
- Myeloproliferative neoplasms
- Spatial relationships
- acute lymphoblastic leukaemia (ALL)
- Fibrosis
- Mesenchymal stromal cell
- Single cell RNA sequencing
Access to Document
Fingerprint
Dive into the research topics of 'Human Bone Marrow Microenvironment in Health and Disease'. Together they form a unique fingerprint.Research output
- 3 Article
-
Identification of phenotypically, functionally, and anatomically distinct stromal niche populations in human bone marrow based on single-cell RNA sequencing
Li, H., Bräunig, S., Dhapolar, P., Karlsson, G., Lang, S. & Scheding, S., 2023, In: eLife. 12, e81656.Research output: Contribution to journal › Article › peer-review
Open Access -
Three-dimensional spatial mapping of the human hematopoietic microenvironment in healthy and diseased bone marrow
Bräunig, S., Karmhag, I., Li, H., Enoksson, J., Hultquist, A. & Scheding, S., 2023, In: Cytometry Part A. 103, 10, p. 763-776Research output: Contribution to journal › Article › peer-review
Open Access -
Early growth response 1 regulates hematopoietic support and proliferation in human primary bone marrow stromal cells
Li, H., Lim, H. C., Zacharaki, D., Xian, X., Kenswil, K. J., Bräunig, S., Raaijmakers, M. H., Woods, N-B., Hansson, J. & Scheding, S., 2020 May, In: Haematologica. 105, 5, p. 1206-1215 10 p.Research output: Contribution to journal › Article › peer-review
Open Access