Human Bone Marrow Microenvironment in Health and Disease

Forskningsoutput: AvhandlingDoktorsavhandling (sammanläggning)

117 Nedladdningar (Pure)

Sammanfattning

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.
Originalspråkengelska
KvalifikationDoktor
Tilldelande institution
  • Institutionen för laboratoriemedicin
Handledare
  • Scheding, Stefan, handledare
  • Karlsson, Göran, Biträdande handledare
  • Hultquist, Anne, Biträdande handledare
  • Zetterberg, Eva, Biträdande handledare
Tilldelningsdatum2023 nov. 24
UtgivningsortLund
Förlag
ISBN (tryckt)978-91-8021-483-4
StatusPublished - 2023

Bibliografisk information

Defence details
Date: 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

Ämnesklassifikation (UKÄ)

  • Klinisk laboratoriemedicin

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